Deciphering Links Between Inflammation and Cancer with IMP-1 Inhibitors



 DESCRIPTION (provided by applicant): There is a critical public health need for the development of anti-cancer chemotherapeutics which selectively target cancerous versus non-cancerous tissues. The RNA-binding protein Insulin-like Growth Factor 2 Binding Protein 1 (IGF2BP1/IMP-1/CRD-BP) represents a novel and selective anti- cancer target because it exhibits an oncofetal pattern of expression-it is virtually absent or undetectable in normal adult tissues, overexpressed in many types of human cancers, and absent in non-cancerous adult tissue. IMP-1 binds to and stabilizes mRNAs encoding oncogenes, c-Myc, K- Ras, ERK and multidrug resistance factor 1 (MDR1) and increases activity of the tumor enabling factor NF-κB. IMP-1 expression is associated with a poor prognosis and reduced survival in several cancers including lung, colon, and ovarian cancer. Transgenic mice with targeted expression of IMP- 1 develop mammary tumors and colorectal tumor growth, further implicating this RNA-binding protein in the development of cancer. Despite its importance in cancer, small molecule inhibitors of IMP-1 do not exist and regulation of this protein is poorly understood. The central hypotheses of the proposed research, which have been formulated based on a strong body of preliminary results is that IMP-1 is a novel molecular link between tumor-enabling inflammation and cancer and a novel therapeutic target at the convergence of these disease processes. We will address these hypotheses through the following Specific Aims: 1) Test the hypothesis that IMP-1 increases NF-κB activity and NF-κB induces IMP-1, establishing a feed- forward regulatory loop, increasing inflammation and 2) Evaluate the ability of Compound 389 to inhibit tumor growth and/or induce tumor regression in IMP-1+ mouse xenograft models and determine specificity and toxicity of the lead small molecule. Previous research has shown that IMP- 1 acts indirectly, increasing NF-κB activity and preliminary data shows that the IMP-1 promoter region contains multiple NF-κB binding sites. I will test the hypothesis that IMP-1 establishes a feed-forward regulatory loop promoting inflammation in which IMP-1 increases NF-κB activity, and NF-κB acts as a transcriptional regulator to induce IMP-1 (Aim 1). My recently identified small molecule inhibitors of IMP-1 will be important probes used to help evaluate the importance of these regulatory pathways in the proliferation and inflammation of cancer cells. The lead IMP-1 inhibitor will be evaluated in mouse xenograft models for melanoma and ovarian cancer (Aim 2). The proposed research is significant because it will greatly advance knowledge on the regulation of IMP-1 and the development of a novel, first-in class IMP-1 small molecule inhibitor, which has strong therapeutic potential in the targeted and selective treatment of IMP-1+ cancers.