Review
Oncology
Masaki Shiota, Shusuke Akamatsu, Shigehiro Tsukahara, Shohei Nagakawa, Takashi Matsumoto, Masatoshi Eto
Summary: Hormonal therapies are commonly used to treat advanced prostate cancer, but treatment resistance often occurs. This review summarizes the clinical landscape of AR mutations in prostate cancer and discusses their potential implications for clinical practice.
ENDOCRINE-RELATED CANCER
(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.
Review
Pharmacology & Pharmacy
Stefan A. J. Buck, Stijn L. W. Koolen, Ron H. J. Mathijssen, Ronald de Wit, Robert J. van Soest
Summary: The expanding landscape of advanced prostate cancer treatment has seen the move of ARSIs and taxane chemotherapy to earlier stages, leading to the emergence of cross-resistance as a major challenge in current clinical practice. Understanding the mechanisms of cross-resistance is crucial in order to overcome this obstacle and improve treatment outcomes.
DRUG RESISTANCE UPDATES
(2021)
Review
Biochemistry & Molecular Biology
Poornachandra Yedla, Ahmed O. Babalghith, Vindhya Vasini Andra, Riyaz Syed
Summary: Cancer treatments with targeted therapy, specifically Proteolysis-Targeting Chimeras (PROTACs), have gained significant attention for their unique mechanism of action and ability to target undruggable proteins. This review focuses on PROTACs in prostate cancer, highlighting their superiority over conventional inhibitors, and discussing the challenges and future prospects in this field. It also explores the underlying pathophysiology of prostate cancer and provides insights into the structural design and linker strategies for PROTAC molecules.
Article
Multidisciplinary Sciences
Nader Al-Nakouzi, Chris Kedong Wang, Htoo Zarni Oo, Irina Nelepcu, Nada Lallous, Charlotte B. Spliid, Nastaran Khazamipour, Joey Lo, Sarah Truong, Colin Collins, Desmond Hui, Shaghayegh Esfandnia, Hans Adomat, Thomas Mandel Clausen, Tobias Gustavsson, Swati Choudhary, Robert Dagil, Eva Corey, Yuzhuo Wang, Anne Chauchereau, Ladan Fazli, Jeffrey D. Esko, Ali Salanti, Peter S. Nelson, Martin E. Gleave, Mads Daugaard
Summary: Inhibition of the androgen receptor pathway leads to the upregulation of chondroitin sulfate (CS), which promotes the growth and metastasis of prostate cancer.
NATURE COMMUNICATIONS
(2022)
Article
Pharmacology & Pharmacy
Yun-Ho Choi, Jaeyoon Kim, Jae Young Shin, Nae-Gyu Kang, Sanghwa Lee
Summary: This study investigated the antiandrogenic effects of FMN in prostate cancer cells. FMN inhibited androgen receptor protein expression, decreased PSA level, and downregulated androgen regulated genes. FMN bound to androgen receptor and regulated androgen receptor signaling through the PI3K-AktMDM2 pathway.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
James E. Melnyk, Veronica Steri, Hao G. Nguyen, Y. Christina Hwang, John D. Gordan, Byron Hann, Felix Y. Feng, Kevan M. Shokat
Summary: The study reveals a potential therapeutic strategy for AR-V7-positive prostate cancer by combining a PKC beta inhibitor with an FDA-approved anti-androgen drug, which can repress the growth of AR-V7-positive prostate cancer cells and increase sensitivity to anti-androgen therapy.
Article
Oncology
Zemin Hou, Shengsong Huang, Zhenfei Li
Summary: Androgens are crucial in the development of prostate cancer, and targeting steroidogenesis and the androgen receptor has been effective in delaying disease progression. New generation androgen receptor pathway inhibitors like abiraterone and enzalutamide continue to emphasize the role of the androgen-AR axis, even in cases of resistance. The importance of this axis in managing the disease after resistance to current treatments, particularly in neuroendocrine prostate cancer, remains uncertain.
Article
Biochemistry & Molecular Biology
Ulrich Sommer, Tiziana Siciliano, Celina Ebersbach, Alicia-Marie K. Beier, Matthias B. Stope, Korinna Joehrens, Gustavo B. Baretton, Angelika Borkowetz, Christian Thomas, Holger H. H. Erb
Summary: PSMA protein plays an important role in the diagnosis and treatment of prostate cancer, and the activation and inhibition of androgen receptor (AR) can affect PSMA protein levels. This study found that AR activation and inhibition affect PSMA protein levels through a possible non-canonical mechanism, and low PSMA expression rates may be necessary to increase PSMA protein through androgen deprivation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Editorial Material
Oncology
Xiaoling Li, Ping Mu
Summary: Prostate cancer is a common malignancy driven by the androgen receptor pathway. Androgen deprivation therapy is the standard treatment, but the development of castration-resistant prostate cancer poses challenges. Recent research suggests that myofibroblastic cancer-associated fibroblasts induced by androgen deprivation therapy play a key role in the development of castration-resistant prostate cancer.
Article
Multidisciplinary Sciences
A. M. Mahedi Hasan, Paolo Cremaschi, Daniel Wetterskog, Anuradha Jayaram, Stephen Q. Wong, Scott Williams, Anupama Pasam, Anna Trigos, Blanca Trujillo, Emily Grist, Stefanie Friedrich, Osvaldas Vainauskas, Marina Parry, Mazlina Ismail, Wout Devlies, Anna Wingate, Mark Linch, Cristina Naceur-Lombardelli, Charles Swanton, Mariam Jamal-Hanjani, Stefano Lise, Shahneen Sandhu, Gerhardt Attard
Summary: By analyzing the genomic complexity of AR across lethal metastases from 10 prostate cancer patients, the study finds diverse and patient-specific AR gene alterations, as well as independent acquisition of related genomic changes within an individual and the existence of AR-neutral clones. The study also confirms a common clone of origin across metastases and identifies clusters of metastases with diverged autosomal copy number alterations. These findings provide insights into the heterogeneity and evolution of AR alterations in metastatic prostate cancer.
NATURE COMMUNICATIONS
(2023)
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
Jimmy L. Zhao, Karim Fizazi, Fred Saad, Kim N. Chi, Mary-Ellen Taplin, Cora N. Sternberg, Andrew J. Armstrong, Johann S. de Bono, William T. Duggan, Howard Scher
Summary: This study found that concurrent corticosteroid use (CCU) in enzalutamide-treated patients with metastatic castration-resistant prostate cancer (mCRPC) was associated with worse clinical outcomes. However, enzalutamide treatment still improved overall survival, radiographic progression-free survival, and time to prostate-specific antigen progression in these patients.
CLINICAL CANCER RESEARCH
(2022)
Article
Cell Biology
Jianneng Li, Michael Berk, Mohammad Alyamani, Navin Sabharwal, Christopher Goins, Joseph Alvarado, Mehdi Baratchian, Ziqi Zhu, Shaun Stauffer, Eric A. Klein, Nima Sharifi
Summary: The study identified that up-regulation of H6PD protein in prostate cancer tissues of men treated with enzalutamide is associated with tumor resistance. Silencing H6PD blocks NADPH generation and reverses resistance. Pharmacologic intervention of H6PD normalizes tumor metabolism and increases sensitivity to enzalutamide.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Pathology
Tobias Furlan, Alexander Kirchmair, Natalie Sampson, Martin Puhr, Martina Gruber, Zlatko Trajanoski, Frederic R. Santer, Walther Parson, Florian Handle, Zoran Culig
Summary: EP300/CREBBP inhibitors affect the MYC/ribosomal protein axis in enzalutamide-resistant cells, showing promising therapeutic implications.
AMERICAN JOURNAL OF PATHOLOGY
(2021)