Abstract 2870: A specific pan-FGFR inhibitor has antitumor activity against prostate cancer patient derived xenografts, PDX, expressing high FGFR1

Abstract

Abstract Prostate Cancer (PCa) is one of the most commonly diagnosed malignancies in men. Patients with advanced metastatic PCa have effective treatment options, but none of them are curative. Androgen deprivation is the most effective therapy, but growth of the cancer resumes over time in most cases, and the disease progresses to castration-resistant PCa (CRPC). Bone is the main site of CRPC progression. Acquired (or inherent) resistance mechanisms to second line therapy options for CRPC eventually lead to disease recurrence and, ultimately, death. The underlying mechanisms of PCa progression to first or second line therapy options are diverse and include fibroblast growth factor (FGF) axis activation. Indeed, we previously reported that blockade of FGFRs with dovitinib (TKI258) (Novartis Pharmaceuticals), a receptor tyrosine kinase inhibitor (TKI) with potent activity against FGFR1-3 and vascular endothelial growth factor receptor (VEGFR) has clinical activity in men with CRPC and bone metastases (PMID: 25186177), thus providing direction for therapy development of FGFR blockade in PCa. Because dovitinib was withdrawn from the clinic by Novartis, we seek to identify an alternative agent with activity against FGFR1 as a candidate for therapy development. With that goal, we tested the antitumor activity of a specific pan-FGFR TKI, JNJ-42756493 (JNJ) (Janssen Pharmaceutical Companies of Johnson&Johnson) against PCa patients derived xenografts (PDXs) expressing high (MDA PCa 118b) and low (MDA PCa 183) endogenous levels of FGFR1. Because bone is the primary site of CRPC progression we tested the antitumor activity of JNJ against these PDXs growing in the bone of mice. By assessing tumor volume by MRI, we found that JNJ has antitumor activity against MDA PCa 118b but not MDA PCa 183. Immunohistochemical analysis of FGFR1 expression exhibited reduction of FGFR1 in tumors of the treated group compared with vehicle treated group in MDA PCa 118b samples. Both these evidences suggest that FGFR1 is the main driver of PCa progression in this PDX and that JNJ is a potent agent against PCas with high FGFR1 expression.Due to the important role that FGF axis has in bone biology, we assessed the effect of JNJ in the bones of mice without tumors by micro-CT analysis. Interestingly, we observed a reduction in bone parameters including bone volume/ total volume (BV/TV) and trabecular thickness (Tb.Th) in the treated group compared with the vehicle treated group, suggesting FGF axis blockade reduces bone mass. However, we identified an increase in the bone surrounding the tumors in the MDA PCa 118b tumor-bearing bones of mice treated with JNJ. These results highlight the complex role of FGF axis in the PCa-bone interaction and warrant further studies to identify candidate patients for this therapy and markers of response in men treated with FGFR inhibition. Citation Format: Estefania Labanca, Jun Yang, Peter Shepherd, Xinhai Wan, Justin M. Roberts, Michael W. Starbuck, Nora M. Navone. A specific pan-FGFR inhibitor has antitumor activity against prostate cancer patient derived xenografts, PDX, expressing high FGFR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2870.