R01CA274967

Functional Characterization and Development of Therapeutic Paradigms for DNA Damage Repair (DDR)-Deficient Lethal Prostate Cancer - Abstract

A leading contributor to the significant mortality burden of prostate cancer, the second cause of cancer death among U.S. men, is the short-lived efficacy of androgen deprivation therapy (ADT), the mainstay of care for advanced and symptomatic disease. Increasingly alterations in DNA damage repair (DDR) genes, predominantly BRCA2, have been linked to ADT resistance and poor prognosis.

We previously showed that deleterious alteration of BRCA2 is sufficient to induce ADT resistance in castration-sensitive prostate cancer (PC) cells. Our current proposal will investigate the molecular mechanism underlying BRCA2 loss/mutation-induced ADT resistance and progression to lethal prostate cancer.

Using a panel of 107 DDR-associated genes from the ProRepair B cohort, we made the novel observation that ~82% of patients with mCRPC harbor alterations of one or more DDR genes. Herein, we aim to comprehensively investigate the role of DDR alterations (other than BRCA2) in the development of mCRPC and resistance to therapy.

To do so, we will use CRISPR screening to prospectively investigate how the gain or loss-of-function alterations of DDR genes induce castration resistance. We have observed high expression levels of prostate-specific membrane antigen (PSMA) in response to the loss of BRCA2 and other DDR genes (e.g., ATM).

Our second aim will investigate the impact of PSMA-targeted radiotherapy with [177Lu]-PSMA-617 and PARP inhibitor combination in BRCA2/DDR-deficient PC. Prostate cancer is predominantly resistant to immunotherapy. Since BRCA2-deficient cells also exhibit higher PSMA expression and are possibly immunogenic due to increased genomic instability, we will explore the effect of PSMA-targeted CAR T cells on BRCA2-deficient prostate cancer.

Finally, as two PARP inhibitors (olaparib and rucaparib) have been approved to treat patients with DDR-deficient prostate cancer, we will investigate whether PARP inhibitors synergize with CAR T-cell therapy.

For the first time, the proposed project will demonstrate the crucial importance of BRCA2/DDR alterations in prostate cancer biology and possibly lay the foundation for consideration of DDR alteration as the master driver of the transformation from indolent, localized prostate cancer to lethal mCRPC. We believe this work will lead to clinical trials that will establish new and effective treatments for this deadly disease.

Icahn School Of Medicine At Mount Sinai

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 325% from $729,450 to $3,102,422.