Abstract 3495: Tumor growth arrest induced by a proprietary inhibitor of JAK2 on TNBC patient-derived xenografts

Introduction: Triple-negative breast cancer (TNBC) has an increased risk for metastasis and poor long-term survival. Breast Cancer Stem Cells (BCSC) are a subpopulation of treatment-resistant cells that survive and re-initiate tumor growth and seed metastases. A specific and proprietary JAK2 inhibitor developed by Bristol-Myers Squibb (BMS) is currently in phase 1/2a clinical study in myelofibrosis. We hypothesized that Jak2/STAT3 inhibition may control an inflammatory microenvironment and eliminate BCSCs. The goal of thie study was to run an animal preclinical trail using 10 patient-derived xenograft (PDX) models to determine whether the BMS-inhibitor will target BCSC therapeutically. PDXs resulted from the engraftment of TNBC-patient tumor tissue into immune-deficient mice. They constitute a phenocopy of human tumors; they can predict accurately the effectiveness of novel therapeutics and drug response on patients. Methods: For in vitro, BMS-inhibitor was dissolved in dimethylsulfoxide (DMSO) while 20% citrate/80%, PEG400 was used as vehicle for in vivo studies. In vitro: BT549 and SUM149 TNBC cell lines were treated daily for 72 hours; proliferation was assayed by WST-1. Western blot analysis was used to measure pSTAT3 expression. Wound healing assay were performed to evaluate cell migration. To measure mammospheres forming efficiency (MSFE) cells were seeded in Methylcellulose-Based Media. In vivo: for each PDX model, treatments included: vehicle, BMS-inhibitor, docetaxel, and docetaxel + BMS-inhibitor. Animals received three cycles of treatment, 14 days each; docetaxel was delivered at day one; BMS-inhibitor was administered daily for five days, followed by two days of “drug holiday”. Tumor volume was measured twice weekly. In the present abstract we report the results of 4 chemotherapy resistant PDXs which include BCM-5998, BCM-4272, BCM-2147 and BCM-3107 models. Results: BMS-inhibitor impaired cell proliferation, declined pSTAT3 levels and reduced cell migration. In BT549 cells, it lowered MSFE of both primary and secondary mammospheres. BMS-inhibitor increased docetaxel cell toxicity when given together. In vivo, this inhibitor alone reduced BCM-5898 tumor growth when compared to vehicle. Combination therapy (i.e., BMS- inhibitor /docetaxel) induced tumor growth arrest and improved survival rate in all models tested. Conclusions: BMS-inhibitor decreased cell proliferation and capacity to migrate and to form mammospheres; it sensitized TNBC PDXs to