The goal of this proposal is to investigate how we can use the molecular actions that cause patients with prostate cancer to develop more advanced or deadly disease to customize the therapeutic maneuvers necessary to improve efficacy or to avoid unnecessary toxicities and ineffective therapies. The research plan I propose is at the core of my training as a physician researcher investigator. The training plan combines formal coursework, clinical and basic science laboratory studies, participation in the Career Development Program of the MSKCC Specialized Program of Research Excellence (SPORE) in Prostate Cancer, and clinical trials, all under the mentorship of Howard I. Scher, M.D., an accomplished physician-investigator. This comprehensive program will give me the background necessary to improve the treatment of prostate cancer with the ultimate goal of developing a paradigm for cure.

Any specific anticancer drug is best used in patients whose disease will respond to that therapy. With prostate cancer, however, physicians lack the means to predict whether a given man's cancer is likely to respond to a specific therapy. In addition, once therapy has begun, assessing whether the cancer is indeed responding is often a slow and uncertain process. Therefore, patients with prostate cancer need better medical tests to establish what kind of chemotherapy is best suited for their particular tumor. Specifically, there is need for a test to find which factors are stimulating the cancer cells to grow in an individual patient at the time chemotherapy is considered.

New markers of tumor response to treatment are likely to be useful for predicting whether a given patient's tumor will respond to specific treatments. Although drug development is beyond the scope of this proposal, the expression at high levels of targets that promote the growth or spread of the cancer will be studied in order to predict if the respective patient will benefit from the specific targeted therapy. Physicians can readily analyze markers in the prostate biopsy that was taken when the patient was initially diagnosed with cancer. Prostate cancer, however, changes characteristics over the course of the disease, so markers in the initial prostate biopsy may no longer be relevant in patients with advanced prostate cancer, that is, prostate cancer that has spread throughout the body. Tumor samples are difficult to obtain from patients with advanced prostate cancer, because attempts to biopsy the cancer at this stage often fail and the attempt may cause side effects to the patient.

This study aims to overcome this problem by developing methods for analyzing markers in circulating tumor cells, which are tumor cells that have broken away from the main tumor and entered the blood. In earlier research, we found it feasible to obtain circulating prostate tumor cells from a standard blood sample. Here, I propose to adapt the tests for prostate cancer markers for use in circulating tumor cells. The true validation of any biomarker is to confirm if these tests can truly predict whether a patient with advanced prostate cancer can benefit from a given treatment, which will be tested in the setting of modern therapies. The only risk these tests will pose to the patient is the minor risks involved in obtaining a blood sample, such as bruising or local pain.

Under this proposal, I propose an integration of my interest in laboratory investigation, clinical research, and hospital clinical laboratory. The resulting training program will streamline my development as an expert physician-scientist ready to translate new discoveries to the bedside. The work is expected to benefit patients with advanced prostate cancer by helping physicians select the best treatment for the individual. It is feasible that patients will benefit within 5 to 7 years. In the longer term, the work will speed the process of drug development, bringing new drugs to patients faster and predicting tumor response with minimally invasive tools.