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Prostate Cancer Research

Brett S. Carver, MD

The David H. Koch – PCF Young Investigator

Brett S. Carver, MD - Memorial Sloan-Kettering Cancer Center, New York, NY

Despite advances in the early detection and management of prostate cancer, hormone-refractory disease remains the second most common cause of male cancer deaths in the United States. Inhibition of the androgen receptor (AR), a key signaling pathway responsible for promoting prostate cancer cell growth, invasion and survival, remains a major target for prostate cancer treatment. Another critical signaling pathway, the PI3K pathway, is frequently activated in primary and metastatic prostate cancer. Activation of the PI3K pathway and molecular alterations promoting AR signaling are associated with the development of hormone refractory disease. A number of novel inhibitors of the PI3K and AR pathways are in early clinical development and are promising therapeutic agents for men with prostate cancer.

Dr. Carver’s research will further define the role of the PI3K pathway in promoting hormone-refractory disease, identify which compounds targeting the PI3K and AR pathways provide maximum therapeutic potential, and identify molecular alterations that predict therapeutic response. Collectively this work will identify which combination of therapeutic agents will provide the greatest survival benefit and for which patients.

2011 PCF Challenge Award

Howard Scher, MD - Memorial Sloan-Kettering Cancer Center

Development of Combined Inhibition of AR and PI3K Signaling as a Therapeutic Strategy for Advanced Prostate Cancer

Co-Investigators: Charles Sawyers, MD; Brett Carver, MD; Neal Rosen, MD, PhD

Cell signaling in cancer causes uncontrolled cell growth and many clinical properties of cancer, such as metastases. Two major pathways of cell signaling in prostate cancer are initiated through a cascade of biochemical pathways. One is regulated through the androgen receptor (AR), the engine of prostate cancer, another is called PI3 Kinase (PI3K) which responds to growth factors on the outside of the cell that send signals for inappropriate cell growth. This team recently showed that targeting just one of these pathways in anticancer therapy has limited benefit because cancer cells adapt to the medication by turning on the other pathway. Therefore, it is crucial to target both the PI3K and AR pathways through combination therapy for effective and durable treatment. Dr. Scher and his team plan to inhibit individual steps in the PI3K pathway and investigate the cancer cell adaptation and survival response in detail. The technical plan will involve investigations of the results of inhibiting either of these pathways and the benefit of combined therapy. This information will then be used to design clinical trials that co-target these two dominant signaling pathways in prostate cancer patients.

Potential patient benefit: Successful clinical trials with combined signaling inhibition with medications against PI3K and AR will provide patients with improved therapy for advanced prostate cancer and better outcomes.

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