Modulation of cabozantinib efficacy by the prostate tumor microenvironment

// Manisha Tripathi 1, * , Srinivas Nandana 1, * , Sandrine Billet 1 , Karen A. Cavassani 1 , Rajeev Mishra 1 , Leland W.K. Chung 1 , Edwin M. Posadas 1 and Neil A. Bhowmick 1, 2 1 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA 2 Department of Research, Greater Los Angeles Veterans Administration, Los Angeles, California 90048, USA * These authors have contributed equally to this work Correspondence to: Neil A. Bhowmick, email: neil.bhowmick@cshs.org Edwin M. Posadas, email: Edwin.Posadas@cshs.org Keywords: carcinoma associated fibroblasts, cabozantinib, metastasis, prostate cancer Received: May 30, 2017 Accepted: August 15, 2017 Published: September 23, 2017 ABSTRACT The tumor microenvironment (TME) is increasingly recognized as the arbiter of metastatic progression and drug resistance in advanced prostate cancer (PCa). Cabozantinib is a potent tyrosine kinase inhibitor (TKI) with reported biological activity in the PCa epithelia, but failed to provide an overall survival benefit in phase 3 clinical trials. However, the promising biologic efficacy of the drug in early trials warranted a better understanding of the mechanism of action, with the goal of improving patient selection for TKI-based therapy such as cabozantinib. We found a 100-fold lower cabozantinib IC 50 in macrophages, PCa associated fibroblasts, and bone marrow fibroblasts compared to PCa epithelia. In PCa mouse models, pre-treatment with cabozantinib potentiated osseous and visceral tumor engraftment, suggesting a pro-tumorigenic host response to the drug. We further found that the host effects of cabozantinib impacted bone turnover, but not necessarily tumor expansion. Cabozantinib affected M1 macrophage polarization in mice. Analogously, circulating monocytes from PCa patients treated with cabozantinib, demonstrated a striking correlation of monocyte reprograming with therapeutic bone responsivity, to support patient selection at early stages of treatment. Thus, a re-evaluation of TKI-based therapeutic strategies in PCa can be considered for suitable patient populations based on TME responses.