Deciphering Links Between Inflammation and Cancer with IMP-1 Inhibitors

 描述（由申请人提供）：对于开发选择性靶向癌性组织与非癌性组织的抗癌化疗药物，存在关键的公共卫生需求。RNA结合蛋白胰岛素样生长因子2结合蛋白1（IGF 2BP 1/IMP-1/CRD-BP）代表了一种新的选择性抗癌靶点，因为它表现出癌胚表达模式-它在正常成人组织中几乎不存在或检测不到，在许多类型的人类癌症中过表达，并且在非癌性成人组织中不存在。IMP-1结合并稳定编码癌基因、c-Myc、K-Ras、ERK和多药耐药因子1（MDR 1）的mRNA，并增加肿瘤促成因子NF-κB的活性。IMP-1表达与包括肺癌、结肠癌和卵巢癌在内的几种癌症的预后不良和生存率降低相关。靶向表达IMP- 1的转基因小鼠发生乳腺肿瘤和结直肠肿瘤生长，进一步暗示这种RNA结合蛋白参与癌症的发展。尽管IMP-1在癌症中很重要，但IMP-1的小分子抑制剂并不存在，并且对这种蛋白质的调控知之甚少。基于大量初步结果制定的拟议研究的中心假设是，IMP-1是肿瘤致炎性炎症和癌症之间的新型分子联系，以及这些疾病过程融合的新型治疗靶点。我们将通过以下具体目的来解决这些假设：1）检验IMP-1增加NF-κB活性和NF-κB诱导IMP-1的假设，建立前馈调节环，增加炎症，和2）评价化合物389在IMP-1+小鼠异种移植模型中抑制肿瘤生长和/或诱导肿瘤消退的能力，并确定先导小分子的特异性和毒性.先前的研究表明，IMP- 1间接地起作用，增加NF-κB活性，并且初步数据显示IMP-1启动子区含有多个NF-κB结合位点。我将检验以下假设：IMP-1建立了一个促进炎症的前馈调节环，其中IMP-1增加NF-κB活性，NF-κB作为转录调节因子诱导IMP-1（目的1）。我最近发现的IMP-1的小分子抑制剂将是重要的探针，用于帮助评估这些调节途径在癌细胞增殖和炎症中的重要性。将在黑色素瘤和卵巢癌的小鼠异种移植模型中评价先导IMP-1抑制剂（目的2）。这项研究意义重大，因为它将极大地推进对IMP-1调控的认识，并开发一种新型的、首个IMP-1小分子抑制剂，这种抑制剂在IMP-1+癌症的靶向和选择性治疗中具有强大的治疗潜力。

 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.