Article
Multidisciplinary Sciences
Jae Duck Choi, Tae Jin Kim, Byong Chang Jeong, Hwang Gyun Jeon, Seong Soo Jeon, Min Yong Kang, Seon Yong Yeom, Seong Il Seo
Summary: Abnormal expression of ISL1 has been closely associated with cancer development and progression, with particular focus on its role in the androgen receptor-dependent prostate cancer cell growth, EMT, and enzalutamide resistance. ISL1 knockdown was found to inhibit AR activity, cell growth, and EMT in enzalutamide-resistant cells, suggesting its potential as a therapeutic target for CRPC. The study highlights the importance of downregulating ISL1 expression to overcome enzalutamide resistance and improve survival in CRPC patients.
SCIENTIFIC REPORTS
(2021)
Review
Biochemistry & Molecular Biology
David Ka-Wai Leung, Peter Ka-Fung Chiu, Chi-Fai Ng, Jeremy Yuen-Chun Teoh
Summary: The management of castration-resistant prostate cancer has seen significant progress, with three novel hormonal agents showing survival benefits in non-metastatic patients and a wider range of management options being investigated for metastatic disease.
Article
Biochemistry & Molecular Biology
Abbas Khan, Yuanshen Mao, Sana Tahreem, Dong-Qing Wei, Yanjing Wang
Summary: This study examines the impact of AR gene mutations on resistance to Enzalutamide using structural bioinformatics and molecular simulation methods. The mutations alter the binding mode of Enzalutamide, disrupting the antagonist activity by misstargeting key residues. These findings provide a structural basis for understanding resistance mechanisms and designing effective drugs.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Oncology
Frantzeska Giginis, Joshua Wang, Aaron Chavez, Manuela Martins-Green
Summary: Prostate Cancer (PCa) is the second most prevalent cancer in the world. Currently, most treatments for PCa involve Androgen Deprivation Therapy (ADT) which is not effective for metastatic Castration-Resistant Prostate Cancer (mCRPC). Decreasing the enzyme catalase, which reduces oxidative stress levels, has the potential to provide another target for Prostate Cancer therapy.
AMERICAN JOURNAL OF CANCER RESEARCH
(2023)
Article
Oncology
Pedro C. Barata, Andrea Leith, Amanda Ribbands, Rachel Montgomery, Matthew Last, Bhakti Arondekar, Jasmina Ivanova, Alexander Niyazov
Summary: The study evaluated the impact of novel hormonal therapy (NHT) and docetaxel use in metastatic castration-sensitive prostate cancer (mCSPC) on first-line treatment patterns in metastatic castration-resistant prostate cancer (mCRPC). The results suggest that physicians consider mCSPC treatment history when making first-line treatment decisions in mCRPC.
Review
Oncology
Carlo Cattrini, Orazio Caffo, Ugo De Giorgi, Alessia Mennitto, Alessandra Gennari, David Olmos, Elena Castro
Summary: This review discusses the use of apalutamide, darolutamide, and enzalutamide in patients with nmCRPC and the clinical implications of novel imaging techniques for treatment selection.
Article
Pharmacology & Pharmacy
Valeria Emma Palmieri, Giandomenico Roviello, Alberto D'Angelo, Chiara Casadei, Ugo De Giorgi, Roberta Giorgione
Summary: Important changes have occurred in prostate cancer treatment in recent years, particularly regarding non-metastatic castration-resistant prostate cancer (nmCRPC). Three drugs have been approved for high-risk disease - apalutamide, enzalutamide, and darolutamide. While clinical efficacy is comparable, darolutamide has a different toxicity profile and greater tolerance. Further trials and clinical experience are needed to determine personalized treatments for patients.
EXPERT REVIEW OF CLINICAL PHARMACOLOGY
(2021)
Correction
Medicine, General & Internal
Karim Fizazi, Neal Shore, Teuvo L. Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas, Murilo Luz, Boris Alekseev, Iris Kuss, Christian Kappeler, Amir Snapir, Toni Sarapohja, Matthew R. Smith
Summary: This article points out incorrect data regarding the application of Darolutamide in nonmetastatic, castration-resistant prostate cancer.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Review
Oncology
Mathieu Roumiguie, Xavier Paoletti, Yann Neuzillet, Romain Mathieu, Sebastien Vincendeau, Francois Kleinclauss, Arnaud Mejean, Laurent Guy, Marc Olivier Timsit, Thierry Lebret
Summary: The study compared the efficacy, safety, and health-related quality of life of apalutamide, enzalutamide, and darolutamide in patients with nonmetastatic castration-resistant prostate cancer. Results showed that all three drugs significantly prolonged survival compared to placebo and were generally well tolerated. Therefore, drug selection in clinical practice should be based on individual patient factors such as tolerability, drug interactions, and comorbidities.
Review
Pharmacology & Pharmacy
Maoping Cai, Xian-Lu Song, Xin-An Li, Mingkun Chen, Jiading Guo, Dong Hua Yang, Zhanghui Chen, Shan-Chao Zhao
Summary: Castration-resistant prostate cancer (CRPC), especially metastatic CRPC (mCRPC), is a common and deadly malignancy in men worldwide. The natural or acquired drug resistance of CRPC makes clinical treatment challenging. Understanding the mechanisms of drug resistance in mCRPC is essential for developing effective therapeutic strategies. This review focuses on new insights in mCRPC treatment and discusses the mechanisms governing resistance to new drugs, such as taxanes, androgen receptor signaling inhibitors (ARSIs), and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Strategies to overcome drug resistance based on these mechanisms are also discussed.
DRUG RESISTANCE UPDATES
(2023)
Review
Biochemistry & Molecular Biology
Stephen Y. C. Choi, Caroline Fidalgo Ribeiro, Yuzhuo Wang, Massimo Loda, Stephen R. Plymate, Takuma Uo
Summary: This article discusses the urgent need to explore new actionable targets other than the androgen receptor to improve treatment outcomes for castration-resistant prostate cancer. Tumor metabolism is considered a hallmark of cancer and understanding its relationship with androgen receptor signaling, genetic drivers, and the tumor microenvironment is important for identifying metabolic vulnerabilities. The article also provides an overview of current metabolism-based pharmacological strategies for treating castration-resistant prostate cancer.
Review
Andrology
Koji Hatano, Norio Nonomura
Summary: The introduction of novel therapeutic agents has expanded the treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). However, cross-resistance between treatments may occur, and the optimal treatment sequence must be considered.
WORLD JOURNAL OF MENS HEALTH
(2022)
Article
Oncology
Ke Gao, Xiaoshun Li, Jianxin Ni, Bin Wu, Jiaheng Guo, Rui Zhang, Guojun Wu
Summary: This article introduces the roles of dysregulation of different subclasses of non-coding RNAs (ncRNAs) in the development of castration-resistant prostate cancer (CRPC) progression and Enzalutamide (Enz) resistance. The mechanisms of Enz resistance, including AR-splice variant-7 (AR-V7), mutations, circRNAs, and lncRNAs that act as miRNA sponges, are discussed. The contributions of epithelial-mesenchymal transition and glucose metabolism to Enz resistance are also highlighted. The article summarizes the different mechanisms of miRNAs, lncRNAs, and circRNAs in the progression of CRPC and Enz resistance, and discusses future therapeutic strategies against Enz resistance.
Article
Biochemistry & Molecular Biology
Kai Lu, Zheng Li, Qiang Hu, Jianfei Sun, Ming Chen
Summary: In this work, a CRPC-targeting nanocomposite with fine biocompatibility was developed using CRPC cell membranes as biomimetic vectors. The encapsulated chemotherapy drug DTX was successfully delivered to the targeting site, improving therapeutic efficiency. The use of CRPC cell membrane coating enabled homotypic targeting and significantly improved therapeutic efficacy in a mice model bearing CRPC tumors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Meng Wu, Rongyu Zhang, Zixiong Zhang, Ning Zhang, Chenfan Li, Yongli Xie, Haoran Xia, Fangjiao Huang, Ruoying Zhang, Ming Liu, Xiaoyu Li, Shan Cen, Jinming Zhou
Summary: A bifunctional small molecule called Z15 was discovered and identified as an effective and selective androgen receptor (AR) antagonist and degrader. It interacts with the ligand-binding domain (LBD) and activation function-1 region of AR, promoting its degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 successfully suppressed AR, AR mutants, and AR splice variants (ARVs) transcription activity, overcoming resistance to second-generation antiandrogens (SGAs) induced by AR LBD mutations, amplification, and ARVs. This highlights the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
Article
Biochemistry & Molecular Biology
Mariia Radaeva, Fuqiang Ban, Fan Zhang, Eric LeBlanc, Nada Lallous, Paul S. Rennie, Martin E. Gleave, Artem Cherkasov
Summary: The research focused on further developing small molecule inhibitors of AR DBD dimerization and demonstrated their improved biological activity in various assays, including mammalian two-hybrid analysis, inhibition of AR-V7 transcriptional activity, and enhanced microsomal stability. These findings provide a foundation for the development of AR inhibitors with entirely novel mechanisms of action.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Victor M. Matias-Barrios, Mariia Radaeva, Yi Song, Zaccary Alperstein, Ahn R. Lee, Veronika Schmitt, Joseph Lee, Fuqiang Ban, Ning Xie, Jianfei Qi, Nada Lallous, Martin E. Gleave, Artem Cherkasov, Xuesen Dong
Summary: TOP2 catalytic inhibitors effectively suppress cancer cell proliferation with low cytotoxicity. The newly discovered compound T60 shows promise as a potential anticancer drug.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Fuqiang Ban, Eric Leblanc, Ayse Derya Cavga, Chia-Chi Flora Huang, Mark R. Flory, Fan Zhang, Matthew E. K. Chang, Helene Morin, Nada Lallous, Kriti Singh, Martin E. Gleave, Hisham Mohammed, Paul S. Rennie, Nathan A. Lack, Artem Cherkasov
Summary: This study reports the discovery of a novel AR-NTD covalent inhibitor VPC-220010, which selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines by disrupting interactions between AR and known coactivators and coregulatory proteins. VPC-220010 shows promise as a small molecule that can be further optimized into an effective AR-NTD inhibitor for the treatment of CRPC.
Article
Biochemistry & Molecular Biology
Anh-Tien Ton, Jane Foo, Kriti Singh, Joseph Lee, Anastasia Kalyta, Helene Morin, Carl Perez, Fuqiang Ban, Eric Leblanc, Nada Lallous, Artem Cherkasov
Summary: The Myc family of transcription factors plays a crucial role in the development and progression of various cancers, including prostate cancer. Neuroendocrine prostate cancer, a lethal form of PCa, lacks effective treatment options. Therefore, there is an urgent need to explore new therapeutic approaches for treating patients with neuroendocrine prostate cancer. In this study, a potential small molecule inhibitor targeting the N-Myc-Max DNA binding domain was discovered through computer-aided drug design, showing promising anti-N-Myc and antiproliferative activities.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Mariia Radaeva, Huifang Li, Eric LeBlanc, Kush Dalal, Fuqiang Ban, Fabrice Ciesielski, Bonny Chow, Helene Morin, Shannon Awrey, Kriti Singh, Paul S. Rennie, Nada Lallous, Artem Cherkasov
Summary: The mutation-driven transformation of anti-androgen drugs into receptor agonists poses a challenge for prostate cancer treatment. We developed inhibitors targeting the receptor's DNA-binding domain and identified a few that exhibited partial agonistic effects towards mutated forms of the receptor. By studying the molecular basis, we designed derivatives to eliminate cross-reactivity with the receptor's androgen binding site while maintaining anti-DNA-binding domain potency.
Article
Biochemistry & Molecular Biology
Fan Zhang, Maitree Biswas, Shabnam Massah, Joseph Lee, Shreyas Lingadahalli, Samantha Wong, Christopher Wells, Jane Foo, Nabeel Khan, Helene Morin, Neetu Saxena, Sonia H. Y. Kung, Bei Sun, Ana Karla Parra Nunez, Christophe Sanchez, Novia Chan, Lauren Ung, Umut Berkay Altintas, Jennifer M. Bui, Yuzhuo Wang, Ladan Fazli, Htoo Zarni Oo, Paul S. Rennie, Nathan A. Lack, Artem Cherkasov, Martin E. Gleave, Jorg Gsponer, Nada Lallous
Summary: Numerous cancers, including prostate cancer (PCa), rely on transcription programs driven by specific genomic regions called super-enhancers. The androgen receptor (AR), the main oncogenic driver in PCa, forms liquid-like foci in different PCa models, and this foci formation is correlated with AR transcriptional activity. AR antagonists inhibit foci formation and phase separation of AR, suggesting that enhanced compartmentalization of AR and coactivators may play a crucial role in the activation of oncogenic transcription programs in androgen-dependent PCa.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Oncology
Mariia Radaeva, Chia-Hao Ho, Ning Xie, Sijie Zhang, Joseph Lee, Liangliang Liu, Nada Lallous, Artem Cherkasov, Xuesen Dong
Summary: This study identified several new Lin28 inhibitors that can block cancer cell stemness and may be further developed into drugs for cancer therapy.
Article
Oncology
Victor M. Matias-Barrios, Mariia Radaeva, Chia-Hao Ho, Joseph Lee, Hans Adomat, Nada Lallous, Artem Cherkasov, Xuesen Dong
Summary: DNA topoisomerase II (TOP2) is a drug target for many types of cancers. Clinically used TOP2 inhibitors can have serious side effects, but new inhibitors with different mechanisms of action are being developed to effectively control tumor growth. The compound T638, a catalytic TOP2 inhibitor, shows promising potential as an anticancer drug candidate with limited genotoxicity to cells.