Prostate-Specific Antigen Dynamics Predict Individual Responses to Intermittent Androgen Deprivation

Renee Brady, John D. Nagy, Travis A. Gerke, Tian Zhang, Andrew Z. Wang, Jingsong Zhang, Robert A. Gatenby, Heiko Enderling

May 22, 2019

Received date 9th May 19

Intermittent androgen deprivation therapy (IADT) is an attractive treatment for biochemically recurrent prostate cancer (PCa), whereby cycling treatment on and off can reduce cumulative dose, limit toxicities, and delay development of treatment resistance. We have developed a quantitative framework to simulate enrichment of prostate cancer stem cell (PCaSC) dynamics during treatment as a plausible mechanism of resistance evolution. Simulated PCa stem and non-stem cells dynamics demonstrate that PCaSC proliferation patterns correlate with longitudinal serum prostate-specific antigen (PSA) measurements in 70 PCa patients undergoing IADT.  By learning dynamics from each treatment cycle, individual model simulations predict evolution of resistance with an overall accuracy of 90% (sensitivity=57%, specificity=94%). Model simulations based on response dynamics from the first IADT cycle identify patients who would benefit from concurrent docetaxel in subsequent cycles. Our results demonstrate the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature