Targeting SDF1/CXCR4 signaling to mobilize and kill circulating and disseminated prostate tumor cells

Johns Hopkins University, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): Approximately 1 in 7 men in the U.S. will be diagnosed with prostate cancer at some point in his lifetime. The five-year survival rate for metastatic prostate cancer is a mere 30%. Bone metastasis is incurable and deadly. Osteoblasts are bone cells that secrete a protein called stromal cell-derived factor (SDF-1). SDF-1 recruits prostate circulating tumor cells (CTCs) to the bone, where they become disseminated tumor cells (DTCs) and interact directly with osteoblasts in the endosteal niche. DTCs often remain dormant, or slowly proliferating, once they enter the endosteal niche. As a result of this dormancy, DTCs are difficult to kill with chemotherapy because they target rapidly proliferating cells. One strategy to overcome this chemoresistance is to mobilize the DTCs from the bone and into circulation where they theoretically begin proliferating and would therefore become chemosensitive. Mobilization is possible by inhibiting the receptor for SDF-1 called C-X-C chemokine receptor 4 (CXCR4). A second strategy to kill DTCs is to use CXCR4 to bring cytotoxic drugs directly to the DTCs by using a CXCR4-antibody-drug conjugate (CXCR4-ADC). It is also essential to learn more about the biology of prostate CTCs so as to better understand them; one strategy to address this is by injecting these cells directly into mice and studying thei migratory patterns, kinetics, and responses to drugs. Our overarching hypothesis is that the CXCR4 receptor can be exploited via small molecule inhibition for combination mobilization therapy and via direct binding for targeted therapy for metastatic prostate cancer. To address this hypothesis, we will perform the following three aims. Aim 1: Determine the proliferative state and chemotherapeutic sensitivity of mobilized prostate CTCs and DTCs. Aim 2: Determine the sensitivity of prostate CTCs and DTCs to a potent CXCR4-antibody-drug conjugate. Aim 3: Determine the viability of mobilized CTCs in in vitro and mouse models. If this work is successful, we would be able to move these laboratory discoveries into the clinic for therapeutic intervention for men with metastatic prostate cancer.