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21 pages, 5978 KiB

Open AccessArticle

Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments

by Enzo M. Scutigliani, Yongxin Liang, Marloes IJff, Hans Rodermond, Xionge Mei, Miriam P. Korver, Vaneesha S. Orie, Ron A. Hoebe, Daisy I. Picavet, Arlene Oei, Roland Kanaar and Przemek M. Krawczyk

Cancers 2022, 14(21), 5250; https://doi.org/10.3390/cancers14215250 - 26 Oct 2022

Cited by 6 | Viewed by 2236

Abstract

Hyperthermia is being used as a radio- and chemotherapy sensitizer for a growing range of tumor subtypes in the clinic. Its potential is limited, however, by the ability of cancer cells to activate a protective mechanism known as the heat stress response (HSR). [...] Read more.

Hyperthermia is being used as a radio- and chemotherapy sensitizer for a growing range of tumor subtypes in the clinic. Its potential is limited, however, by the ability of cancer cells to activate a protective mechanism known as the heat stress response (HSR). The HSR is marked by the rapid overexpression of molecular chaperones, and recent advances in drug development make their inhibition an attractive option to improve the efficacy of hyperthermia-based therapies. Our previous in vitro work showed that a single, short co-treatment with a HSR (HSP90) inhibitor ganetespib prolongs and potentiates the effects of hyperthermia on DNA repair, enhances hyperthermic sensitization to radio- and chemotherapeutic agents, and reduces thermotolerance. In the current study, we first validated these results using an extended panel of cell lines and more robust methodology. Next, we examined the effects of hyperthermia and ganetespib on global proteome changes. Finally, we evaluated the potential of ganetespib to boost the efficacy of thermo-chemotherapy and thermo-radiotherapy in a xenograft murine model of cervix cancer. Our results revealed new insights into the effects of HSR inhibition on cellular responses to heat and show that ganetespib could be employed to increase the efficacy of hyperthermia when combined with radiation. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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17 pages, 2947 KiB

Open AccessArticle

Cytospin-A Regulates Colorectal Cancer Cell Division and Migration by Modulating Stability of Microtubules and Actin Filaments

by Fan Fan, Jason Roszik, Ling Xia, Susmita Ghosh, Rui Wang, Xiangcang Ye, David Hawke, Lee M. Ellis and Rajat Bhattacharya

Cancers 2022, 14(8), 1977; https://doi.org/10.3390/cancers14081977 - 14 Apr 2022

Cited by 3 | Viewed by 2160

Abstract

Proteins that interact with cytoskeletal elements play important roles in cell division and are potentially important targets for therapy in cancer. Cytospin-A (CYTSA), a protein known to interact with actin and microtubules, has been previously described to be important in various developmental disorders, [...] Read more.

Proteins that interact with cytoskeletal elements play important roles in cell division and are potentially important targets for therapy in cancer. Cytospin-A (CYTSA), a protein known to interact with actin and microtubules, has been previously described to be important in various developmental disorders, including oblique facial clefting. We hypothesized that CYTSA plays an important role in colorectal cancer (CRC) cell division. The effects of CYTSA depletion on CRC cell proliferation were analyzed using cell growth assays, microscopic analyses of live and fixed cells, and time-lapse imaging. CYTSA depletion led to inhibition of cell proliferation, significant increases in CRC cell death, and accumulation of doublet cells during and following cell division. Depletion of CYTSA also resulted in strong inhibition of CRC cell migration and invasion. Mechanistically, CYTSA depletion resulted in significant decreases in the stability of microtubules and altered polymerization of actin filaments in CRC cells. Finally, bioinformatic analyses were performed to determine the correlation between CYTSA expression and survival of patients with CRC. Interestingly, a strong correlation between high CYTSA expression and poor survival was observed in the TCGA adenocarcinoma data set but not in an independent data set. Since inhibiting CYTSA significantly reduces CRC cell proliferation, migration, and invasion, targeting CYTSA may be a potential novel therapeutic option for patients with metastatic CRC. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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22 pages, 72889 KiB

Open AccessArticle

Immune Landscape and an RBM38-Associated Immune Prognostic Model with Laboratory Verification in Malignant Melanoma

by Jinfang Liu, Jun Xu, Binlin Luo, Jian Tang, Zuoqiong Hou, Zhechen Zhu, Lingjun Zhu, Gang Yao and Chujun Li

Cancers 2022, 14(6), 1590; https://doi.org/10.3390/cancers14061590 - 21 Mar 2022

Cited by 3 | Viewed by 2554

Abstract

Background: Current studies have revealed that RNA-binding protein RBM38 is closely related to tumor development, while its role in malignant melanoma remains unclear. Therefore, this research aimed to investigate the function of RBM38 in melanoma and the prognosis of the disease. Methods: Functional [...] Read more.

Background: Current studies have revealed that RNA-binding protein RBM38 is closely related to tumor development, while its role in malignant melanoma remains unclear. Therefore, this research aimed to investigate the function of RBM38 in melanoma and the prognosis of the disease. Methods: Functional experiments (CCK-8 assay, cell colony formation, transwell cell migration/invasion experiment, wound healing assay, nude mouse tumor formation, and immunohistochemical analysis) were applied to evaluate the role of RBM38 in malignant melanoma. Immune-associated differentially expressed genes (DEGs) on RBM38 related immune pathways were comprehensively analyzed based on RNA sequencing results. Results: We found that high expression of RBM38 promoted melanoma cell proliferation, invasion, and migration, and RBM38 was associated with immune infiltration. Then, a five-gene (A2M, NAMPT, LIF, EBI3, and ERAP1) model of RBM38-associated immune DEGs was constructed and validated. Our signature showed superior prognosis capacity compared with other melanoma prognostic signatures. Moreover, the risk score of our signature was connected with the infiltration of immune cells, immune-regulatory proteins, and immunophenoscore in melanoma. Conclusions: We constructed an immune prognosis model using RBM38-related immune DEGs that may help evaluate melanoma patient prognosis and immunotherapy modalities. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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9 pages, 1036 KiB

Open AccessArticle

Salvage Radiotherapy versus Observation for Biochemical Recurrence following Radical Prostatectomy for Prostate Cancer: A Matched Pair Analysis

by Derya Tilki, Felix Preisser, Reinhard Thamm, Raisa S. Pompe, Felix K.-H. Chun, Markus Graefen, Alessandra Siegmann, Dirk Böhmer, Volker Budach and Thomas Wiegel

Cancers 2022, 14(3), 740; https://doi.org/10.3390/cancers14030740 - 31 Jan 2022

Cited by 8 | Viewed by 2884

Abstract

Background: Salvage radiotherapy (SRT) improves oncologic outcomes in prostate cancer (PCa) patients who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, evidence on hard clinical endpoints is scarce. We compare long-term oncologic outcomes of SRT versus no radiotherapy (noRT) in patients with [...] Read more.

Background: Salvage radiotherapy (SRT) improves oncologic outcomes in prostate cancer (PCa) patients who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, evidence on hard clinical endpoints is scarce. We compare long-term oncologic outcomes of SRT versus no radiotherapy (noRT) in patients with BCR after RP. Patients and methods: Within a multi-institutional database, we identified patients with BCR after RP between 1989 and 2016 for PCa. Patients with lymph node invasion, with adjuvant radiotherapy, or with additional androgen deprivation therapy at BCR were excluded. In all patients with SRT, SRT was delivered to the prostatic bed only. Propensity score matching (PSM) was performed to account for differences in pathologic tumor characteristics. Kaplan–Meier analyses and Cox regression models tested the effect of SRT versus no RT on metastasis-free (MFS) and overall survival (OS). Results: Of 1832 patients with BCR, 32.9% (n = 603) received SRT without ADT. The median follow-up was 95.9 months. Median total SRT dose was 70.2 Gy. After 1:1 PSM, at 15 years after RP, MFS and OS rates were 84.3 versus 76.9% (p < 0.001) and 85.3 versus 74.4% (p = 0.04) for SRT and noRT, respectively. In multivariable Cox regression models, SRT was an independent predictor for metastasis (HR: 0.37, p < 0.001) and OS (HR: 0.64, p = 0.03). Conclusion: This is the first matched-pair analysis investigating the impact of SRT versus observation only in post-RP recurrent PCa. After compensating for established risk factors, SRT was associated with better long-term MFS and OS. These results on clinical endpoints underline the curative potential of SRT. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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18 pages, 4600 KiB

Open AccessArticle

Nuclear Localization of BRAF^V600E Is Associated with HMOX-1 Upregulation and Aggressive Behavior of Melanoma Cells

by Mourad Zerfaoui, Eman Toraih, Emmanuelle Ruiz, Youssef Errami, Abdallah S. Attia, Moroz Krzysztof, Zakaria Y. Abd Elmageed and Emad Kandil

Cancers 2022, 14(2), 311; https://doi.org/10.3390/cancers14020311 - 9 Jan 2022

Cited by 6 | Viewed by 2573

Abstract

Background: Previously, we have demonstrated that nuclear BRAF^V600E is associated with melanoma aggressiveness and vemurafenib resistance. However, the underlying mechanisms of how nuclear localization of BRAF^V600E promotes cell aggressiveness have not yet been investigated. Despite therapeutic advancements targeting cutaneous melanoma, unknown [...] Read more.

Background: Previously, we have demonstrated that nuclear BRAF^V600E is associated with melanoma aggressiveness and vemurafenib resistance. However, the underlying mechanisms of how nuclear localization of BRAF^V600E promotes cell aggressiveness have not yet been investigated. Despite therapeutic advancements targeting cutaneous melanoma, unknown cellular processes prevent effective treatment for this malignancy, prompting an urgent need to identify new biological targets. This study aims to explore the association of inducible heme oxygenase 1 (HMOX-1) with nuclear BRAF^V600E in promoting melanoma aggressiveness. Methods: Proteomics analysis was performed to identify the interacting partner(s) of nuclear BRAF^V600E. Immunohistochemistry was applied to evaluate the levels of HMOX-1 and nuclear BRAF^V600E expression in melanoma and adjacent healthy tissues. Immunofluorescence assessed the nuclear localization of BRAF^V600E in vemurafenib-resistant A375R melanoma cells. Further study of HMOX-1 knockdown or BRAF^V600E overexpression in melanoma cells suggested a role for HMOX-1 in the regulation of cell proliferation in vivo and in vitro. Finally, Western blot analysis was performed to confirm the pathway by which HMOX-1 mediates Akt signaling. Results: Proteomics results showed that HMOX-1 protein expression was 10-fold higher in resistant A375R cells compared to parental counterpart cells. In vitro and in vivo results illustrate that nuclear BRAF^V600E promotes HMOX-1 overexpression, whereas HMOX-1 reduction represses melanoma cell proliferation and tumor growth. Mechanistic studies revealed that HMOX-1 was associated with nuclear BRAF^V600E localization, thus promoting melanoma proliferation via a persistent activation of the AKT pathway. Conclusions: Our results highlight a previously unknown mechanism in which the nuclear BRAF^V600E/HMOX-1/AKT axis plays an essential role in melanoma cell proliferation. Targeting HMOX-1 could be a novel method for treating melanoma patients who develop BRAF inhibitor resistance. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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11 pages, 2823 KiB

Open AccessArticle

Landscape of Immune-Related Markers and Potential Therapeutic Targets in Soft Tissue Sarcoma

by Jason Roszik, Lisa Maria Mustachio, John A. Livingston, Roman Groisberg, Roberto Carmagnani Pestana, Vivek Subbiah and Anthony P. Conley

Cancers 2021, 13(20), 5249; https://doi.org/10.3390/cancers13205249 - 19 Oct 2021

Cited by 4 | Viewed by 2651

Abstract

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key [...] Read more.

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key immunotherapy target genes are present in sarcomas. Here, we extend our findings by demonstrating that sarcomas with a relatively high mutational load are likely to be more sensitive to immunotherapy compared to sarcomas with a lower mutation load. We also show that sarcomas with a higher mutation load are associated with the expression of key immune-related genes. We found that CD8+ T cells are present in sarcoma subtypes and that PD-L2 is highly expressed. These findings further define potential mechanisms behind the immunotherapy response of specific sarcoma subtypes and can be used to develop more optimal treatments in the future. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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17 pages, 15255 KiB

Open AccessArticle

Extracorporeal Shock Wave Enhances the Cisplatin Efficacy by Improving Tissue Infiltration and Cellular Uptake in an Upper Urinary Tract Cancer Animal and Human-Derived Organoid Model

by Hao-Lun Luo, Hui-Ying Liu, Yin-Lun Chang, Yu-Li Su, Chun-Chieh Huang, Xin-Jie Lin and Yao-Chi Chuang

Cancers 2021, 13(18), 4558; https://doi.org/10.3390/cancers13184558 - 11 Sep 2021

Cited by 7 | Viewed by 2751

Abstract

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare cancer with a poor prognosis if diagnosed at an advanced stage. Although cisplatin-based chemotherapy is a common treatment strategy, it has a limited response rate. Shock wave lithotripsy is a common treatment for [...] Read more.

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare cancer with a poor prognosis if diagnosed at an advanced stage. Although cisplatin-based chemotherapy is a common treatment strategy, it has a limited response rate. Shock wave lithotripsy is a common treatment for upper urinary tract stones. Low-energy shock waves (LESWs) temporarily increase tissue permeability and enhance drug penetration to the targeted tissue. However, no study has investigated the efficacy of the combination of shock wave lithotripsy and chemotherapy in UTUC. Hence, in this study, we aimed to identify the potential application of the combination of LESW and chemotherapy in UTUC. We evaluated the synergistic effects of LESW and cisplatin in vitro, in vivo, and in patient-derived organoid (PDO) models. Compared with cisplatin alone, the combination treatment caused more significant tumour suppression in vitro and in animal models, without increased toxicity. Histological examination showed that compared with animals treated with cisplatin alone, those who received the combination treatment showed more deteriorated cell arrangement and cell oedema. Moreover, LESW improved the cytotoxicity of cisplatin in the preclinical PDO model of UTUC. Thus, LESW combined with cisplatin is a potential new antitumour strategy for improving the treatment response in locally advanced UTUC. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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15 pages, 1545 KiB

Open AccessArticle

A Targeted-Covalent Inhibitor of 17β-HSD1 Blocks Two Estrogen-Biosynthesis Pathways: In Vitro (Metabolism) and In Vivo (Xenograft) Studies in T-47D Breast Cancer Models

by Donald Poirier, Jenny Roy and René Maltais

Cancers 2021, 13(8), 1841; https://doi.org/10.3390/cancers13081841 - 13 Apr 2021

Cited by 10 | Viewed by 4293

Abstract

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays an important role in estrogen-dependent breast tumor growth. In addition to being involved in the production of estradiol (E2), the most potent estrogen in women, 17β-HSD1 is also responsible for the production of 5-androsten-3β,17β-diol (5-diol), a weaker [...] Read more.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays an important role in estrogen-dependent breast tumor growth. In addition to being involved in the production of estradiol (E2), the most potent estrogen in women, 17β-HSD1 is also responsible for the production of 5-androsten-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17β-HSD1 is therefore a target of choice for the treatment of estrogen-dependent diseases such as breast cancer and endometriosis. After we developed the first targeted-covalent (irreversible) and non-estrogenic inhibitor of 17β-HSD1, a molecule named PBRM, our goal was to demonstrate its therapeutic potential. Enzymatic assays demonstrated that estrone (E1) and dehydroepiandrosterone (DHEA) were transformed into E2 and 5-diol in T-47D human breast cancer cells, and that PBRM was able to block these transformations. Thereafter, we tested PBRM in a mouse tumor model (cell-derived T-47D xenografts). After treatment of ovariectomized (OVX) mice receiving E1 or DHEA, PBRM given orally was able to reduce the tumor growth at the control (OVX) level without any observed toxic effects. Thanks to its irreversible type of inhibition, PBRM retained its anti-tumor growth effect, even after reducing its frequency of administration to only once a week, a clear advantage over reversible inhibitors. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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Review

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26 pages, 6659 KiB

Open AccessReview

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

by Kazumasa Wakamatsu, Akira Ito, Yasuaki Tamura, Tokimasa Hida, Takafumi Kamiya, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito and Kowichi Jimbow

Cancers 2022, 14(22), 5588; https://doi.org/10.3390/cancers14225588 - 14 Nov 2022

Cited by 4 | Viewed by 2363

Abstract

Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo–dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout [...] Read more.

Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo–dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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13 pages, 1698 KiB

Open AccessReview

Targeted Therapies in Advanced and Metastatic Urothelial Carcinoma

by Andrew B. Katims, Peter A. Reisz, Lucas Nogueira, Hong Truong, Andrew T. Lenis, Eugene J. Pietzak, Kwanghee Kim and Jonathan A. Coleman

Cancers 2022, 14(21), 5431; https://doi.org/10.3390/cancers14215431 - 4 Nov 2022

Cited by 7 | Viewed by 3674

Abstract

This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an [...] Read more.

This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an urgent need for alternative therapies. The advent of next-generation sequencing has allowed widespread comprehensive molecular characterization of urothelial tumors and, subsequently, the development of therapies targeting specific molecular pathways implicated in carcinogenesis such as FGFR inhibition, Nectin-4, Trop-2, and HER2 targeting. As these therapies are demonstrated to be effective in the second-line setting, they will be advanced in the treatment paradigm to localized and even non-muscle invasive disease. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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34 pages, 2626 KiB

Open AccessReview

CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

by Aaron R. Waddell, Haojie Huang and Daiqing Liao

Cancers 2021, 13(12), 2872; https://doi.org/10.3390/cancers13122872 - 8 Jun 2021

Cited by 58 | Viewed by 11289

Abstract

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in [...] Read more.

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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22 pages, 13483 KiB

Open AccessReview

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

by Hai Huang, Mee-Hyun Lee, Kangdong Liu, Zigang Dong, Zeayoung Ryoo and Myoung Ok Kim

Cancers 2021, 13(9), 2232; https://doi.org/10.3390/cancers13092232 - 6 May 2021

Cited by 22 | Viewed by 4638

Abstract

T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and [...] Read more.

T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and melanoma, and it is associated with increased development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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26 pages, 464 KiB

Open AccessReview

Targeted Cancer Therapy: What’s New in the Field of Neuroendocrine Neoplasms?

by Anna La Salvia, Paula Espinosa-Olarte, Maria Del Carmen Riesco-Martinez, Beatriz Anton-Pascual and Rocío Garcia-Carbonero

Cancers 2021, 13(7), 1701; https://doi.org/10.3390/cancers13071701 - 3 Apr 2021

Cited by 21 | Viewed by 4191

Abstract

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also [...] Read more.

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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