Abstract 3495: Tumor growth arrest induced by a proprietary inhibitor of JAK2 on TNBC patient-derived xenografts
Authors: Davila-Gonzalez Daniel , Granados Sergio , Rosato Roberto , Chang Jenny C. 
Published: August 2015

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 docetaxel, resulting in tumor growth arrest and improved survival rate. The BMS-inhibitor/docetaxel combination therapy warrants additional studies as it shows promising therapeutic efficacy and improved survival rates in TNBC models. Furthermore, we speculate that including additional inhibitors to target other BCSC signature pathways, would possibly improve chemotherapy action and lead to complete tumor regression.

Citation Format: Daniel Davila-Gonzalez, Sergio Granados, Roberto Rosato, Jenny C. Chang. Tumor growth arrest induced by a proprietary inhibitor of JAK2 on TNBC patient-derived xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3495. doi:10.1158/1538-7445.AM2015-3495