Stage- & cell-specific targeting of RTK in tumorigenesis

描述（由申请人提供）：本项目将使用基因工程小鼠癌症模型来研究抑制肿瘤发生过程中诱导的血管生成血管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的不同阶段启动的治疗试验设计；结果是，某些血管生成抑制剂显示出特定阶段的疗效，其中一些在疾病进展的早期阶段最有效，而另一些在疾病进展的晚期最有效。令人振奋的是，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，并且通过对每种细胞类型的受体激酶进行功能性抑制，可以实现具有更广泛分期特异性的组合疗效。基于令人兴奋的初步结果，该项目将验证这样一个命题，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，可以对癌前（预防）和恶性疾病产生客观和显著的反应。其目的是：1。评估各种干扰肿瘤内皮细胞中VEGF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. 评估组合策略，包括使用受体酪氨酸激酶抑制剂靶向多种细胞类型，以扩大分期特异性并提高疗效。4. 评估“节拍”化疗在胰岛癌发生阶段的疗效和靶细胞类型，并确定将传统化疗与RTK抑制剂联合使用的益处。5. 使用微阵列表达谱技术识别不同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。该结果将为激酶抑制剂靶向肿瘤血管两种成分细胞类型的潜力提供新的视角，从而在不同的进展阶段扩大活性并提高疗效，从而可能对这些药物在治疗不同阶段和种类的人类癌症中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.