Recent Advances in Anticancer Strategies

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Topic Information

Dear Colleagues,

The topic "Recent Advances in Anticancer Strategies" aims to provide an overview of the latest developments in the field of cancer treatment. Cancer remains one of the leading causes of death worldwide, and researchers have been working to develop more effective and targeted treatments to improve outcomes for patients. The existing cancer therapies suffer from severe side effects and drug resistance, leading to an increase in cancer incidence and mortality worldwide. Hence, there is a pressing need to develop and discover novel therapeutic strategies that can offer more effective and less toxic treatment options for cancer patients. Novel anticancer approaches are being developed, which can selectively identify and eliminate cancerous cells while minimizing harm to healthy tissues, unlike traditional therapies. For this topic, we welcome original articles and comprehensive reviews that showcase the latest advances in novel anticancer strategies with reduced toxicity and improved therapeutic indices. These articles can suggest potential prospects for optimizing cancer therapies with significant clinical value in the near future. We encourage submissions that focus on the development and validation of various anticancer approaches, including ligand-/receptor-based targeting, controlled drug delivery, gene therapy, gene delivery, immunotherapy, targeted anticancer prodrugs and conjugates (such as photoactivatable caged prodrugs, ADEPT, ADAPT and ADCs), magnetic and ultrasound-mediated drug targeting, and cancer stem cell therapy, as well as strategies that explore the targeting of signaling cascades and the tumor microenvironment. Overall, the topic aims at providing recent advances in anticancer strategies, highlighting the potential impact of these new approaches on cancer treatment and patient outcomes. We eagerly anticipate your valuable contribution to this exciting topic.

Dr. Hassan Bousbaa
Dr. Zhiwei Hu
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	15.3 Days	CHF 2600
Cancers cancers	4.5	8.0	2009	16.3 Days	CHF 2900
Future Pharmacology futurepharmacol	-	-	2021	25 Days	CHF 1000
Pharmaceutics pharmaceutics	4.9	7.9	2009	14.9 Days	CHF 2900
Current Oncology curroncol	2.8	3.3	1994	17.6 Days	CHF 2200

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19 pages, 729 KiB  

Open AccessReview

Antibody–Drug Conjugates: A Start of a New Era in Gynecological Cancers

by Samir Fasih, Stephen Welch and Ana Elisa Lohmann

Curr. Oncol. 2024, 31(11), 7088-7106; https://doi.org/10.3390/curroncol31110522 - 13 Nov 2024

Viewed by 549

Abstract

Antibody–drug conjugates (ADCs) are a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy agents. ADCs have been available for over a decade, but in gynecological cancers, these [...] Read more.

Antibody–drug conjugates (ADCs) are a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy agents. ADCs have been available for over a decade, but in gynecological cancers, these agents are relatively new with great promise ahead. More than 80% of ongoing trials in gynecological cancers are evaluating ADCs’ safety and efficacy, of which 40% are early-phase trials. Around twenty ADCs are currently under investigation, either alone or in combination with chemotherapies or immune checkpoint inhibitors. Among them, mirvetuximab soravtansine has been recently approved by the Food and Drug Administration (FDA) in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent or in combination. Tisotumab vedotin and trastuzumab deruxtecan are also now approved by the FDA in patients with pre-treated cervical and uterine cancers and further investigation is ongoing. Overall, the toxicity profiles of ADCs are acceptable. Ocular toxicity is one of the specific side effects of some ADCs, but most of the cases are manageable with the use of prophylactic steroids and dose adjustments. This review aims to provide an overview of the fundamental and operational features of ADCs and examine the latest and most promising data, with a particular focus on the Canadian viewpoint. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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29 pages, 7635 KiB  

Open AccessArticle

Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death

by Mafalda Calheiros-Lobo, João P. N. Silva, Leonor Delgado, Bárbara Pinto, Luís Monteiro, Carlos Lopes, Patrícia M. A. Silva and Hassan Bousbaa

Cancers 2024, 16(22), 3732; https://doi.org/10.3390/cancers16223732 - 5 Nov 2024

Viewed by 527

Abstract

Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including [...] Read more.

Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab’s therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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33 pages, 12531 KiB  

Open AccessReview

Design Principles and Applications of Fluorescent Kinase Inhibitors for Simultaneous Cancer Bioimaging and Therapy

by Ab Majeed Ganai, Eirinaios I. Vrettos, Stavroula G. Kyrkou, Vasiliki Zoi, Tabasum Khan Pathan, Rajshekhar Karpoormath, Penelope Bouziotis, George A. Alexiou, George A. Kastis, Nicholas E. Protonotarios and Andreas G. Tzakos

Cancers 2024, 16(21), 3667; https://doi.org/10.3390/cancers16213667 - 30 Oct 2024

Viewed by 633

Abstract

Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. [...] Read more.

Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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9 pages, 310 KiB  

Open AccessArticle

Randomized Phase II Cancer Clinical Trials to Validate Predictive Biomarkers

by Baoshan Zhang, Jong-Mu Sun, Myung-Ju Ahn and Sin-Ho Jung

Biomedicines 2024, 12(10), 2185; https://doi.org/10.3390/biomedicines12102185 - 26 Sep 2024

Viewed by 495

Abstract

Objectives: The design of cancer clinical trials incorporating biomarkers depends on various factors, including the trial phase, the type of biomarker and whether its role has been validated. This article aims to present a method for designing and analyzing phase II cancer clinical [...] Read more.

Objectives: The design of cancer clinical trials incorporating biomarkers depends on various factors, including the trial phase, the type of biomarker and whether its role has been validated. This article aims to present a method for designing and analyzing phase II cancer clinical trials that validate predictive biomarkers. Methods: We propose a randomized trial design where patients are allocated between a targeted therapy and a non-targeted therapy stratified by biomarker status. Tumor response is used as the primary endpoint to validate the biomarker through interaction testing between treatment and biomarker positivity. Additionally we propose a sample size calculation method for this design, considering two types of interaction: one based on logit-transformed response rates and the other on raw response rates. Results: The proposed sample size method is applied to the design of a real randomized phase II trial. Extensive simulations are conducted to evaluate the performance of the test statistic and the sample size method under different scenarios. Conclusions: Our method provides a practical approach to validating predictive biomarkers in phase II cancer trials. The simulations demonstrate robust performance for both interaction models, offering guidance for the sample size selection and analysis strategy in biomarker-stratified trials. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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25 pages, 19339 KiB  

Open AccessArticle

Identifying Key Genes as Progression Indicators of Prostate Cancer with Castration Resistance Based on Dynamic Network Biomarker Algorithm and Weighted Gene Correlation Network Analysis

by Siyuan Liu, Yi Hu, Fei Liu, Yizheng Jiang, Hongrui Wang, Xusheng Wu and Dehua Hu

Biomedicines 2024, 12(9), 2157; https://doi.org/10.3390/biomedicines12092157 - 23 Sep 2024

Viewed by 1044

Abstract

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the [...] Read more.

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the weighted gene co-expression network analysis (WGCNA) to identify key genes associated with the progression to a castration-resistant state in prostate cancer via the integration of single-cell and bulk RNA sequencing data. Based on the gene expression profiles of CRPC in the GEO dataset, the DNB method was used to clarify the condition of epithelial cells and find out the most significant transition signal DNB modules and genes included. Then, we calculated gene modules associated with the clinical phenotype stage based on the WGCNA. IHC was conducted to validate the expression of the key genes in CRPC and primary PCa patients Results:Nomograms, calibration plots, and ROC curves were applied to evaluate the good prognostic accuracy of the risk prediction model. Results: By combining single-cell RNA sequence data and bulk RNA sequence data, we identified a set of DNBs, whose roles involved in androgen-associated activities indicated the signals of a prostate cancer cell transition from an androgen-dependent state to a castration-resistant state. In addition, a risk prediction model including the risk score of four key genes (SCD, NARS2, ALDH1A1, and NFXL1) and other clinical–pathological characteristics was constructed and verified to be able to reasonably predict the prognosis of patients receiving ADT. Conclusions: In summary, four key genes from DNBs were identified as potential diagnostic markers for patients treated with ADT and a risk score-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions of CRPC. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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8 pages, 502 KiB  

Open AccessArticle

Comparison of Weekly Paclitaxel Regimens in Recurrent Platinum-Resistant Ovarian Cancer: A Single Institution Retrospective Study

by Laurence Morin, Louis-Philippe Grenier, Nicolas Foucault, Éric Lévesque, François Fabi, Eve-Lyne Langlais, Alexandra Sebastianelli, Marianne Lavoie, Marc Lalancette, Marie Plante, Mahukpe Narcisse Ulrich Singbo and Vincent Castonguay

Curr. Oncol. 2024, 31(8), 4624-4631; https://doi.org/10.3390/curroncol31080345 - 15 Aug 2024

Cited by 1 | Viewed by 1059

Abstract

Weekly paclitaxel (WP) is a chemotherapeutic cornerstone in the management of patients with platinum-resistant ovarian carcinoma. Multiple WP dosing regimens have been used clinically and studied individually. However, no formal comparison of these regimens is available to provide objective guidance in clinical decision [...] Read more.

Weekly paclitaxel (WP) is a chemotherapeutic cornerstone in the management of patients with platinum-resistant ovarian carcinoma. Multiple WP dosing regimens have been used clinically and studied individually. However, no formal comparison of these regimens is available to provide objective guidance in clinical decision making. The primary objective of this study was to compare the cumulative dose of paclitaxel delivered using 80 mg/m²/week, administered using either a 3 weeks out of 4 (WP3) or a 4 weeks out of 4 (WP4) regimen. The secondary objective was to evaluate the clinical outcomes associated with both regimens, including efficacy and toxicity parameters. Our retrospective cohort comprised 149 patients harboring platinum-resistant ovarian cancer treated at the CHU de Québec from January 2012 to January 2023. WP3 and WP4 reached a similar cumulative dose (1353.7 vs. 1404.2 mg/m²; p = 0.29). No significant differences in the clinical outcomes were observed. The frequency of dose reduction was significantly higher for WP4 than WP3 (44.7% vs. 4.9%; p < 0.01), mainly due to treatment intolerance from toxicity (34.0% vs. 3.9%; p < 0.01). Our data suggest that a WP3 regimen delivers a similar cumulative dose to WP4, hence offering a better tolerability profile without compromising efficacy. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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18 pages, 7028 KiB  

Open AccessArticle

Curcumin and Baicalin Co-Loaded Nanoliposomes for Synergistic Treatment of Non-Small Cell Lung Cancer

by Qijun Su, Junqian Pan, Chunxin Wang, Meng Zhang, Haixin Cui and Xiang Zhao

Pharmaceutics 2024, 16(8), 973; https://doi.org/10.3390/pharmaceutics16080973 - 23 Jul 2024

Cited by 1 | Viewed by 909

Abstract

Currently, the treatment of patients with advanced non-small cell lung cancer (NSCLC) mainly relies on traditional chemotherapeutic drugs; however, most of them have limited therapeutic effects and high toxicity. Some natural products with good therapeutic efficacy and low toxicity and side effects are [...] Read more.

Currently, the treatment of patients with advanced non-small cell lung cancer (NSCLC) mainly relies on traditional chemotherapeutic drugs; however, most of them have limited therapeutic effects and high toxicity. Some natural products with good therapeutic efficacy and low toxicity and side effects are limited in clinical application due to their low solubility and bioavailability. In this study, a nanoliposome drug-carrying system (Lip-Cur/Ba) was developed for the co-delivery of curcumin (Cur) and baicalin (Ba) using the thin-film hydration method. In vitro experiments demonstrated that Lip-Cur/Ba had a strong killing effect on A549 cells, and the inhibitory effect of Lip-Cur/Ba on A549 cells was enhanced by 67.8% and 51.9% relative to that of the single-carrier system, which could reduce the use of a single-drug dose (Lip-Cur and Lip-Ba), delay the release rate of the drug and improve the bioavailability. In vivo experiments demonstrated the antitumor activity of Lip-Cur/Ba by intravitreal injection in BALB/c mice, and there were no obvious toxic side effects. This study provides a new idea for curcumin and baicalin to be used in the co-treatment of NSCLC by constructing a new vector. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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32 pages, 7516 KiB  

Open AccessArticle

Novel Thienopyrimidine-Hydrazinyl Compounds Induce DRP1-Mediated Non-Apoptotic Cell Death in Triple-Negative Breast Cancer Cells

by Saloni Malla, Angelique Nyinawabera, Rabin Neupane, Rajiv Pathak, Donghyun Lee, Mariam Abou-Dahech, Shikha Kumari, Suman Sinha, Yuan Tang, Aniruddha Ray, Charles R. Ashby, Jr., Mary Qu Yang, R. Jayachandra Babu and Amit K. Tiwari

Cancers 2024, 16(15), 2621; https://doi.org/10.3390/cancers16152621 - 23 Jul 2024

Viewed by 1666

Abstract

Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this [...] Read more.

Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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15 pages, 3060 KiB  

Open AccessReview

Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer

by Fabio Volpe, Carmela Nappi, Emilia Zampella, Erica Di Donna, Simone Maurea, Alberto Cuocolo and Michele Klain

Curr. Oncol. 2024, 31(7), 3870-3884; https://doi.org/10.3390/curroncol31070286 - 3 Jul 2024

Viewed by 2578

Abstract

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop [...] Read more.

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. ¹⁸F-FDG PET/CT has been widely used and has demonstrated prognostic value, but ¹⁸F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. Conclusions: RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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18 pages, 1842 KiB  

Open AccessReview

Prospect of Gold Nanoparticles in Pancreatic Cancer

by Tianyi Yin, Jingrun Han, Yuying Cui, Dong Shang and Hong Xiang

Pharmaceutics 2024, 16(6), 806; https://doi.org/10.3390/pharmaceutics16060806 - 14 Jun 2024

Viewed by 1236

Abstract

Pancreatic cancer (PC) is characterized by its notably poor prognosis and high mortality rate, underscoring the critical need for advancements in its diagnosis and therapy. Gold nanoparticles (AuNPs), with their distinctive physicochemical characteristics, demonstrate significant application potential in cancer therapy. For example, upon [...] Read more.

Pancreatic cancer (PC) is characterized by its notably poor prognosis and high mortality rate, underscoring the critical need for advancements in its diagnosis and therapy. Gold nanoparticles (AuNPs), with their distinctive physicochemical characteristics, demonstrate significant application potential in cancer therapy. For example, upon exposure to lasers of certain wavelengths, they facilitate localized heating, rendering them extremely effective in photothermal therapy. Additionally, their extensive surface area enables the conjugation of therapeutic agents or targeting molecules, increasing the accuracy of drug delivery systems. Moreover, AuNPs can serve as radiosensitizers, enhancing the efficacy of radiotherapy by boosting the radiation absorption in tumor cells. Here, we systematically reviewed the application and future directions of AuNPs in the diagnosis and treatment of PC. Although AuNPs have advantages in improving diagnostic and therapeutic efficacy, as well as minimizing damage to normal tissues, concerns about their potential toxicity and safety need to be comprehensively evaluated. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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15 pages, 4102 KiB  

Open AccessArticle

Cytotoxic Effects of Doxorubicin on Cancer Cells and Macrophages Depend Differently on the Microcarrier Structure

by Daria Kalenichenko, Irina Kriukova, Alexander Karaulov, Igor Nabiev and Alyona Sukhanova

Pharmaceutics 2024, 16(6), 785; https://doi.org/10.3390/pharmaceutics16060785 - 9 Jun 2024

Viewed by 1441

Abstract

Microparticles are versatile carriers for controlled drug delivery in personalized, targeted therapy of various diseases, including cancer. The tumor microenvironment contains different infiltrating cells, including immune cells, which can affect the efficacy of antitumor drugs. Here, prototype microparticle-based systems for the delivery of [...] Read more.

Microparticles are versatile carriers for controlled drug delivery in personalized, targeted therapy of various diseases, including cancer. The tumor microenvironment contains different infiltrating cells, including immune cells, which can affect the efficacy of antitumor drugs. Here, prototype microparticle-based systems for the delivery of the antitumor drug doxorubicin (DOX) were developed, and their cytotoxic effects on human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells were compared in vitro. DOX-containing calcium carbonate microparticles with or without a protective polyelectrolyte shell and polyelectrolyte microcapsules of about 2.4–2.5 μm in size were obtained through coprecipitation and spontaneous loading. All the microstructures exhibited a prolonged release of DOX. An estimation of the cytotoxicity of the DOX-containing microstructures showed that the encapsulation of DOX decreased its toxicity to macrophages and delayed the cytotoxic effect against tumor cells. The DOX-containing calcium carbonate microparticles with a protective polyelectrolyte shell were more toxic to the cancer cells than DOX-containing polyelectrolyte microcapsules, whereas, for the macrophages, the microcapsules were most toxic. It is concluded that DOX-containing core/shell microparticles with an eight-layer polyelectrolyte shell are optimal drug microcarriers due to their low toxicity to immune cells, even upon prolonged incubation, and strong delayed cytotoxicity against tumor cells. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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27 pages, 1737 KiB  

Open AccessReview

Emerging Treatment Options for Neuroendocrine Neoplasms of Unknown Primary Origin: Current Evidence and Future Perspectives

by Francesca Corti, Roberta Elisa Rossi, Pietro Cafaro, Gaia Passarella, Antonella Turla, Sara Pusceddu, Jorgelina Coppa, Simone Oldani, Alessandro Guidi, Raffaella Longarini and Diego Luigi Cortinovis

Cancers 2024, 16(11), 2025; https://doi.org/10.3390/cancers16112025 - 27 May 2024

Cited by 1 | Viewed by 1640

Abstract

Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs [...] Read more.

Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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19 pages, 3970 KiB  

Open AccessArticle

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing

by João P. N. Silva, Bárbara Pinto, Luís Monteiro, Patrícia M. A. Silva and Hassan Bousbaa

Cancers 2024, 16(11), 2014; https://doi.org/10.3390/cancers16112014 - 25 May 2024

Cited by 1 | Viewed by 1356

Abstract

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting [...] Read more.

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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24 pages, 5816 KiB  

Open AccessEditor’s ChoiceReview

Functionalized Calcium Carbonate-Based Microparticles as a Versatile Tool for Targeted Drug Delivery and Cancer Treatment

by Lara Biny, Evgeniia Gerasimovich, Alexander Karaulov, Alyona Sukhanova and Igor Nabiev

Pharmaceutics 2024, 16(5), 653; https://doi.org/10.3390/pharmaceutics16050653 - 13 May 2024

Viewed by 2037

Abstract

Nano- and microparticles are increasingly widely used in biomedical research and applications, particularly as specific labels and targeted delivery vehicles. Silica has long been considered the best material for such vehicles, but it has some disadvantages limiting its potential, such as the proneness [...] Read more.

Nano- and microparticles are increasingly widely used in biomedical research and applications, particularly as specific labels and targeted delivery vehicles. Silica has long been considered the best material for such vehicles, but it has some disadvantages limiting its potential, such as the proneness of silica-based carriers to spontaneous drug release. Calcium carbonate (CaCO₃) is an emerging alternative, being an easily available, cost-effective, and biocompatible material with high porosity and surface reactivity, which makes it an attractive choice for targeted drug delivery. CaCO₃ particles are used in this field in the form of either bare CaCO₃ microbeads or core/shell microparticles representing polymer-coated CaCO₃ cores. In addition, they serve as removable templates for obtaining hollow polymer microcapsules. Each of these types of particles has its specific advantages in terms of biomedical applications. CaCO₃ microbeads are primarily used due to their capacity for carrying pharmaceutics, whereas core/shell systems ensure better protection of the drug-loaded core from the environment. Hollow polymer capsules are particularly attractive because they can encapsulate large amounts of pharmaceutical agents and can be so designed as to release their contents in the target site in response to specific stimuli. This review focuses first on the chemistry of the CaCO₃ cores, core/shell microbeads, and polymer microcapsules. Then, systems using these structures for the delivery of therapeutic agents, including drugs, proteins, and DNA, are outlined. The results of the systematic analysis of available data are presented. They show that the encapsulation of various therapeutic agents in CaCO₃-based microbeads or polymer microcapsules is a promising technique of drug delivery, especially in cancer therapy, enhancing drug bioavailability and specific targeting of cancer cells while reducing side effects. To date, research in CaCO₃-based microparticles and polymer microcapsules assembled on CaCO₃ templates has mainly dealt with their properties in vitro, whereas their in vivo behavior still remains poorly studied. However, the enormous potential of these highly biocompatible carriers for in vivo applications is undoubted. This last issue is addressed in depth in the Conclusions and Outlook sections of the review. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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28 pages, 1776 KiB  

Open AccessReview

DNA Damage Responses in Tumors Are Not Proliferative Stimuli, but Rather They Are DNA Repair Actions Requiring Supportive Medical Care

by Zsuzsanna Suba

Cancers 2024, 16(8), 1573; https://doi.org/10.3390/cancers16081573 - 19 Apr 2024

Cited by 3 | Viewed by 1965

Abstract

Background: In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.Purpose: Justifying that [...] Read more.

Background: In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.Purpose: Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways. Results: 1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation. Conclusions: Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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18 pages, 2345 KiB  

Open AccessSystematic Review

Systematic Review and Meta-Analysis of Laparoscopic versus Robotic-Assisted Surgery for Colon Cancer: Efficacy, Safety, and Outcomes—A Focus on Studies from 2020–2024

by Roxana Loriana Negrut, Adrian Cote, Vasile Aurel Caus and Adrian Marius Maghiar

Cancers 2024, 16(8), 1552; https://doi.org/10.3390/cancers16081552 - 18 Apr 2024

Cited by 1 | Viewed by 2540

Abstract

Background: Minimally invasive surgery in the treatment of colon cancer has significantly advanced over the years. This systematic review and meta-analysis aimed to compare the operative outcomes of robotic and laparoscopic surgery in the treatment of colon cancer, focusing on operative time, hospital [...] Read more.

Background: Minimally invasive surgery in the treatment of colon cancer has significantly advanced over the years. This systematic review and meta-analysis aimed to compare the operative outcomes of robotic and laparoscopic surgery in the treatment of colon cancer, focusing on operative time, hospital stay, conversion rates, anastomotic leak rates, and total number lymph node harvested. Methods: Following PRISMA guidelines, we conducted a systematic search across four databases up to January 2024, registering our protocol with PROSPERO (CRD42024513326). We included studies comparing robotic and laparoscopic surgeries for colon cancer, assessing operative time, hospital length of stay, and other perioperative outcomes. Risk of bias was evaluated using the JBI Critical Appraisal Checklist. Statistical analysis utilized a mix of fixed and random-effects models based on heterogeneity. Results: A total of 21 studies met the inclusion criteria, encompassing 50,771 patients, with 21.75% undergoing robotic surgery and 78.25% laparoscopic surgery. Robotic surgery was associated with longer operative times (SMD = −1.27, p < 0.00001) but shorter hospital stays (MD = 0.42, p = 0.003) compared to laparoscopic surgery. Conversion rates were significantly higher in laparoscopic procedures (OR = 2.02, p < 0.00001). No significant differences were found in anastomotic leak rates. A higher number of lymph nodes was harvested by robotic approach (MD = −0.65, p = 0.04). Publication bias was addressed through funnel plot analysis and Egger’s test, indicating the presence of asymmetry (p = 0.006). Conclusions: The choice of surgical method should be individualized, considering factors such as surgeon expertise, medical facilities, and patient-specific considerations. Future research should aim to elucidate long-term outcomes to further guide the clinical decision-making. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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17 pages, 2995 KiB  

Open AccessArticle

Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia

by Joana Pereira-Vieira, Daniela D. Weber, Sâmia Silva, Catarina Barbosa-Matos, Sara Granja, Rui Manuel Reis, Odília Queirós, Young H. Ko, Barbara Kofler, Margarida Casal and Fátima Baltazar

Pharmaceutics 2024, 16(4), 442; https://doi.org/10.3390/pharmaceutics16040442 - 22 Mar 2024

Cited by 1 | Viewed by 1621

Abstract

Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of [...] Read more.

Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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19 pages, 2083 KiB  

Open AccessSystematic Review

Intraoperative Techniques That Define the Mucosal Margins of Oral Cancer In-Vivo: A Systematic Review

by Klijs J. de Koning, Carleen M. E. M. Adriaansens, Rob Noorlag, Remco de Bree and Robert J. J. van Es

Cancers 2024, 16(6), 1148; https://doi.org/10.3390/cancers16061148 - 14 Mar 2024

Cited by 1 | Viewed by 1387

Abstract

Background: This systematic review investigates techniques for determining adequate mucosal margins during the resection of oral squamous cell carcinoma (SCC). The primary treatment involves surgical removal with ≥5 mm margins, highlighting the importance of accurate differentiation between SCC and dysplasia during surgery. Methods: [...] Read more.

Background: This systematic review investigates techniques for determining adequate mucosal margins during the resection of oral squamous cell carcinoma (SCC). The primary treatment involves surgical removal with ≥5 mm margins, highlighting the importance of accurate differentiation between SCC and dysplasia during surgery. Methods: A comprehensive Embase and PubMed literature search was performed. Studies underwent quality assessment using QUADAS-2. Results: After the full-text screening and exclusion of studies exhibiting high bias, eight studies were included, focusing on three margin visualization techniques: autofluorescence, iodine staining, and narrow-band imaging (NBI). Negative predictive value (NPV) was calculable across the studies, though reference standards varied. Results indicated NPVs for autofluorescence, iodine, and NBI ranging from 61% to 100%, 92% to 99%, and 86% to 100%, respectively. Autofluorescence did not significantly enhance margins compared to white light-guided surgery, while iodine staining demonstrated improvement for mild or moderate dysplasia. NBI lacked comparison with a white light-guided surgery cohort. Conclusions: We recommend studying and comparing the diagnostic accuracy of iodine staining and NBI in larger cohorts of patients with oral SCC, focusing on discriminating between SCC and (severe) dysplasia. Furthermore, we advise reporting the diagnostic accuracy alongside the treatment effects to improve the assessment of these techniques. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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16 pages, 1007 KiB  

Open AccessReview

¹⁷⁷Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: A Review of the Evidence and Implications for Canadian Clinical Practice

by Kim N. Chi, Steven M. Yip, Glenn Bauman, Stephan Probst, Urban Emmenegger, Christian K. Kollmannsberger, Patrick Martineau, Tamim Niazi, Frédéric Pouliot, Ricardo Rendon, Sebastien J. Hotte, David T. Laidley and Fred Saad

Curr. Oncol. 2024, 31(3), 1400-1415; https://doi.org/10.3390/curroncol31030106 - 7 Mar 2024

Cited by 1 | Viewed by 3040

Abstract

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (¹⁷⁷Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a [...] Read more.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (¹⁷⁷Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of ¹⁷⁷Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of ¹⁷⁷Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of ¹⁷⁷Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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23 pages, 4819 KiB  

Open AccessArticle

New MoS₂/Tegafur-Containing Pharmaceutical Formulations for Selective LED-Based Skin Cancer Photo-Chemotherapy

by Miguel T. Campos, Filipa A. L. S. Silva, José Ramiro Fernandes, Susana G. Santos, Fernão D. Magalhães, Maria J. Oliveira and Artur M. Pinto

Pharmaceutics 2024, 16(3), 360; https://doi.org/10.3390/pharmaceutics16030360 - 4 Mar 2024

Viewed by 1773

Abstract

Non-melanoma skin cancer (NMSC) is one of the most common types of cancer worldwide. Despite the low mortality rate, rising incidence and recurrence rates are a burden on healthcare systems. Standard treatments such as chemotherapy, radiotherapy, and surgery are either invasive or toxic [...] Read more.

Non-melanoma skin cancer (NMSC) is one of the most common types of cancer worldwide. Despite the low mortality rate, rising incidence and recurrence rates are a burden on healthcare systems. Standard treatments such as chemotherapy, radiotherapy, and surgery are either invasive or toxic to healthy tissues; therefore, new, alternative, selective treatments are needed. In this work, a combined photothermal and chemotherapeutic approach is proposed. MoS₂ was used as photothermal agent. It was prepared by a liquid-phase exfoliation and intercalation method using polyvinylpyrrolidone (PVP), followed by recirculation through a custom-built high-power ultrasonication probe. After 6 h of ultrasonication treatment, the average particle size was 165 ± 170 nm. Near-infrared (NIR) irradiation assays (810 nm, 0.1 W/cm², 30 min, 180 J/cm²) confirmed that MoS₂ nanosheets can efficiently convert NIR light into heat and reach 52 °C. The therapeutic doses of MoS₂ (125 µg/mL) and Tegafur (50 µg/mL) were optimized and both were simultaneously incorporated into a Carbopol hydrogel. The cells were brought into contact with the hydrogel and irradiated with a custom-built NIR LED system. In HFF-1 cells (normal human fibroblasts), the metabolic activity was 78% (above the 70% toxicity limit—ISO 10993-5:2009(E)), while in A-431 skin cancer cells, it was 28%. In addition, the MoS₂ + Tegafur hydrogels led to a 1.9-fold decrease in A-431 cancer cell metabolic activity, 72 h after irradiation, in comparison to MoS₂ hydrogels, indicating a combined effect of photothermal and chemotherapy. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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10 pages, 770 KiB  

Open AccessArticle

Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study

by Akinori Minato, Nobuki Furubayashi, Yujiro Nagata, Toshihisa Tomoda, Hiroyuki Masaoka, Yoohyun Song, Yoshifumi Hori, Keijiro Kiyoshima, Takahito Negishi, Kentaro Kuroiwa, Narihito Seki, Ikko Tomisaki, Kenichi Harada, Motonobu Nakamura and Naohiro Fujimoto

Curr. Oncol. 2024, 31(2), 862-871; https://doi.org/10.3390/curroncol31020064 - 3 Feb 2024

Cited by 5 | Viewed by 1892

Abstract

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of [...] Read more.

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of patients with SUC treated with EV for metastatic disease. We retrospectively evaluated consecutive patients with advanced lower and upper urinary tract cancer who received EV after platinum-based chemotherapy and immune checkpoint blockade therapy at six institutions. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with SUC. We identified 44 and 18 patients with PUC and SUC, respectively. Squamous differentiation was the most common subtype element, followed by glandular differentiation and sarcomatoid subtype. Although patients with SUC had a comparable ORR to those with PUC, the duration of response for SUC was short. Patients with SUC had poorer PFS than those with PUC; however, no significant difference was observed in OS. Multivariate analysis revealed that SUC was significantly associated with shorter PFS. Although the response of metastatic SUC to EV was similar to that of PUC, SUC showed faster progression than PUC. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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21 pages, 4725 KiB  

Open AccessArticle

Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction

by Bárbara Pinto, João P. N. Silva, Patrícia M. A. Silva, Daniel José Barbosa, Bruno Sarmento, Juliana Carvalho Tavares and Hassan Bousbaa

Pharmaceutics 2024, 16(1), 56; https://doi.org/10.3390/pharmaceutics16010056 - 29 Dec 2023

Cited by 2 | Viewed by 1752

Abstract

Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use. They can be classified into mitotic blockers, [...] Read more.

Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use. They can be classified into mitotic blockers, causing SAC-induced mitotic arrest, or mitotic drivers, pushing cells through aberrant mitosis by overriding SAC. These drugs, although advancing to clinical trials, exhibit unsatisfactory cancer treatment outcomes as monotherapy, probably due to variable cell fate responses driven by cyclin B degradation and apoptosis signal accumulation networks. We investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic navitoclax in lung cancer cells treated with the selective CENPE inhibitor GSK923295 (mitotic blocker) or the MPS1 inhibitor BAY1217389 (mitotic driver). Our aim was to steer treated cancer cells towards cell death. BH3-mimetics, in combination with both mitotic blockers and drivers, induced substantial cell death, mainly through apoptosis, in 2D and 3D cultures. Crucially, these synergistic concentrations were less toxic to non-tumor cells. This highlights the significance of combining BH3-mimetics with antimitotics, either blockers or drivers, which have reached the clinical trial phase, to enhance their effectiveness. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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9 pages, 554 KiB  

Open AccessArticle

IGF1 and Insulin Receptor Single Nucleotide Variants Associated with Response in HER2-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without a Fasting Mimicking Diet (BOOG 2013-04 DIRECT Trial)

by Nadia de Gruil, Stefan Böhringer, Stefanie de Groot, Hanno Pijl, Judith R. Kroep and Jesse J. Swen

Cancers 2023, 15(24), 5872; https://doi.org/10.3390/cancers15245872 - 17 Dec 2023

Viewed by 1297

Abstract

Aim: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor [...] Read more.

Aim: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. Methods: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. Results: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). Conclusions: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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14 pages, 656 KiB  

Open AccessSystematic Review

Combination of Local Ablative Techniques with Radiotherapy for Primary and Recurrent Lung Cancer: A Systematic Review

by Paolo Bonome, Donato Pezzulla, Valentina Lancellotta, Anna Rita Scrofani, Gabriella Macchia, Elena Rodolfino, Luca Tagliaferri, György Kovács, Francesco Deodato and Roberto Iezzi

Cancers 2023, 15(24), 5869; https://doi.org/10.3390/cancers15245869 - 16 Dec 2023

Viewed by 1203

Abstract

In patients with early-stage or recurrent NSCLC who are unable to tolerate surgery, a benefit could derive only from a systemic therapy or another few forms of local therapy. A systematic review was performed to evaluate the feasibility and the effectiveness of radiotherapy [...] Read more.

In patients with early-stage or recurrent NSCLC who are unable to tolerate surgery, a benefit could derive only from a systemic therapy or another few forms of local therapy. A systematic review was performed to evaluate the feasibility and the effectiveness of radiotherapy combined with local ablative therapies in the treatment of primary and recurrent lung cancer in terms of toxicity profile and local control rate. Six studies featuring a total of 115 patients who met eligibility criteria and 119 lesions were included. Three studies evaluated lung cancer patients with a medically inoperable condition treated with image-guided local ablative therapies followed by radiotherapy: their local control rate (LC) ranged from 75% to 91.7% with only 15 patients (19.4%) reporting local recurrence after combined modality treatment. The other three studies provided a salvage option for patients with locally recurrent NSCLC after RT: the median follow-up period varied from 8.3 to 69.3 months with an LC rate ranging from 50% to 100%. The most common complications were radiation pneumonitis (9.5%) and pneumothorax (29.8%). The proposed intervention appears to be promising in terms of toxicity profile and local control rate. Further prospective studies are need to better delineate combining LTA-RT treatment benefits in this setting. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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18 pages, 1451 KiB  

Open AccessReview

Navigating the Immune Maze: Pioneering Strategies for Unshackling Cancer Immunotherapy Resistance

by Liqin Yao, Qingqing Wang and Wenxue Ma

Cancers 2023, 15(24), 5857; https://doi.org/10.3390/cancers15245857 - 15 Dec 2023

Cited by 8 | Viewed by 1669

Abstract

Cancer immunotherapy has ushered in a transformative era in oncology, offering unprecedented promise and opportunities. Despite its remarkable breakthroughs, the field continues to grapple with the persistent challenge of treatment resistance. This resistance not only undermines the widespread efficacy of these pioneering treatments, [...] Read more.

Cancer immunotherapy has ushered in a transformative era in oncology, offering unprecedented promise and opportunities. Despite its remarkable breakthroughs, the field continues to grapple with the persistent challenge of treatment resistance. This resistance not only undermines the widespread efficacy of these pioneering treatments, but also underscores the pressing need for further research. Our exploration into the intricate realm of cancer immunotherapy resistance reveals various mechanisms at play, from primary and secondary resistance to the significant impact of genetic and epigenetic factors, as well as the crucial role of the tumor microenvironment (TME). Furthermore, we stress the importance of devising innovative strategies to counteract this resistance, such as employing combination therapies, tailoring immune checkpoints, and implementing real-time monitoring. By championing these state-of-the-art methods, we anticipate a paradigm that blends personalized healthcare with improved treatment options and is firmly committed to patient welfare. Through a comprehensive and multifaceted approach, we strive to tackle the challenges of resistance, aspiring to elevate cancer immunotherapy as a beacon of hope for patients around the world. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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17 pages, 1471 KiB  

Open AccessReview

Colorectal Cancer Stem Cells and Targeted Agents

by Haobin Zhao, Ruining Han, Zhankun Wang, Junfang Xian and Xiaosu Bai

Pharmaceutics 2023, 15(12), 2763; https://doi.org/10.3390/pharmaceutics15122763 - 12 Dec 2023

Cited by 4 | Viewed by 2161

Abstract

Since their discovery, cancer stem cells have become a hot topic in cancer therapy research. These cells possess stem cell-like self-renewal and differentiation capacities and are important factors that dominate cancer metastasis, therapy-resistance and recurrence. Worse, their inherent characteristics make them difficult to [...] Read more.

Since their discovery, cancer stem cells have become a hot topic in cancer therapy research. These cells possess stem cell-like self-renewal and differentiation capacities and are important factors that dominate cancer metastasis, therapy-resistance and recurrence. Worse, their inherent characteristics make them difficult to eliminate. Colorectal cancer is the third-most common cancer and the second leading cause of cancer death worldwide. Targeting colorectal cancer stem cells (CR-CSCs) can inhibit colorectal cancer metastasis, enhance therapeutic efficacy and reduce recurrence. Here, we introduced the origin, biomarker proteins, identification, cultivation and research techniques of CR-CSCs, and we summarized the signaling pathways that regulate the stemness of CR-CSCs, such as Wnt, JAK/STAT3, Notch and Hh signaling pathway. In addition to these, we also reviewed recent anti-CR-CSC drugs targeting signaling pathways, biomarkers and other regulators. These will help researchers gain insight into the current agents targeting to CR-CSCs, explore new cancer drugs and propose potential therapies. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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29 pages, 2646 KiB  

Open AccessReview

Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance

by Andrea Cunha, Patrícia M. A. Silva, Bruno Sarmento and Odília Queirós

Pharmaceutics 2023, 15(11), 2610; https://doi.org/10.3390/pharmaceutics15112610 - 10 Nov 2023

Cited by 6 | Viewed by 3554

Abstract

The “Warburg effect” consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and [...] Read more.

The “Warburg effect” consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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20 pages, 2401 KiB  

Open AccessEditor’s ChoiceReview

The Value of Microbes in Cancer Neoantigen Immunotherapy

by Junrui Tian and Jian Ma

Pharmaceutics 2023, 15(8), 2138; https://doi.org/10.3390/pharmaceutics15082138 - 14 Aug 2023

Cited by 1 | Viewed by 1866

Abstract

Tumor neoantigens are widely used in cancer immunotherapy, and a growing body of research suggests that microbes play an important role in these neoantigen-based immunotherapeutic processes. The human body and its surrounding environment are filled with a large number of microbes that are [...] Read more.

Tumor neoantigens are widely used in cancer immunotherapy, and a growing body of research suggests that microbes play an important role in these neoantigen-based immunotherapeutic processes. The human body and its surrounding environment are filled with a large number of microbes that are in long-term interaction with the organism. The microbiota can modulate our immune system, help activate neoantigen-reactive T cells, and play a great role in the process of targeting tumor neoantigens for therapy. Recent studies have revealed the interconnection between microbes and neoantigens, which can cross-react with each other through molecular mimicry, providing theoretical guidance for more relevant studies. The current applications of microbes in immunotherapy against tumor neoantigens are mainly focused on cancer vaccine development and immunotherapy with immune checkpoint inhibitors. This article summarizes the related fields and suggests the importance of microbes in immunotherapy against neoantigens. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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44 pages, 2410 KiB  

Open AccessReview

The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies

by Hasan Slika, Paolo Alimonti, Divyaansh Raj, Chad Caraway, Safwan Alomari, Eric M. Jackson and Betty Tyler

Cancers 2023, 15(15), 3889; https://doi.org/10.3390/cancers15153889 - 30 Jul 2023

Cited by 4 | Viewed by 3355

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with [...] Read more.

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with medulloblastoma remains dismal. Additionally, the high doses of radiation and the chemotherapeutic agents used are associated with significant short- and long-term complications and adverse effects, most notably neurocognitive delay. Hence, there is an urgent need for the development and clinical integration of targeted treatment regimens with greater efficacy and superior safety profiles. Since the adoption of the molecular-based classification of medulloblastoma into wingless (WNT) activated, sonic hedgehog (SHH) activated, group 3, and group 4, research efforts have been directed towards unraveling the genetic, epigenetic, transcriptomic, and proteomic profiles of each subtype. This review aims to delineate the progress that has been made in characterizing the neurodevelopmental and molecular features of each medulloblastoma subtype. It further delves into the implications that these characteristics have on the development of subgroup-specific targeted therapeutic agents. Furthermore, it highlights potential future avenues for combining multiple agents or strategies in order to obtain augmented effects and evade the development of treatment resistance in tumors. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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Open AccessReview

FLASH Radiotherapy and the Use of Radiation Dosimeters

by Sarkar Siddique, Harry E. Ruda and James C. L. Chow

Cancers 2023, 15(15), 3883; https://doi.org/10.3390/cancers15153883 - 30 Jul 2023

Cited by 14 | Viewed by 3531

Abstract

Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. [...] Read more.

Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. Monte Carlo (MC) simulation is a valuable tool for dose calculation in RT and has been investigated for optimizing FLASH RT. Various MC codes, such as EGSnrc, DOSXYZnrc, and Geant4, have been used to simulate dose distributions and optimize treatment plans. Accurate dosimetry is essential for FLASH RT, and radiation detectors play a crucial role in measuring dose delivery. Solid-state detectors, including diamond detectors such as microDiamond, have demonstrated linear responses and good agreement with reference detectors in UHDR and ultra-high dose per pulse (UHDPP) ranges. Ionization chambers are commonly used for dose measurement, and advancements have been made to address their response nonlinearities at UHDPP. Studies have proposed new calculation methods and empirical models for ion recombination in ionization chambers to improve their accuracy in FLASH RT. Additionally, strip-segmented ionization chamber arrays have shown potential for the experimental measurement of dose rate distribution in proton pencil beam scanning. Radiochromic films, such as Gafchromic^TM EBT3, have been used for absolute dose measurement and to validate MC simulation results in high-energy X-rays, triggering the FLASH effect. These films have been utilized to characterize ionization chambers and measure off-axis and depth dose distributions in FLASH RT. In conclusion, MC simulation provides accurate dose calculation and optimization for FLASH RT, while radiation detectors, including diamond detectors, ionization chambers, and radiochromic films, offer valuable tools for dosimetry in UHDR environments. Further research is needed to refine treatment planning techniques and improve detector performance to facilitate the widespread implementation of FLASH RT, potentially revolutionizing cancer treatment. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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