Stage- & cell-specific targeting of RTK in tumorigenesis

描述（由申请人提供）：该项目将使用基因工程小鼠癌症模型来研究抑制血管生成血管系统的内皮或内皮周围支持细胞中表达的受体酪氨酸激酶功能的药物的功效，该细胞在肿瘤发生过程中被诱导。该模型涉及在RIP 1-Tag 2转基因小鼠中的胰岛癌发生，其中通过可区分的癌前和恶性阶段的连续出现来展开途径。RIP-Tag模型已被用于开发一套治疗试验设计，这些设计在胰岛癌发生的不同阶段启动;结果是某些血管生成抑制剂显示出阶段特异性疗效，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，使用两种激酶抑制剂的试验表明了这样的假设，即肿瘤内皮细胞和肿瘤周细胞都可以分别靶向，并且通过功能性地抑制每种细胞类型上的受体激酶，可以实现具有更广泛阶段特异性的组合功效。基于令人兴奋的初步结果，该项目将测试这样一个命题，即在这些血管细胞类型中表达的激酶的组合靶向，在有和没有化疗的情况下，可以对癌前（预防）和恶性疾病产生客观和显著的反应。目的是：1.评估肿瘤内皮细胞中不同程度干扰VEGF受体信号传导的药物的阶段特异性和相对获益。 2.研究PDGF受体信号传导抑制剂靶向周细胞，从而破坏肿瘤血管系统，损害血管生成、血管完整性和肿瘤生长的假设。 3.评估涉及用受体酪氨酸激酶抑制剂靶向多种细胞类型的组合策略，以扩大阶段特异性并提高疗效。 4.评估胰岛癌发生阶段“节拍式”化疗的疗效和靶细胞类型，并确定传统化疗与节拍式化疗联合RTK抑制剂的益处。 5.使用微阵列表达谱分析技术确定独特靶向策略的生物反应标记物，该技术可用于这些药物在其他模型和人体临床试验中的转化研究。 这些结果将为激酶抑制剂靶向肿瘤血管系统的两种组分细胞类型的潜力提供新的视角，以便在不同的进展阶段扩大活性并提高疗效，从而可能显著影响此类药物在治疗不同阶段和种类的人类癌症中的临床应用。

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.