This suggests that by using HDAC inhibitors, doctors might be able to effectively "turn off" the driver of lineage plasticity and stop the growth of tumors that have become resistant to standard hormone therapies. Because these drugs are already FDA-approved for other indications, the path to clinical trials for prostate cancer patients could be significantly shorter than it would be for an entirely new compound.
"Our work implicates PROX1 as an important early driver away from androgen receptor dependence," Alumkal noted. "HDAC inhibitors can block PROX1 and reduce survival of aggressive prostate tumor models that have transitioned away from androgen receptor reliance. Our results suggest this class of drugs should be prioritized for clinical trials in patients who have aggressive prostate cancer subtypes, for which there are few treatment options."
The implications of this research are far-reaching. For patients currently facing a diagnosis of double-negative or neuroendocrine prostate cancer, the prognosis has historically been poor due to the lack of targeted therapies. By identifying PROX1 as an early marker, doctors may one day be able to use diagnostic tests to identify patients whose tumors are just beginning to undergo lineage plasticity, allowing for earlier intervention with HDAC inhibitors before the cancer becomes fully resistant.
The study was a massive collaborative effort involving dozens of researchers from various institutions. Along with lead author Zhi Duan and senior author Joshi J. Alumkal, the contributing authors include Mingchen Shi, Anbarasu Kumaraswamy, Dong Lin, Dhruv Khokhani, Yong Wang, Chao Zhang, Fiana Flores, Eva Rodansky, Olivia A. Swaim, William K. Storck, Hannah Beck, Radhika A. Patel, Erolcan Sayar, Brian P. Hanratty, Hui Xue, Xin Dong, Zoe R. Maylin, Rensheng Wan, David A. Quigley, Martin Sjostrom, Ya-Mei Hu, Faming Zhao, Zheng Xia, Siyuan Cheng, Xiuping Yu, Felix Y. Feng, Li Zhang, Rahul Aggarwal, Eric J. Small, Visweswaran Ravikumar, Arvind Rao, Karan Bedi, John K. Lee, Colm Morrissey, Ilsa Coleman, Peter S. Nelson, Eva Corey, Aaron Udager, Ryan Rebernick, Marcin P. Cieslik, Arul M. Chinnaiyan, Joel A. Yates, Michael C. Haffner, and Yuzhuo Wang.
The breadth of the research was supported by a wide array of funding sources, underscoring the importance of the findings to the medical community. Significant support was provided by multiple grants from the National Institutes of Health (NIH), including CA251245, CA282005, CA186786, P30CA046592, T90DE030859, GM147365, CA214955-01A1, CA274336, P50CA97186, and CA163227. Additional funding came from the U.S. Department of Defense, the Joint Institute for Cancer Research, the Prostate Cancer Foundation, the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Canadian Cancer Society, the BC Cancer Foundation, the Smith Family Scholar Award, the Sheppard Family Foundation, the Benioff Initiative for Prostate Cancer Research, the Silver Family Innovation Foundation, the National Science Foundation, and the Institute for Prostate Cancer Research.
As the research moves toward the clinical trial phase, the focus will remain on identifying the specific patient populations most likely to benefit from HDAC inhibition. By targeting the "shapeshifting" ability of prostate cancer cells, the team at the University of Michigan Rogel Cancer Center is opening a new chapter in the fight against one of the most challenging forms of the disease.
