This finding is particularly significant because it suggests that a class of drugs already available and safety-tested could be repurposed to treat a group of patients who currently have very few options.
"Our work implicates PROX1 as an important early driver away from androgen receptor dependence," Alumkal said. "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 the study extend beyond just identifying a new drug target; it provides a clearer map of how prostate cancer evolves. By identifying PROX1 as an early marker, clinicians may eventually be able to predict which patients are at the highest risk of developing resistance, potentially allowing for earlier intervention with HDAC inhibitors before the cancer becomes fully untreatable.
The research was a massive collaborative effort involving a wide array of specialists and institutions. Co-authors on the study included 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 scale of the project was matched by the breadth of its support. Funding for the research was provided by numerous National Institutes of Health (NIH) grants, including CA251245, CA282005, CA186786, P30CA046592, T90DE030859, GM147365, CA214955-01A1, CA274336, P50CA97186, and CA163227. Additional support came from several U.S. Department of Defense grants (W81XWH-22-1-0833, HT94252410252, W81XWH2110539), 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 oncology community looks toward the next steps, the focus will likely shift to designing clinical trials that specifically enroll patients with the double-negative and neuroendocrine subtypes of prostate cancer. For the Rogel Cancer Center team, the hope is that by targeting the mechanisms of lineage plasticity, they can stop the "chameleon-like" behavior of prostate cancer and provide more durable outcomes for those facing the most aggressive forms of the disease.
