Serum insulin-like growth factor-1 levels in response to dasatinib-based regimens in bone-metastatic prostate cancer.

Abstract

166 Background: Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer (PCa) progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions. Methods: We first measured serum IGF-1 levels in men with CRPC treated with dasatinib plus docetaxel. To investigate the source of IGF-1, we utilized different mouse models harboring human PCa cells, and used species-specific IGF-1 ELISA kits (mouse vs. human). Results: In men with CRPC, an increase in IGF-1 levels after one cycle of treatment is associated with a higher response rate and longer duration of treatment with docetaxel and dasatinib. Xenograft experiments with subcutaneous, and intratibial injection of PCa cells and treatment of mice with dasatinib-based combinations suggest that direct interaction of PCa cells with bone microenvironment is necessary for IGF-1 induction, is entirely host-derived, and occurs only in mice that respond to dasatinib-based therapy. Conclusions: Our results support a role for serum IGF-1 as a potential biomarker for dasatinib-based combination treatments in CRPC. Inoculation of human PCa cells into murine hosts was essential in determining that IGF-1 results from the bone microenvironment. Further studies are warranted to validate these findings in a larger cohort of patients in a prospective manner.