Cancers

25 pages, 1386 KiB

Open AccessEditor’s ChoiceReview

Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes

by Yue Ma, Natisha R. Field, Tao Xie, Sarina Briscas, Emily G. Kokinogoulis, Tali S. Skipper, Amani Alghalayini, Farhana A. Sarker, Nham Tran, Nikola A. Bowden, Kristie-Ann Dickson and Deborah J. Marsh

Cancers 2024, 16(17), 3068; https://doi.org/10.3390/cancers16173068 - 3 Sep 2024

Cited by 1 | Viewed by 2499

Abstract

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations [...] Read more.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade. Full article

(This article belongs to the Special Issue Rare Gynecological Cancers)

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26 pages, 1512 KiB

Open AccessEditor’s ChoiceReview

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment

by Nikolaos Vitorakis, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos and Athanasios G. Papavassiliou

Cancers 2024, 16(16), 2876; https://doi.org/10.3390/cancers16162876 - 19 Aug 2024

Cited by 2 | Viewed by 2015

Abstract

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug [...] Read more.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing. Full article

(This article belongs to the Special Issue Clinical Applications of Molecular Subtyping of Pancreatic Cancer)

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29 pages, 5058 KiB

Open AccessEditor’s ChoiceReview

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”

by Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro and Filippo de Marinis

Cancers 2024, 16(16), 2877; https://doi.org/10.3390/cancers16162877 - 19 Aug 2024

Cited by 1 | Viewed by 1830

Abstract

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading [...] Read more.

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. Full article

(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))

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20 pages, 642 KiB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Detection, Management, and Prognosis of Bone Metastasis: A Systematic Review

by Giuseppe Francesco Papalia, Paolo Brigato, Luisana Sisca, Girolamo Maltese, Eliodoro Faiella, Domiziana Santucci, Francesco Pantano, Bruno Vincenzi, Giuseppe Tonini, Rocco Papalia and Vincenzo Denaro

Cancers 2024, 16(15), 2700; https://doi.org/10.3390/cancers16152700 - 29 Jul 2024

Cited by 3 | Viewed by 2954

Abstract

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, [...] Read more.

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, radiological, and pathological aspects of bone metastases. Methods: We included studies that evaluated the use of AI applications in patients affected by bone metastases. Two reviewers performed a digital search on 31 December 2023 on PubMed, Scopus, and Cochrane library and extracted authors, AI method, interest area, main modalities used, and main objectives from the included studies. Results: We included 59 studies that analyzed the contribution of computational intelligence in diagnosing or forecasting outcomes in patients with bone metastasis. Six studies were specific for spine metastasis. The study involved nuclear medicine (44.1%), clinical research (28.8%), radiology (20.4%), or molecular biology (6.8%). When a primary tumor was reported, prostate cancer was the most common, followed by lung, breast, and kidney. Conclusions: Appropriately trained AI models may be very useful in merging information to achieve an overall improved diagnostic accuracy and treatment for metastasis in the bone. Nevertheless, there are still concerns with the use of AI systems in medical settings. Ethical considerations and legal issues must be addressed to facilitate the safe and regulated adoption of AI technologies. The limitations of the study comprise a stronger emphasis on early detection rather than tumor management and prognosis as well as a high heterogeneity for type of tumor, AI technology and radiological techniques, pathology, or laboratory samples involved. Full article

(This article belongs to the Special Issue Artificial Intelligence and MRI Characterization of Tumors: 2nd Edition)

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17 pages, 1234 KiB

Open AccessEditor’s ChoiceArticle

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

by Woong Ki Park, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Se Kyung Lee, Jai Min Ryu and Byung Joo Chae

Cancers 2024, 16(14), 2566; https://doi.org/10.3390/cancers16142566 - 17 Jul 2024

Cited by 2 | Viewed by 1269

Abstract

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data [...] Read more.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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22 pages, 3817 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Immunotherapy Response Prediction in Metastatic Lung Adenocarcinoma: Leveraging Shallow and Deep Learning with CT-Based Radiomics across Single and Multiple Tumor Sites

by Cécile Masson-Grehaigne, Mathilde Lafon, Jean Palussière, Laura Leroy, Benjamin Bonhomme, Eva Jambon, Antoine Italiano, Sophie Cousin and Amandine Crombé

Cancers 2024, 16(13), 2491; https://doi.org/10.3390/cancers16132491 - 8 Jul 2024

Cited by 2 | Viewed by 1449

Abstract

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint [...] Read more.

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint inhibitors (CPIs). To do so, all adults with newly diagnosed MLUAD, pre-treatment contrast-enhanced CT scan, and performance status ≤ 2 who were treated at our cancer center with first-line CPI between November 2016 and November 2022 were included. RFs were extracted from all measurable lesions with a volume ≥ 1 cm³ on the CT scan. To capture intra- and inter-tumor heterogeneity, RFs from the largest tumor of each patient, as well as lowest, highest, and average RF values over all lesions per patient were collected. Intra-patient inter-tumor heterogeneity metrics were calculated to measure the similarity between each patient lesions. After filtering predictors with univariable Cox p < 0.100 and analyzing their correlations, five survival machine-learning algorithms (stepwise Cox regression [SCR], LASSO Cox regression, random survival forests, gradient boosted machine [GBM], and deep learning [Deepsurv]) were trained in 100-times repeated 5-fold cross-validation (rCV) to predict PFS on three inputs: (i) clinicopathological variables, (ii) all radiomics-based and clinicopathological (full input), and (iii) uncorrelated radiomics-based and clinicopathological variables (uncorrelated input). The Models’ performances were evaluated using the concordance index (c-index). Overall, 140 patients were included (median age: 62.5 years, 36.4% women). In rCV, the highest c-index was reached with Deepsurv (c-index = 0.631, 95%CI = 0.625–0.647), followed by GBM (c-index = 0.603, 95%CI = 0.557–0.646), significantly outperforming standard SCR whatever its input (c-index range: 0.560–0.570, all p < 0.0001). Thus, single- and multi-site pre-treatment radiomics data provide valuable prognostic information for predicting PFS in MLUAD patients undergoing first-line CPI treatment when analyzed with advanced machine-learning survival algorithms. Full article

(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)

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17 pages, 4025 KiB

Open AccessEditor’s ChoiceArticle

CRISPR-Cas9 Knockout Screens Identify DNA Damage Response Pathways and BTK as Essential for Cisplatin Response in Diffuse Large B-Cell Lymphoma

by Issa Ismail Issa, Hanne Due, Rasmus Froberg Brøndum, Vidthdyan Veeravakaran, Hulda Haraldsdóttir, Cathrine Sylvester, Asta Brogaard, Soniya Dhanjal, Bernhard Schmierer and Karen Dybkær

Cancers 2024, 16(13), 2437; https://doi.org/10.3390/cancers16132437 - 2 Jul 2024

Cited by 2 | Viewed by 2038

Abstract

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify [...] Read more.

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify genes affecting the cisplatin response in DLBCL, cisplatin-based whole-genome CRISPR-Cas9 knockout screens were performed in this study. We discovered DNA damage response (DDR) pathways as enriched among identified sensitizing CRISPR-mediated gene knockouts. In line, the knockout of the nucleotide excision repair genes XPA and ERCC6 sensitized DLBCL cells to platinum drugs irrespective of proliferation rate, thus documenting DDR as essential for cisplatin sensitivity in DLBCL. Functional analysis revealed that the loss of XPA and ERCC6 increased DNA damage levels and altered cell cycle distribution. Interestingly, we also identified BTK, which is involved in B-cell receptor signaling, to affect cisplatin response. The knockout of BTK increased cisplatin sensitivity in DLBCL cells, and combinatory drug screens revealed a synergistic effect of the BTK inhibitor, ibrutinib, with platinum drugs at low concentrations. Applying local and external DLBCL cohorts, we addressed the clinical relevance of the genes identified in the CRISPR screens. BTK was among the most frequently mutated genes with a frequency of 3–5%, and XPA and ERCC6 were also mutated, albeit at lower frequencies. Furthermore, 27–54% of diagnostic DLBCL samples had mutations in pathways that can sensitize cells to cisplatin. In conclusion, this study shows that XPA and ERCC6, in addition to BTK, are essential for the response to platinum-based drugs in DLBCL. Full article

(This article belongs to the Section Molecular Cancer Biology)

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25 pages, 3138 KiB

Open AccessEditor’s ChoiceReview

Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development

by Whi-An Kwon, Seo-Yeon Lee, Tae Yoong Jeong, Hyeon Hoe Kim and Min-Kyung Lee

Cancers 2024, 16(13), 2420; https://doi.org/10.3390/cancers16132420 - 30 Jun 2024

Cited by 4 | Viewed by 2509

Abstract

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to [...] Read more.

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to cells expressing specific surface proteins, which are abundant in UC owing to their high antigen expression. UC is an ideal candidate for ADC therapy, as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has been made in understanding the biology and mechanisms of tumor progression in UC. However, despite the introduction of immune checkpoint inhibitors, advanced UC is characterized by rapid progression and poor survival rates. Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease. Full article

(This article belongs to the Special Issue Advances in Drug Delivery for Cancer Therapy)

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18 pages, 5955 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

by Ruhi Gulati, Yasmeen Fleifil, Katherine Jennings, Alex Bondoc, Greg Tiao, James Geller, Lubov Timchenko and Nikolai Timchenko

Cancers 2024, 16(13), 2300; https://doi.org/10.3390/cancers16132300 - 22 Jun 2024

Cited by 4 | Viewed by 1228

Abstract

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer [...] Read more.

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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23 pages, 2134 KiB

Open AccessEditor’s ChoiceReview

The Anticancer Application of Delivery Systems for Honokiol and Magnolol

by Katarzyna Dominiak, Aleksandra Gostyńska, Michał Szulc and Maciej Stawny

Cancers 2024, 16(12), 2257; https://doi.org/10.3390/cancers16122257 - 18 Jun 2024

Cited by 1 | Viewed by 1285

Abstract

Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular [...] Read more.

Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular mechanisms underlying the observed anticancer effects, emphasizing both in vitro and in vivo studies. The effects of HON application, primarily in the common types of cancers, are presented. Because the therapeutic potential of HON may be limited by its physicochemical properties, appropriate delivery systems are sought to overcome this problem. This review discusses the effect of different nanotechnology-based delivery systems on the efficiency of HON. The data presented show that HON exhibits anticancer effects and can be successfully administered to the site of action. Honokiol exerts its anticancer activity through several mechanisms. Moreover, some authors used the combinations of classical anticancer drugs with HON. Such an approach is very interesting and worth further investigation. Understanding HON’s multiple molecular mechanisms would provide valuable insights into how HON might be developed as an effective therapeutic. Therefore, further research is needed to explore its specific applications and optimize its efficacy in diverse cancer types. Full article

(This article belongs to the Section Cancer Drug Development)

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18 pages, 1834 KiB

Open AccessEditor’s ChoiceReview

Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer

by Iseult M. Browne and Alicia F. C. Okines

Cancers 2024, 16(12), 2259; https://doi.org/10.3390/cancers16122259 - 18 Jun 2024

Cited by 3 | Viewed by 3879

Abstract

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the [...] Read more.

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer’s mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

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16 pages, 2077 KiB

Open AccessEditor’s ChoiceReview

Dendritic Cells in Shaping Anti-Tumor T Cell Response

by Luciano Mazzoccoli and Bei Liu

Cancers 2024, 16(12), 2211; https://doi.org/10.3390/cancers16122211 - 13 Jun 2024

Cited by 6 | Viewed by 3800

Abstract

Among professional antigen-presenting cells, dendritic cells (DCs) orchestrate innate and adaptive immunity and play a pivotal role in anti-tumor immunity. DCs are a heterogeneous population with varying functions in the tumor microenvironment (TME). Tumor-associated DCs differentiate developmentally and functionally into three main subsets: [...] Read more.

Among professional antigen-presenting cells, dendritic cells (DCs) orchestrate innate and adaptive immunity and play a pivotal role in anti-tumor immunity. DCs are a heterogeneous population with varying functions in the tumor microenvironment (TME). Tumor-associated DCs differentiate developmentally and functionally into three main subsets: conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (MoDCs). There are two major subsets of cDCs in TME, cDC1 and cDC2. cDC1 is critical for cross-presenting tumor antigens to activate cytotoxic CD8⁺ T cells and is also required for priming earlier CD4⁺ T cells in certain solid tumors. cDC2 is vital for priming anti-tumor CD4⁺ T cells in multiple tumor models. pDC is a unique subset of DCs and produces type I IFN through TLR7 and TLR9. Studies have shown that pDCs are related to immunosuppression in the TME through the secretion of immunosuppressive cytokines and by promoting regulatory T cells. MoDCs differentiate separately from monocytes in response to inflammatory cues and infection. Also, MoDCs can cross-prime CD8⁺ T cells. In this review, we summarize the subsets and functions of DCs. We also discuss the role of different DC subsets in shaping T cell immunity in TME and targeting DCs for potential immunotherapeutic benefits against cancer. Full article

(This article belongs to the Special Issue Evidence from the Real World Provides New Insights into the Evolving Landscape of Cancer Immunotherapy)

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17 pages, 320 KiB

Open AccessEditor’s ChoiceReview

Topical and Intralesional Immunotherapy for the Management of Basal Cell Carcinoma

by Aurora Fernández-Galván, Pedro Rodríguez-Jiménez, Beatriz González-Sixto, María Teresa Abalde-Pintos and Beatriz Butrón-Bris

Cancers 2024, 16(11), 2135; https://doi.org/10.3390/cancers16112135 - 4 Jun 2024

Cited by 2 | Viewed by 1645

Abstract

Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal [...] Read more.

Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal treatment objectives for BCC involve achieving the total excision of the tumor while maximizing the preservation of function and cosmesis. Surgery is considered the treatment of choice for BCC for two main reasons: it allows for the highest cure rates and facilitates histological control of resection margins. However, in the subgroup of patients with low-risk recurrence or medical contraindications for surgery, new non-surgical treatment alternatives can provide an excellent oncological and cosmetic outcome. An evident and justified instance of these local therapies occurred during the COVID-19 pandemic, a period when surgical interventions carried out in hospital settings were not a viable option. Full article

(This article belongs to the Special Issue Topical and Intralesional Immunotherapy for Skin Cancer)

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17 pages, 625 KiB

Open AccessEditor’s ChoiceReview

Targeting Neoantigens in Pancreatic Ductal Adenocarcinoma

by Gurkaranjot Singh, Drew Kutcher, Rajeshwar Lally and Vikrant Rai

Cancers 2024, 16(11), 2101; https://doi.org/10.3390/cancers16112101 - 31 May 2024

Cited by 5 | Viewed by 1680

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death by 2030. The diagnosis at a late stage is the underlying cause for higher mortality and poor prognosis after surgery. Treatment resistance to chemotherapy and immunotherapy results in recurrence after surgery and poor prognosis. Neoantigen burden and CD8+ T-cell infiltration are associated with clinical outcomes in PDAC and paucity of neoantigen-reactive tumor-infiltrating lymphocytes may be the underlying cause for treatment resistance for immunotherapy. This suggests a need to identify additional neoantigens and therapies targeting these neoantigens to improve clinical outcomes in PDAC. In this review, we focus on describing the pathophysiology, current treatment strategies, and treatment resistance in PDAC followed by the need to target neoantigens in PDAC. Full article

(This article belongs to the Special Issue Current Clinical Studies of Pancreatic Ductal Adenocarcinoma)

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17 pages, 950 KiB

Open AccessEditor’s ChoiceArticle

Acceptance of Self-Sampling by Women Not Regularly Participating in Cervical Cancer Screening in Areas with Low Medical Density: A Qualitative Study within the French CapU4 Trial

by Johane Le Goff, Anne-Sophie Le Duc-Banaszuk, Caroline Lefeuvre, Adeline Pivert, Alexandra Ducancelle, Hélène De Pauw, Marc Arbyn, Aubeline Vinay and Franck Rexand-Galais

Cancers 2024, 16(11), 2066; https://doi.org/10.3390/cancers16112066 - 30 May 2024

Cited by 1 | Viewed by 1432

Abstract

Cervical cancer (CC) was diagnosed in 3159 women in France in 2023, and 1117 died from it. Organized screening for cervical cancer is potentially very effective for participating women. However, reaching under-screened populations remains a major challenge. The present qualitative study explored women’s [...] Read more.

Cervical cancer (CC) was diagnosed in 3159 women in France in 2023, and 1117 died from it. Organized screening for cervical cancer is potentially very effective for participating women. However, reaching under-screened populations remains a major challenge. The present qualitative study explored women’s opinions on what discourages or encourages them to participate in CC screening and assessed the acceptability of two experimental strategies (urinary or vaginal self-sampling kits) to increase the screening coverage in three rural French administrative departments with low medical density and/or low screening participation rates. Forty-eight semi-structured interviews and four focus groups were conducted by a team of psychologists. Results showed that the participants accepted at-home self-sampling to reach non-participating women in medically underserved areas. However, they suggested that the type of kit sent should be adapted to the patient’s profile (embarrassment from earlier exams, cultural aspects, fear of invasiveness, etc.), and that kits should be simple to use (in understandable language taking sociocultural aspects into account). Women wished to be assured that testing on self-samples is accurate and needed information about further actions in case of a positive result. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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12 pages, 911 KiB

Open AccessEditor’s ChoiceArticle

Diagnostic Accuracy of DNA-Methylation in Detection of Cervical Dysplasia: Findings from a Population-Based Screening Program

by Narcisa Muresu, Mariangela V. Puci, Giovanni Sotgiu, Illari Sechi, Manuela Usai, Andrea Cossu, Marianna Martinelli, Clementina Elvezia Cocuzza and Andrea Piana

Cancers 2024, 16(11), 1986; https://doi.org/10.3390/cancers16111986 - 23 May 2024

Cited by 2 | Viewed by 1801

Abstract

Background: Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive [...] Read more.

Background: Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive women and during treatment. The present study focuses on evaluating the clinical performance of the FAM19A4/miR124-2 methylation test in a population-based cervical screening program. Methods: Previously collected cervical samples, after bisulfite-converted DNA, were analyzed by PreCursor-M+ kit (distributed by Fujirebio Europe), for DNA methylation. The sensitivity, specificity, and negative/positive predictive values of DNA methylation were compared to histology, colposcopy, the HPV-DNA test, and cytology results. Results: Among the 61-sample set, the specificity of methylation vs. positive histology (≥CIN2) and colposcopy (≥G2) were 87% and 90%, whereas the sensitivity was 50% and 33.3%, respectively. The combination of methylation analysis with standard methods increases diagnostic accuracy. Conclusions: Overall, we found a good specificity of DNA methylation in comparison to currently used techniques. Further larger studies could support the use of FAM19A4/miR124-2 as reliable biomarkers in the prevention of cervical cancer as triage in the screening protocol. Full article

(This article belongs to the Special Issue Cervical Cancer: Risk Factors, Screening, and Prevention Strategies)

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15 pages, 1635 KiB

Open AccessEditor’s ChoiceSystematic Review

Sex Differences in Anxiety and Depression Conditions among Cancer Patients: A Systematic Review and Meta-Analysis

by Elsa Vitale, Kurvatteppa Halemani, Asha Shetty, Yun-Chen Chang, Wen-Yu Hu, Raffaella Massafra and Annamaria Moretti

Cancers 2024, 16(11), 1969; https://doi.org/10.3390/cancers16111969 - 22 May 2024

Cited by 2 | Viewed by 1757

Abstract

(1) Background: Evidence suggested inconsistent results in anxiety and depression scores among female and male cancer patients. The present systematic review and meta-analysis aimed to assess how anxiety and depression conditions among cancer patients vary according to sex. (2) Methods: This systematic review [...] Read more.

(1) Background: Evidence suggested inconsistent results in anxiety and depression scores among female and male cancer patients. The present systematic review and meta-analysis aimed to assess how anxiety and depression conditions among cancer patients vary according to sex. (2) Methods: This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). The protocol was registered in PROSPERO with id no. CRD42024512553. The search strategy involved combining keywords using Boolean operators, including “Anxiety”, “Cancer”, and “Depression”, across several databases: Embase, PubMed, Scopus, and Web of Science. The outcomes were evaluated using the Hospital Anxiety and Depression Scale (HADS). (3) Results: Data were collected from five studies, enrolling a total of 6317 cancer patients, of whom 2961 were females and 3356 males. For each study, HADS-A and HADS-D scores were considered, also differentiating HADS scores according to cancer typology, and then three different meta-analyses were performed. Generally, females reported significantly higher levels of depression scores than males and, conversely, males reported significantly greater levels of anxiety than females. (4) Conclusions: Previous studies suggested higher rates of depression and anxiety conditions in females than in males, but the present data highlighted controversial findings, since males reported significantly higher levels of anxiety than females. In this scenario, the theoretical approach justified females being more open than males to expressing anxiety or depression conditions. It would be necessary for healthcare professionals to improve effective measures purposed at assessing and mitigating depressive symptoms in cases of advanced cancer, thereby improving their mental health, given the high rates of depression in advanced cancer patients, due to the difficulty level of performing their daily living activities, which deteriorate further over time. Full article

(This article belongs to the Special Issue Updates on Depression among Cancer Patients)

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17 pages, 775 KiB

Open AccessEditor’s ChoiceReview

Intralesional and Infusional Updates for Metastatic Melanoma

by Michelle M. Dugan, Adrienne B. Shannon, Danielle K. DePalo, Matthew C. Perez and Jonathan S. Zager

Cancers 2024, 16(11), 1957; https://doi.org/10.3390/cancers16111957 - 22 May 2024

Cited by 3 | Viewed by 1655

Abstract

Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of [...] Read more.

Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma. Full article

(This article belongs to the Special Issue Contemporary Surgical Management of Melanoma)

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20 pages, 1932 KiB

Open AccessEditor’s ChoiceReview

The Transformative Role of 3D Culture Models in Triple-Negative Breast Cancer Research

by Xavier S. Bittman-Soto, Evelyn S. Thomas, Madeline E. Ganshert, Laura L. Mendez-Santacruz and J. Chuck Harrell

Cancers 2024, 16(10), 1859; https://doi.org/10.3390/cancers16101859 - 13 May 2024

Cited by 3 | Viewed by 3559

Abstract

Advancements in cell culturing techniques have allowed the development of three-dimensional (3D) cell culture models sourced directly from patients’ tissues and tumors, faithfully replicating the native tissue environment. These models provide a more clinically relevant platform for studying disease progression and treatment responses [...] Read more.

Advancements in cell culturing techniques have allowed the development of three-dimensional (3D) cell culture models sourced directly from patients’ tissues and tumors, faithfully replicating the native tissue environment. These models provide a more clinically relevant platform for studying disease progression and treatment responses compared to traditional two-dimensional (2D) models. Patient-derived organoids (PDOs) and patient-derived xenograft organoids (PDXOs) emerge as innovative 3D cancer models capable of accurately mimicking the tumor’s unique features, enhancing our understanding of tumor complexities, and predicting clinical outcomes. Triple-negative breast cancer (TNBC) poses significant clinical challenges due to its aggressive nature, propensity for early metastasis, and limited treatment options. TNBC PDOs and PDXOs have significantly contributed to the comprehension of TNBC, providing novel insights into its underlying mechanism and identifying potential therapeutic targets. This review explores the transformative role of various 3D cancer models in elucidating TNBC pathogenesis and guiding novel therapeutic strategies. It also provides an overview of diverse 3D cell culture models, derived from cell lines and tumors, highlighting their advantages and culturing challenges. Finally, it delves into live-cell imaging techniques, endpoint assays, and alternative cell culture media and methodologies, such as scaffold-free and scaffold-based systems, essential for advancing 3D cancer model research and development. Full article

(This article belongs to the Special Issue Advances in Triple-Negative Breast Cancer)

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12 pages, 1826 KiB

Open AccessEditor’s ChoiceSystematic Review

Prognostic Significance of the Royal Marsden Hospital (RMH) Score in Patients with Cancer: A Systematic Review and Meta-Analysis

by Taha Koray Sahin, Alessandro Rizzo, Sercan Aksoy and Deniz Can Guven

Cancers 2024, 16(10), 1835; https://doi.org/10.3390/cancers16101835 - 11 May 2024

Cited by 83 | Viewed by 2548

Abstract

Background: Cancer remains a leading cause of death globally, necessitating the identification of prognostic biomarkers to guide treatment decisions. The Royal Marsden Hospital (RMH) score, based on readily available blood tests and clinical features, has emerged as a prognostic tool, although its performance [...] Read more.

Background: Cancer remains a leading cause of death globally, necessitating the identification of prognostic biomarkers to guide treatment decisions. The Royal Marsden Hospital (RMH) score, based on readily available blood tests and clinical features, has emerged as a prognostic tool, although its performance across variable clinical scenarios is not thoroughly delineated. Therefore, we aimed to systematically assess the association between RMH score and survival in cancer patients. Methods: We conducted a systematic literature search across Pubmed, Scopus, and Web of Science databases for studies published up to 15 February 2024. We performed a meta-analysis with the generic inverse variance method with a random-effects model and reported hazard ratios (HR) with 95% confidence intervals (CI). Results: Nineteen studies encompassing 127,230 patients were included. A higher RMH score was significantly associated with worse overall survival (OS) (HR: 2.09, 95% CI: 1.87–2.33, p < 0.001) and progression-free survival (PFS) (HR: 1.80, 95% CI: 1.48–2.18, p < 0.001). This association was consistent across various subgroups, including study population (clinical trial vs. real-world cohort), geographic region, and tumor type. Conclusion: This meta-analysis, including over a hundred thousand patients, demonstrates a negative association between a higher RMH score and survival in cancer patients. The RMH score holds promise as a readily available prognostic tool across diverse cancer types and clinical settings. Future research should focus on validating and refining this score to aid clinical decision-making. Full article

(This article belongs to the Special Issue Novel Prognostic Biomarkers in Human Cancers: From Discovery to Application)

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23 pages, 2587 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress

by Linda Galasso, Lucia Cerrito, Valeria Maccauro, Fabrizio Termite, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco

Cancers 2024, 16(10), 1837; https://doi.org/10.3390/cancers16101837 - 11 May 2024

Cited by 2 | Viewed by 1575

Abstract

Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma [...] Read more.

Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor’s defensive fort. Full article

(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)

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20 pages, 1207 KiB

Open AccessEditor’s ChoiceReview

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy

by Olamide T. Olaoba, Temitope I. Adelusi, Ming Yang, Tessa Maidens, Eric T. Kimchi, Kevin F. Staveley-O’Carroll and Guangfu Li

Cancers 2024, 16(10), 1808; https://doi.org/10.3390/cancers16101808 - 9 May 2024

Cited by 2 | Viewed by 2953

Abstract

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack [...] Read more.

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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9 pages, 240 KiB

Open AccessEditor’s ChoiceReview

Efficacy and Safety of Cemiplimab for the Management of Non-Melanoma Skin Cancer: A Drug Safety Evaluation

by Luca Potestio, Massimiliano Scalvenzi, Aimilios Lallas, Fabrizio Martora, Luigi Guerriero, Luigi Fornaro, Laura Marano and Alessia Villani

Cancers 2024, 16(9), 1732; https://doi.org/10.3390/cancers16091732 - 29 Apr 2024

Cited by 4 | Viewed by 1662

Abstract

Non-melanoma skin cancer includes several types of cutaneous tumors, with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) as the commonest. Among the available therapeutic options, surgical excision is the mainstay of treatment for both tumors. However, tumor features and patients’ [...] Read more.

Non-melanoma skin cancer includes several types of cutaneous tumors, with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) as the commonest. Among the available therapeutic options, surgical excision is the mainstay of treatment for both tumors. However, tumor features and patients’ comorbidities may limit the use of these techniques, making the treatment challenging. As regards BCC, even if hedgehog inhibitors revolutionized the therapeutic scenario, there are still patients unresponsive or intolerant to these drugs. In this context, cemiplimab has been approved as second-line treatment. As regards SCC, cemiplimab was the first systemic therapy approved. The objective of this manuscript was to investigate the efficacy and safety of cemiplimab for the management of BCC and cSCC. Cemiplimab has a durable and significant effect for the management of BCC and CSCC, with a favorable safety profile. Different specialists including oncologists, radiologists, dermatologists, and surgeons are required to guarantee an integrated approach, leading to the best management of patients. Moreover, the collaboration among specialists will allow them to best manage the TEAEs, reducing the risk of treatment suspension or discontinuation. Certainly, ongoing studies and more and more emerging real-world evidence, will allow us to better characterize the role of cemiplimab for the management of advanced non-melanoma skin cancer. Full article

(This article belongs to the Special Issue Research Progress of Cutaneous Squamous and Basal Cell Carcinomas (Volume II))

14 pages, 1361 KiB

Open AccessEditor’s ChoiceArticle

High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy

by Julian Kött, Inka Lilott Hoehne, Isabel Heidrich, Noah Zimmermann, Kim-Lea Reese, Tim Zell, Glenn Geidel, Alessandra Rünger, Stefan W. Schneider, Klaus Pantel, Daniel J. Smit and Christoffer Gebhardt

Cancers 2024, 16(9), 1737; https://doi.org/10.3390/cancers16091737 - 29 Apr 2024

Cited by 1 | Viewed by 1782

Abstract

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the [...] Read more.

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02–3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88, p = 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma. Full article

(This article belongs to the Special Issue Novel Developments on Skin Cancer Diagnostics and Treatment)

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16 pages, 1764 KiB

Open AccessEditor’s ChoiceArticle

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors

by Ryan A. Denu, Cissimol P. Joseph, Elizabeth S. Urquiola, Precious S. Byrd, Richard K. Yang, Ravin Ratan, Maria Alejandra Zarzour, Anthony P. Conley, Dejka M. Araujo, Vinod Ravi, Elise F. Nassif Haddad, Michael S. Nakazawa, Shreyaskumar Patel, Wei-Lien Wang, Alexander J. Lazar and Neeta Somaiah

Cancers 2024, 16(9), 1707; https://doi.org/10.3390/cancers16091707 - 27 Apr 2024

Cited by 2 | Viewed by 2897

Abstract

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack [...] Read more.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. Full article

(This article belongs to the Special Issue Genome Sequencing of Cancer: Identifying Targets and Biomarkers for Therapy)

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22 pages, 323 KiB

Open AccessEditor’s ChoiceReview

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine

by Hammad Tashkandi and Ismail Elbaz Younes

Cancers 2024, 16(9), 1679; https://doi.org/10.3390/cancers16091679 - 26 Apr 2024

Cited by 2 | Viewed by 4908

Abstract

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of [...] Read more.

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders. Full article

(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)

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29 pages, 1077 KiB

Open AccessEditor’s ChoiceReview

Deregulation of New Cell Death Mechanisms in Leukemia

by Gregorio Favale, Federica Donnarumma, Vincenza Capone, Laura Della Torre, Antonio Beato, Daniela Carannante, Giulia Verrilli, Asmat Nawaz, Francesco Grimaldi, Maria Carla De Simone, Nunzio Del Gaudio, Wouter Leonard Megchelenbrink, Michele Caraglia, Rosaria Benedetti, Lucia Altucci and Vincenzo Carafa

Cancers 2024, 16(9), 1657; https://doi.org/10.3390/cancers16091657 - 25 Apr 2024

Cited by 1 | Viewed by 1775

Abstract

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues [...] Read more.

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation. Full article

(This article belongs to the Special Issue Emerging Insights into Cell Death in Cancer)

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12 pages, 834 KiB

Open AccessEditor’s ChoiceArticle

The Current Achievements of Multi-Gene Panel Tests in Clinical Settings for Patients with Non-Small-Cell Lung Cancer

by Tadashi Sakaguchi, Akemi Iketani, Seiya Esumi, Maki Esumi, Yuta Suzuki, Kentaro Ito, Kentaro Fujiwara, Yoichi Nishii, Koji Katsuta, Hiroki Yasui, Osamu Taguchi and Osamu Hataji

Cancers 2024, 16(9), 1670; https://doi.org/10.3390/cancers16091670 - 25 Apr 2024

Cited by 3 | Viewed by 1807

Abstract

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx^® Pan [...] Read more.

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx^® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings. Full article

(This article belongs to the Section Cancer Biomarkers)

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27 pages, 965 KiB

Open AccessEditor’s ChoiceReview

Clinical Prediction Models for Prognosis of Colorectal Liver Metastases: A Comprehensive Review of Regression-Based and Machine Learning Models

by Stamatios Kokkinakis, Ioannis A. Ziogas, Jose D. Llaque Salazar, Dimitrios P. Moris and Georgios Tsoulfas

Cancers 2024, 16(9), 1645; https://doi.org/10.3390/cancers16091645 - 25 Apr 2024

Cited by 2 | Viewed by 1772

Abstract

Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of “high-risk” patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to [...] Read more.

Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of “high-risk” patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to derive prediction models for these patients, and lately, focus has shifted to artificial intelligence-based models, with employment of variable supervised and unsupervised techniques. Multiple endpoints, like overall survival (OS), disease-free survival (DFS) and development or recurrence of postoperative complications have all been used as outcomes in these studies. This review provides an extensive overview of available clinical prediction models focusing on the prognosis of CRLM and highlights the different predictor types incorporated in each model. An overview of the modelling strategies and the outcomes chosen is provided. Specific patient and treatment characteristics included in the models are discussed in detail. Model development and validation methods are presented and critically appraised, and model performance is assessed within a proposed framework. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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14 pages, 1677 KiB

Open AccessEditor’s ChoiceArticle

tRNA-Derived Fragments as Biomarkers in Bladder Cancer

by Olaf Strømme, Kathleen A. Heck, Gaute Brede, Håvard T. Lindholm, Marit Otterlei and Carl-Jørgen Arum

Cancers 2024, 16(8), 1588; https://doi.org/10.3390/cancers16081588 - 20 Apr 2024

Cited by 2 | Viewed by 2075

Abstract

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), [...] Read more.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small noncoding RNA such as transfer RNA-derived fragments (tRF) and microRNA. Here, we performed small-RNA next-generation sequencing from EVs from urine and serum, as well as from serum supernatant. RNA was extracted from 15 non-cancer patients (NCPs) with benign findings in cystoscopy and 41 patients with non-muscle invasive BC. Urine and serum were collected before transurethral resection of bladder tumors (TUR-b) and at routine post-surgery check-ups. We compared levels of tRFs in pre-surgery samples to samples from NCPs and post-surgery check-ups. To further verify our findings, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between T1 stage BC patients and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing pre-surgery to post-surgery samples and four DEtRFs were found when comparing pre-surgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC. Full article

(This article belongs to the Section Cancer Biomarkers)

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26 pages, 1409 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular Carcinoma: Current Drug Therapeutic Status, Advances and Challenges

by Shunzhen Zheng, Siew Wee Chan, Fei Liu, Jun Liu, Pierce Kah Hoe Chow, Han Chong Toh and Wanjin Hong

Cancers 2024, 16(8), 1582; https://doi.org/10.3390/cancers16081582 - 20 Apr 2024

Cited by 7 | Viewed by 4326

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of [...] Read more.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of HCC over the past decade, the incidence and mortality rates of HCC remain a challenge. With the widespread use of the hepatitis B vaccine and antiviral therapy, the etiology of HCC is shifting more toward metabolic-associated steatohepatitis (MASH). Early-stage HCC can be treated with potentially curative strategies such as surgical resection, liver transplantation, and radiofrequency ablation, improving long-term survival. However, most HCC patients, when diagnosed, are already in the intermediate or advanced stages. Molecular targeted therapy, followed by immune checkpoint inhibitor immunotherapy, has been a revolution in HCC systemic treatment. Systemic treatment of HCC especially for patients with compromised liver function is still a challenge due to a significant resistance to immune checkpoint blockade, tumor heterogeneity, lack of oncogenic addiction, and lack of effective predictive and therapeutic biomarkers. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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37 pages, 2553 KiB

Open AccessEditor’s ChoiceReview

Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance

by Anna Fateeva, Kevinn Eddy and Suzie Chen

Cancers 2024, 16(8), 1571; https://doi.org/10.3390/cancers16081571 - 19 Apr 2024

Cited by 7 | Viewed by 3239

Abstract

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs. Significant progress has been made in the last few decades in melanoma therapeutics, most notably in targeted therapy and immunotherapy. These approaches [...] Read more.

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs. Significant progress has been made in the last few decades in melanoma therapeutics, most notably in targeted therapy and immunotherapy. These approaches have greatly improved treatment response outcomes; however, they remain limited in their abilities to hinder disease progression due, in part, to the onset of acquired resistance. In parallel, intrinsic resistance to therapy remains an issue to be resolved. In this review, we summarize currently available therapeutic options for melanoma treatment and focus on possible mechanisms that drive therapeutic resistance. A better understanding of therapy resistance will provide improved rational strategies to overcome these obstacles. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 2352 KiB

Open AccessEditor’s ChoiceArticle

A Novel ceRNET Relying on the lncRNA JPX, miR-378a-3p, and Its mRNA Targets in Lung Cancer

by Nicola Mosca, Mariaceleste Pezzullo, Ilenia De Leo, Anna Truda, Giovanna Marchese, Aniello Russo and Nicoletta Potenza

Cancers 2024, 16(8), 1526; https://doi.org/10.3390/cancers16081526 - 17 Apr 2024

Cited by 2 | Viewed by 2050

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal [...] Read more.

Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal lungs, as expected for an oncogene. Intriguingly, the predicted binding miR-378a-3p showed a significant inverse correlation with JPX expression. The lncRNA/miRNA physical interaction was validated by reporter vectors. Then, the oncogenic activity of JPX, the tumor-suppressive role of miR-378a-3p, and the contribution of their functional interaction to cancer hallmarks were demonstrated using assays for cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, molecular circuits were investigated by boosting the expression of both JPX and miR-378a-3p, singularly and in combination, demonstrating that JPX counteracted miR-378a-3p silencing activity toward its oncogenic targets GLUT1, NRP1, YY1, and Wnt5a. Overall, the data unveil a novel ceRNET (competing endogenous RNA network), wherein JPX acts as a ceRNA by binding to miR-378a-3p, thus reducing the miRNA silencing activity toward its downstream targets, and eliciting oncogenic pathways driving lung cancer. The knowledge of the network may pave the way to develop new diagnostic panels, and innovative RNA-targeted and RNA-based therapeutic strategies. Full article

(This article belongs to the Special Issue RNA in Non-Small-Cell Lung Cancer)

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19 pages, 4940 KiB

Open AccessEditor’s ChoiceArticle

Proteomic Analysis of Spatial Heterogeneity Identifies HMGB2 as Putative Biomarker of Tumor Progression in Adult-Type Diffuse Astrocytomas

by Aline P. Becker, Valesio Becker, Joseph McElroy, Amy Webb, Chunhua Han, Yingshi Guo, Erica H. Bell, Jessica Fleming, Ilinca Popp, Ori Staszewski, Marco Prinz, Jose J. Otero, Saikh Jaharul Haque, Anca-Ligia Grosu and Arnab Chakravarti

Cancers 2024, 16(8), 1516; https://doi.org/10.3390/cancers16081516 - 16 Apr 2024

Cited by 1 | Viewed by 1424

Abstract

Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) [...] Read more.

Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) validate the high mobility group protein B2 (HMGB2) as a key player in tumor progression and as a prognostic/predictive biomarker for diffuse astrocytomas. We performed liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple areas of adult-type astrocytomas and validated our finding in multiplatform-omics studies and high-throughput IHC analysis. LC-MS/MSdetected proteomic signatures characterizing glioma evolution towards higher grades associated with, but not completely dependent, on IDH status. Spatial heterogeneity of diffuse astrocytomas was associated with dysregulation of specific molecular pathways, and HMGB2 was identified as a putative driver of tumor progression, and an early marker of worse overall survival in grades 2 and 3 diffuse gliomas, at least in part regulated by DNA methylation. In grade 4 astrocytomas, HMGB2 expression was strongly associated with proliferative activity and microvascular proliferation. Grounded in proteomic findings, our results showed that HMGB2 expression assessed by IHC detected early signs of tumor progression in grades 2 and 3 astrocytomas, as well as identified GBMs that had a better response to the standard chemoradiation with temozolomide. Full article

(This article belongs to the Section Cancer Biomarkers)

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17 pages, 13335 KiB

Open AccessEditor’s ChoiceArticle

Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice

by Manasi Das, Deepak Kumar, Consuelo Sauceda, Alexis Oberg, Lesley G. Ellies, Liping Zeng, Lily J. Jih, Isabel G. Newton and Nicholas J. G. Webster

Cancers 2024, 16(8), 1513; https://doi.org/10.3390/cancers16081513 - 16 Apr 2024

Cited by 3 | Viewed by 2501

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation, fibrosis, and cirrhosis, and ultimately can lead to hepatocellular carcinoma (HCC). There are currently very few approved therapies for MASH. Weight loss strategies such as caloric restriction can ameliorate the harmful metabolic effect of MASH and inhibit HCC; however, it is difficult to implement and maintain in daily life, especially in individuals diagnosed with HCC. In this study, we tested a time-restricted feeding (TRF) nutritional intervention in mouse models of MASH and HCC. We show that TRF abrogated metabolic dysregulation induced by a Western diet without any calorie restriction or weight loss. TRF improved insulin sensitivity and reduced hyperinsulinemia, liver steatosis, inflammation, and fibrosis. Importantly, TRF inhibited liver tumors in two mouse models of obesity-driven HCC. Our data suggest that TRF is likely to be effective in abrogating MASH and HCC and warrant further studies of time-restricted eating in humans with MASH who are at higher risk of developing HCC. Full article

(This article belongs to the Special Issue Circadian Rhythms, Cancers and Chronotherapy)

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38 pages, 1732 KiB

Open AccessEditor’s ChoiceReview

Heat Shock Proteins, a Double-Edged Sword: Significance in Cancer Progression, Chemotherapy Resistance and Novel Therapeutic Perspectives

by Dominika Kunachowicz, Magdalena Król-Kulikowska, Wiktoria Raczycka, Jakub Sleziak, Marta Błażejewska and Julita Kulbacka

Cancers 2024, 16(8), 1500; https://doi.org/10.3390/cancers16081500 - 14 Apr 2024

Cited by 4 | Viewed by 3650

Abstract

Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention [...] Read more.

Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention to the possibilities of using Hsps in developing new cancer therapy methods, as well as to indicate directions for future research on this topic. In order to discuss this matter, a thorough review of the latest scientific literature was carried out, taking into account the importance of selected proteins from the Hsp family, including Hsp27, Hsp40, Hsp60, Hsp70, Hsp90 and Hsp110. One of the more characteristic features of all Hsps is that they play a multifaceted role in cancer progression, which makes them an obvious target for modern anticancer therapy. Some researchers emphasize the importance of directly inhibiting the action of these proteins. In turn, others point to their possible use in the design of cancer vaccines, which would work by inducing an immune response in various types of cancer. Due to these possibilities, it is believed that the use of Hsps may contribute to the progress of oncoimmunology, and thus help in the development of modern anticancer therapies, which would be characterized by higher effectiveness and lower toxicity to the patients. Full article

(This article belongs to the Special Issue Heat Shock Proteins in Cancers)

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16 pages, 4375 KiB

Open AccessEditor’s ChoiceArticle

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

by Anna Tutusaus, Marco Sanduzzi-Zamparelli, Loreto Boix, Patricia Rider, Silvia Subías, Pablo García de Frutos, Anna Colell, Montserrat Marí, María Reig and Albert Morales

Cancers 2024, 16(8), 1491; https://doi.org/10.3390/cancers16081491 - 13 Apr 2024

Cited by 3 | Viewed by 2095

Abstract

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described [...] Read more.

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC. Full article

(This article belongs to the Special Issue Immunotherapy for Hepatocellular Carcinoma: Novel Experimental Approaches and Biomarkers)

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16 pages, 1638 KiB

Open AccessEditor’s ChoiceReview

Role of the Atypical MAPK ERK3 in Cancer Growth and Progression

by Lobna Elkhadragy, Amanda Myers and Weiwen Long

Cancers 2024, 16(7), 1381; https://doi.org/10.3390/cancers16071381 - 31 Mar 2024

Cited by 1 | Viewed by 2244

Abstract

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose structural and regulatory features are distinct from those of conventional MAPKs, such as ERK1/2. Since its identification in 1991, the regulation, substrates and functions of ERK3 have remained largely unknown. [...] Read more.

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose structural and regulatory features are distinct from those of conventional MAPKs, such as ERK1/2. Since its identification in 1991, the regulation, substrates and functions of ERK3 have remained largely unknown. However, recent years have witnessed a wealth of new findings about ERK3 signaling. Several important biological functions for ERK3 have been revealed, including its role in neuronal morphogenesis, inflammation, metabolism, endothelial cell tube formation and epithelial architecture. In addition, ERK3 has been recently shown to play important roles in cancer cell proliferation, migration, invasion and chemoresistance in multiple types of cancers. Furthermore, accumulating studies have uncovered various molecular mechanisms by which the expression level, protein stability and activity of ERK3 are regulated. In particular, several post-translational modifications (PTMs), including ubiquitination, hydroxylation and phosphorylation, have been shown to regulate the stability and activity of ERK3 protein. In this review, we discuss recent findings regarding biochemical and cellular functions of ERK3, with a main focus on its roles in cancers, as well as the molecular mechanisms of regulating its expression and activity. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Regulation of Cancer Metastasis)

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17 pages, 1340 KiB

Open AccessEditor’s ChoiceReview

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging

by Giuseppe Corrias, Eleonora Lai, Pina Ziranu, Stefano Mariani, Clelia Donisi, Nicole Liscia, Giorgio Saba, Andrea Pretta, Mara Persano, Daniela Fanni, Dario Spanu, Francesca Balconi, Francesco Loi, Simona Deidda, Angelo Restivo, Valeria Pusceddu, Marco Puzzoni, Cinzia Solinas, Elena Massa, Clelia Madeddu, Clara Gerosa, Luigi Zorcolo, Gavino Faa, Luca Saba and Mario Scartozzi Show full author list Hide full author list

Cancers 2024, 16(7), 1364; https://doi.org/10.3390/cancers16071364 - 30 Mar 2024

Cited by 4 | Viewed by 1972

Abstract

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical [...] Read more.

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes. Full article

(This article belongs to the Special Issue Predictive Biomarkers for Colorectal Cancer)

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14 pages, 277 KiB

Open AccessEditor’s ChoiceReview

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer

by Maciej Jaromin, Tomasz Konecki and Piotr Kutwin

Cancers 2024, 16(7), 1366; https://doi.org/10.3390/cancers16071366 - 30 Mar 2024

Cited by 5 | Viewed by 2924

Abstract

Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of [...] Read more.

Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of BCG-unresponsive tumors is scarce and usually leads to Radical Cystectomy. In this paper, we review recent advancements in conservative treatment of BCG-unresponsive tumors. The main focus of the paper is FDA-approved medications: Pembrolizumab and Nadofaragene Firadenovec (Adstiladrin). Other, less researched therapeutic possibilities are also included, namely: N-803 immunotherapy, TAR-200 and TAR-210 intravesical delivery systems and combined Cabazitaxel, Gemcitabine and Cisplatin chemotherapy. Conservative treatment and delaying radical cystectomy would greatly benefit patients’ quality of life; it is undoubtedly the future of BCG-unresponsive NMIBC. Full article

(This article belongs to the Special Issue Time for a Paradigm Shift in Non-muscle-invasive Bladder Cancer (Volume II))

11 pages, 1189 KiB

Open AccessEditor’s ChoiceArticle

Early Serum Markers for Immune Checkpoint Inhibitor Induced Hypophysitis in Melanoma Patients

by Fouad Mitri, Devayani Machiraju, Christina Naoum and Jessica C. Hassel

Cancers 2024, 16(7), 1340; https://doi.org/10.3390/cancers16071340 - 29 Mar 2024

Cited by 1 | Viewed by 1719

Abstract

Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. Methods: We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Results: Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Conclusion: Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Germany)

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24 pages, 879 KiB

Open AccessEditor’s ChoiceReview

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy

by Saurav Verma, Daniel Breadner, Abhenil Mittal, David A. Palma, Rahul Nayak, Jacques Raphael and Mark Vincent

Cancers 2024, 16(7), 1302; https://doi.org/10.3390/cancers16071302 - 27 Mar 2024

Cited by 3 | Viewed by 4992

Abstract

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the [...] Read more.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space. Full article

(This article belongs to the Special Issue Treatment of Lung Cancer)

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12 pages, 473 KiB

Open AccessEditor’s ChoiceArticle

Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study

by Mariana Bastos-Oreiro, Antonio Gutierrez, Almudena Cabero, Javier López, Paola Villafuerte, Ana Jiménez-Ubieto, Raquel de Oña, Adolfo De la Fuente, Belén Navarro, Javier Peñalver, Pilar Martínez, Carmen Alonso, María Infante, Raúl Córdoba, Blanca Perez-Montero, Jaime Pérez de Oteyza, Sonia González de Villambrosio, Paula Fernández-Caldas, Raquel del Campo, Daniel García Belmonte, Javier Diaz-Gálvez, Antonio Salar and Juan-Manuel Sancho Show full author list Hide full author list

Cancers 2024, 16(7), 1285; https://doi.org/10.3390/cancers16071285 - 26 Mar 2024

Cited by 1 | Viewed by 3828

Abstract

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the [...] Read more.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77–86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72–86) for R-bendamustine vs. 67% (95% CI: 61–73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86–96) for R-B vs. 91% (95% CI: 87–94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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12 pages, 852 KiB

Open AccessEditor’s ChoiceArticle

Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer: Anthracyclin Triplets versus FLOT

by Julie F. M. Geerts, Charlène J. van der Zijden, Pieter C. van der Sluis, Manon C. W. Spaander, Grard A. P. Nieuwenhuijzen, Camiel Rosman, Hanneke W. M. van Laarhoven, Rob H. A. Verhoeven, Bas P. L. Wijnhoven, Sjoerd M. Lagarde and Bianca Mostert

Cancers 2024, 16(7), 1291; https://doi.org/10.3390/cancers16071291 - 26 Mar 2024

Cited by 2 | Viewed by 2473

Abstract

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes [...] Read more.

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015–2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77–1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p < 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09–1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08–1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05–2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting. Full article

(This article belongs to the Special Issue Clinical Trials in Gastroesophageal Cancer)

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28 pages, 6424 KiB

Open AccessEditor’s ChoiceArticle

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

by Vuong Trieu, Anthony E. Maida and Sanjive Qazi

Cancers 2024, 16(6), 1202; https://doi.org/10.3390/cancers16061202 - 19 Mar 2024

Cited by 1 | Viewed by 3394

Abstract

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal [...] Read more.

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p < 0.0001), 8.9-fold (p < 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase, p < 0.0001) and TGFB2 (2.2-fold increase, p < 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p < 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2^high HR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation in TGFB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes. Full article

(This article belongs to the Special Issue Past, Present, and Future Strategies in the Treatment and Management of Gliomas)

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20 pages, 3034 KiB

Open AccessEditor’s ChoiceReview

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

by Can Chen and Ji Zhang

Cancers 2024, 16(6), 1171; https://doi.org/10.3390/cancers16061171 - 16 Mar 2024

Cited by 5 | Viewed by 2648

Abstract

Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino [...] Read more.

Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia. Full article

(This article belongs to the Special Issue Novel Combination Therapies for Acute Leukemia)

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22 pages, 1410 KiB

Open AccessEditor’s ChoiceReview

Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets

by Amalia Sofianidi, Ecaterina E. Dumbrava, Konstantinos N. Syrigos and Azadeh Nasrazadani

Cancers 2024, 16(6), 1139; https://doi.org/10.3390/cancers16061139 - 13 Mar 2024

Cited by 6 | Viewed by 4278

Abstract

Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are [...] Read more.

Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are continuously explored; these include ATR inhibitors, which target the ATR kinase involved in the DNA damage response (DDR) pathway, and CHK1/2 inhibitors, which target the Checkpoint Kinase 1/2 (CHK1/2) involved in cell cycle arrest and DNA repair. ATR and CHK1/2 inhibitors show potential as prospective treatments for TNBC by focusing on the DDR and interfering with cell cycle regulation in cancer cells. Preliminary preclinical and clinical findings suggest that when combined with chemotherapy, ATR and CHK1/2 inhibitors demonstrate significant anti-proliferative efficacy against TNBC. In this article, we introduce ATR and CHK1/2 inhibitors as promising therapeutic approaches for the management of TNBC. Preclinical and clinical studies performed evaluating ATR and CHK1/2 inhibitors for the treatment of TNBC and associated challenges encountered in this context to date are reviewed. Full article

(This article belongs to the Special Issue Women’s Health and Gynaecological Cancers: From Nutrition and Environmental Factors to Novel Diagnostics and Therapies)

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12 pages, 761 KiB

Open AccessEditor’s ChoiceReview

Low-Volume Metastases in Cervical Cancer: Does Size Matter?

by Tommaso Bianchi, Tommaso Grassi, Giampaolo Di Martino, Serena Negri, Gaetano Trezzi, Robert Fruscio and Fabio Landoni

Cancers 2024, 16(6), 1107; https://doi.org/10.3390/cancers16061107 - 9 Mar 2024

Cited by 2 | Viewed by 1936

Abstract

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer, and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. Part of the undisputed value of SLN [...] Read more.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer, and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. Part of the undisputed value of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make reaching any conclusions on this topic hard. Current guidelines suggest considering micrometastases (MIC) as a node-positive disease, while considering isolated tumor cells (ITC) as a node-negative disease with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, and prognostic and therapeutic roles of LVM and to underline the present and future challenges we are facing. We hope that this review will guide further research, giving robust evidence on LVM and their impacts on clinical practice. Full article

(This article belongs to the Special Issue Lymph Node Dissection for Gynecologic Cancers)

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26 pages, 1847 KiB

Open AccessEditor’s ChoiceReview

Stereotactic Radiosurgery and Stereotactic Fractionated Radiotherapy in the Management of Brain Metastases

by Sofian Benkhaled, Luis Schiappacasse, Ali Awde and Remy Kinj

Cancers 2024, 16(6), 1093; https://doi.org/10.3390/cancers16061093 - 8 Mar 2024

Cited by 8 | Viewed by 2676

Abstract

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM [...] Read more.

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM patients have changed. Considering and addressing the fact that patients with BM are living longer, the need to provide effective local control while preserving quality of life and neurocognition is fundamental. Over the past decade, SRS and SRT have become a more commonly chosen treatment option for BM. Despite significant advances in the treatment of BM, numerous questions remain regarding patient selection and optimal treatment sequencing. Clinical trials are critical to advancing our understanding of BM, especially as more therapeutic alternatives become available. Therefore, it is imperative for interdisciplinary teams to improve their understanding of the latest advances in SRS-SRT. This review aims to comprehensively explore SRS and SRT as treatments for BM, covering clinical considerations in their application (e.g., patient selection and eligibility), managing limited and multiple intact BM, addressing brainstem metastases, exploring combination therapies with systemic treatments, and considering the health economic perspective. Full article

(This article belongs to the Special Issue Stereotactic Radiotherapy in Tumor Ablation)

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15 pages, 3594 KiB

Open AccessEditor’s ChoiceArticle

Identification of GB3 as a Novel Biomarker of Tumor-Derived Vasculature in Neuroblastoma Using a Stiffness-Based Model

by Aranzazu Villasante, Josep Corominas, Clara Alcon, Andrea Garcia-Lizarribar, Jaume Mora, Monica Lopez-Fanarraga and Josep Samitier

Cancers 2024, 16(5), 1060; https://doi.org/10.3390/cancers16051060 - 5 Mar 2024

Cited by 1 | Viewed by 2006

Abstract

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development [...] Read more.

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development of tumor-derived endothelial cells (TECs) associated with chemoresistance. We lack specific biomarkers for TECs. Therefore, identifying new TEC biomarkers is vital for effective NB therapies. A stiffness-based platform simulating human arterial and venous stiffness was developed to study NB TECs in vitro. Adrenergic cells cultured on arterial-like stiffness transdifferentiated into TECs, while mesenchymal state cells did not. The TECs derived from adrenergic cells served as a model to explore new biomarkers, with a particular focus on GB3, a glycosphingolipid receptor implicated in angiogenesis, metastasis, and drug resistance. Notably, the TECs unequivocally expressed GB3, validating its novelty as a marker. To explore targeted therapeutic interventions, nanoparticles functionalized with the non-toxic subunit B of the Shiga toxin were generated, because they demonstrated a robust affinity for GB3-positive cells. Our results demonstrate the value of the stiffness-based platform as a predictive tool for assessing NB aggressiveness, the discovery of new biomarkers, and the evaluation of the effectiveness of targeted therapeutic strategies. Full article

(This article belongs to the Section Cancer Biomarkers)

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