Urology, University of Wisconsin - Madison

Biological Impact of Senescence Induction in Prostate Cancer Therapy

Funding:

Department of Defense

Principal Investigator:

David F. Jarrard, MD

Project Summary:

We are in dire need for new, minimally toxic agents that control prostate cancer. Over the last year, roughly 30,000 men died from this disease. With improved longevity, it is likely that these numbers will increase over the next 30 years unless novel treatments are developed. Normal cells divide a limited number of times before undergoing senescence, a distinct cell process that results in the cessation of growth. Cancer cells have bypassed these senescence blocks that allows them to proliferate for extended periods of time. It is the goal of this proposal to determine if senescence can be reactivated in cancer cells, whether this results in a improved therapeutic response, and whether new agents can be identified that induce senescence.

We present preliminary data demonstrating that senescence occurs in cancer cells with selected types of chemotherapy that are found to be active in prostate cancer. A major hurdle has been the identification of senescent cells. To address this, we have attached a recent manuscript in which our laboratory has identified a number of molecular markers associated with senescence. Thus, we stand poised to address several important questions that are required prior to the application of senescence to therapy. We will determine if senescent cells inhibit the growth of surrounding cancer cells, thus acting in an additive fashion. Another aim will address whether senescence occurs in prostate cancer both in mice and in human prostate tissues after treatment with successful chemotherapy. Finally, we will identify in a 16,000 compound library, using a high-throughput robotic screening approach, those chemicals that induce senescence and we will further investigate the mechanisms through which they work.

Our laboratory is uniquely positioned to answer these questions based on our preliminary data and experience in identifying senescent cells, the assembled team of expert prostate cancer and basic science investigators, and our access to the unique and necessary resources. If this proposal is funded by the PCRP, our understanding of senescence as therapy will take a quantum leap forward which, in turn, will lead to the near term application of this knowledge to the treatment and cure of men with this disease.

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