Stage- & cell-specific targeting of RTK in tumorigenesis

描述(申请人提供)：这个项目将使用一个基因工程的癌症小鼠模型来研究药物的疗效，这些药物抑制在肿瘤形成过程中诱导的血管新生血管的内皮或内皮周围支持细胞中表达的受体酪氨酸激酶的功能。该模型涉及RIP1-Tag2转基因小鼠的胰岛癌变，其中一条途径通过可区分的癌前阶段和恶性阶段的顺序出现而展开。RIP-TAG模型已被用于开发一套在胰岛癌变不同阶段启动的治疗性试验设计；结果是某些血管生成抑制剂显示出阶段特异性的疗效，其中一些在疾病进展的早期阶段最有效，另一些在疾病进展的晚期阶段最有效。具有挑衅性的是，两种激酶抑制剂的试验表明，肿瘤内皮细胞和肿瘤周细胞都可以单独靶向，通过对每种细胞类型上的受体激酶进行功能性抑制，可以实现具有更广泛的阶段特异性的组合疗效。基于令人兴奋的初步结果，该项目将测试这样一个命题，即在化疗和不化疗的情况下，对这些血管细胞类型中表达的激酶进行组合靶向可以产生对癌前疾病(预防)和恶性疾病的客观和显著的反应。其目的是：1.评估不同干扰血管内皮细胞血管内皮生长因子受体信号的药物的阶段特异性和相对益处。2.研究PDGF受体信号转导抑制剂靶向周细胞从而破坏肿瘤血管生成、血管完整性和肿瘤生长的假说。3.评价与受体酪氨酸激酶抑制剂靶向多种细胞类型的组合策略，以扩大阶段特异性和提高疗效。4.评估“节律”化疗在胰岛癌变阶段的疗效和靶细胞类型，并确定将传统的节律化疗与RTK抑制剂相结合的益处。5.使用微阵列表达谱技术确定不同靶向策略的生物反应标记，这些标记可用于这些药物在其他模型中的转译研究和人类临床试验。这一结果将为用激酶抑制剂靶向肿瘤血管的两种成分细胞类型以扩大活性和提高不同进展阶段的疗效的潜力提供新的视角，从而可能对此类药物在治疗不同阶段和种类的人类癌症的临床应用产生重大影响。

DESCRIPTION (provided by applicant): This project will use a genetically engineered mouse model of cancer to study the efficacy of drugs that inhibit the function of receptor tyrosine kinases expressed in endothelial or peri-endothelial support cells of the angiogenic vasculature that is induced during tumorigenesis. The model involves pancreatic islet carcinogenesis in RIP1-Tag2 transgenic mice, wherein a pathway unfolds through the sequential appearance of distinguishable premalignant and malignant stages. The RIP-Tag model has been used to develop a set of therapeutic trial designs that are initiated at different stages of islet carcinogenesis; the result is that certain angiogenesis inhibitors show stage-specific efficacy, with some most effective at early stages and others at late stages of disease progression. Provocatively, trials with two kinase inhibitors suggest the hypothesis that both tumor endothelial cells and tumor pericytes can be separately targeted, and that by functionally inhibiting receptor kinases on each cell type, combinatorial efficacy with broader stage specificity can be achieved. Based on exciting preliminary results, this project will test the proposition that combinatorial targeting of kinases expressed in these vascular cell types, with and without chemotherapy, can produce objective and significant responses against both premalignant (prevention) and malignant disease. The aims are to: 1. Evaluate stage specificity and relative benefits of agents that variously interfere with VEGF receptor signaling in tumor endothelial cells. 2. Investigate the hypothesis that inhibitors of PDGF receptor signaling target pericytes and thereby disrupt the tumor vasculature, impairing angiogenesis, vascular integrity, and tumor growth. 3. Evaluate combinatorial strategies involving targeting of multiple cell types with receptor tyrosine kinase inhibitors to broaden stage specificity and improve efficacy. 4. Assess efficacy and target cell types of 'metronomic' chemotherapy in the stages of islet carcinogenesis, and determine the benefits of combining traditional vs. metronomic chemotherapy with RTK inhibitors. 5. Identify biological response markers of the distinctive targeting strategies using microarray expression profiling technology that might be used in translational studies with these drugs in other models and in human clinical trials. The results will give new perspective into the potential of targeting two component cell types of the tumor vasculature with kinase inhibitors so as to broaden activity and improve efficacy in distinct stages of progression, and thereby may significantly impact the clinical applications of such agents in treating different stages and kinds of human cancer.