Abstract A50: Targeting CXCR4 and CXCR7 to mobilize and kill prostate tumor cells

Abstract

Abstract Prostate cancer bone metastasis is a lethal incurable disease. Prostate cancer cells home to bone, where they are termed disseminated tumor cells (DTCs) and may reside dormant for years and/or grow into overt metastatic lesions. The bone homing process is largely thought to occur via local signaling of stromal-derived growth factor 1 (SDF1), secreted by osteoblasts within the bone marrow, to C-X-C chemokine receptor 4 (CXCR4), expressed on prostate cancer cells. Hematopoietic stem cells (HSCs) are also recruited to bone via SDF1/CXCR4 signaling. Specifically, HSCs reside in the osteoblastic endosteal niche, where they remain mostly quiescent. We have previously shown that prostate tumor cells occupy this HSC niche, and that the niche affords DTCs a chemoprotective status. Similar to HSCs, prostate DTCs can be mobilized from the niche by inhibiting the SDF1/CXCR4 signaling axis via small molecule CXCR4 inhibitors such as AMD3100 (trade name Plerixafor). Combining CXCR4 antagonism with the microtubule inhibitor docetaxel in mice injected subcutaneously with prostate cancer cells causes greater tumor regression than either compound alone. It is thought that mobilization of DTCs from the bone (we refer to mobilized DTCs as mobDTCs) causes them to proliferate in circulation, causing them to become susceptible to chemotherapy. We are using this strategy in a first-in-man clinical trial; we will treat bone metastatic prostate cancer patients with a potent next-generation CXCR4 antagonist coupled with standard docetaxel treatment. SDF1 also binds to the receptor CXCR7, which is overexpressed on prostate cancer cells as well. It is unknown whether CXCR7 will play a compensatory role when CXCR4 is antagonized. Therefore, it is crucial that we determine individual and overlapping roles of CXCR4 and CXCR7 in prostate cancer cells, particularly during bone metastasis. We hypothesized that CXCR7 can compensate for loss of CXCR4 function. We first assessed CXCR4 and CXCR7 expression across a panel of prostate cancer cell lines. We then stably overexpressed CXCR4 and CXCR7 in prostate cancer PC3 cells and determined classic cellular properties necessary for metastasis in vitro, such as proliferation, migration, and invasion. PC3 cells overexpressing either CXCR4 or CXCR7 had higher proliferation rates relative to PC3 parental cells. In addition, they were more migratory and invasive than parental cells. We are currently working to delete CXCR4 and/or CXCR7 from PC3 cells using the CRISPR-Cas9 system. We will perform in vivo xenograft metastasis experiments using prostate cancer cells with CXCR4 and/or CXCR7 overexpressed or knocked out. We hypothesize that loss of both receptors will be required to prevent bone metastasis. Future work will include small molecule inhibition of both CXCR4 and CXCR7 to mobilize prostate DTCs from bone. Citation Format: Kenneth C. Valkenburg, Sounak Roy, Kenneth J. Pienta. Targeting CXCR4 and CXCR7 to mobilize and kill prostate tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A50.