Abstract 4942: Small molecule inhibition of CXCR4 mobilizes prostate disseminated tumor cells (DTCs) from the chemoprotective bone marrow niche, thereby sensitizing them to chemotherapy
Authors: Valkenburg Kenneth C. , Toom Emma E. van der , Pienta Kenneth J. 
Published: July 2017

Abstract
Bone metastasis results in the deaths of approximately 28,000 prostate cancer patients each year in the United States. Disseminated tumor cells (DTCs) go from the primary tumor site to the bone marrow, which provides a chemoprotective environment. C-X-C chemokine receptor 4 (CXCR4), highly overexpressed in prostate cancer, is at least partially responsible for bone homing. CXCR4 is also expressed in hematopoietic stem cells (HSCs), which occupy the same niche within the bone marrow as DTCs. HSCs can be mobilized from the bone marrow niche via CXCR4 antagonism. We have previously shown that human tumor cells can be similarly mobilized from the bone marrow niche via small molecule inhibition of CXCR4. We believe this represents an ideal strategy for treating bone metastasis and hypothesize that mobilized DTCs will proliferate in the vascular niche, causing them to become chemosensitive. Several outstanding questions still exist that we are in the process of answering. First is the percentage of DTCs that are mobilized with CXCR4 antagonism. Previously, we used a qPCR strategy to quantify tumor cells in the bone marrow and blood of mice. This was imperfect because we could not reliably count cells, nor could we query the cells further. Therefore, we developed a novel immunofluorescence protocol to detect, quantify, and query tumor cells residing in the bone marrow or blood of mice. We will use this technique to determine the percentage of bone marrow DTCs that are mobilized. The second outstanding question is whether or not mobilized DTCs proliferate once mobilized. This is crucial to know, considering most chemotherapy relies on tumor cell proliferation. Using our novel protocol, we will determine the percentage of bone marrow DTCs and mobilized DTCs that are proliferating. Finally, while there is evidence that combining CXCR4 antagonism with chemotherapy kills more tumor cells than chemotherapy alone, no one has shown definitively that it works specifically for prostate bone marrow DTCs or bone metastasis. Not only will we do this, but we will also be able to quantify how effective each therapy strategy is by quantifying the tumor cells present in each scenario. The data from these in vivo murine experiments, which would be impossible to get from humans, will go hand in hand with a first-in-prostate cancer clinical trial we are running that tests the same hypothesis. Combined, these data will be critically important in deciding whether mobilization therapy combined with chemotherapy is an effective strategy for treating metastatic prostate cancer.
Citation Format: Kenneth C. Valkenburg, Emma E. van der Toom, Kenneth J. Pienta. Small molecule inhibition of CXCR4 mobilizes prostate disseminated tumor cells (DTCs) from the chemoprotective bone marrow niche, thereby sensitizing them to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4942. doi:10.1158/1538-7445.AM2017-4942