Colorectal Cancer Treatment and Drug Resistance; the Role of IGF2BP1 - ABSTRACT Advances in chemotherapy treatment regimens for advanced colorectal cancer (CRC) have significantly improved patient survival, yet drug resistance remains an important clinical challenge that is associated with poor patient outcomes. Insulin-like Growth Factor 2 mRNA-binding protein 1 (IGF2BP1) is a bona fide transcriptional target of the Wnt/β-catenin signaling pathway, a central mechanism that drives colorectal carcinogenesis. IGF2BP1 is unique in that it promotes cell proliferation and induction of MDR1 gene. Further, we have shown that inhibition of IGF2BP1 sensitized CRC cells to drugs in vitro. Our long-term goal is to accelerate the development of clinically useful mechanism-based therapeutics for treating colorectal cancer resistance. The overall objective for this application is to determine the in vivo efficacy of IGF2BP1 inhibition in the chemotherapeutic treatment of chemoresistant CRC and delineate its mode of action. The central hypothesis is that inhibition of IGF2BP1 will modulate a set of known and unknown genes unique to resistant CRC cells to sensitize them to chemotherapeutics resulting in tumor regression. The rationale is that the determination of the preclinical therapeutic efficacy and associated mechanisms of IGF2BP1 inhibition is likely to provide strong basis for the development of a new class of drugs for an effective colorectal cancer treatment. Guided by strong preliminary data, the following two specific aims are proposed: 1) To determine the effects of IGF2BP1 inhibition in sensitizing chemoresistant colorectal cancer cells to chemotherapeutics in a human xenograft tumor model; 2) To assess the effects of IGF2BP1 inhibition in sensitizing colorectal cancer to chemotherapeutics in an immunocompetent and autochthonous model. For the first aim, chemoresistant CRC cells and a human xenograft tumor model will be used to elucidate the mechanisms by which inhibition of IGF2BP1 sensitizes resistant CRC cells to chemotherapeutics and determine its efficacy in vivo. For the second aim, we will use intestinal-specific IGF2BP1 knockout in an immunocompetent and autochthonous model of CRC to assess the efficacy of IGF2BP1 inhibition in sensitizing colorectal cancer to chemotherapeutics in vivo. We will also assess the effects of IGF2BP1 inhibition on tumor heterogeneity in this study. The proposed research is innovative as it proposes a novel approach to treat advanced and chemoresistant CRC that targets IGF2BP1 to sensitize resistant CRC cells to chemotherapeutics. In this study, we will also identify the mechanisms by which inhibition of IGF2BP1 sensitizes chemoresistant cells to drug which is thus far unknown. The proposed research is significant because in vivo, mechanism-based proof of principle evidence for a preclinical role of IGF2BP1 inhibition in sensitizing resistant CRC to chemotherapy is likely to inform the subsequent development of novel strategies for reducing resistance in human patients.
