Rectifying defects in tumor vasculature to improve chemo- and radiation therapies

纠正肿瘤血管系统缺陷以改善化疗和放射治疗

• 批准号: 7585251
• 负责人: DONALD R SENGER
• 金额: $ 35.28万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-14 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585251
• 关键词: Architecture; Blood Vessels; Blood flow; Calpain; Cancer Patient; Cancerous; Clinical; Clinical Research; Cytoskeleton; Cytotoxic agent; Defect; Development; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Design; Effectiveness; Elements; Endothelial Cells; Exhibits; Family; Goals; Guanosine Triphosphate Phosphohydrolases; Hypoxia; Lead; Link; Malignant Neoplasms; Measures; Mediating; Modeling; Morphogenesis; Neoplasms in Vascular Tissue; Outcome; Oxygen; Patients; Peptide Hydrolases; Perfusion; Pharmaceutical Preparations; Phenotype; Radiation therapy; Reaction Time; Research; Scheme; Signal Pathway; Solid Neoplasm; Testing; Therapeutic; Time; Tumor Angiogenesis; Tumor Oxygenation; Tumor-Associated Vasculature; Validation; Work; antiangiogenesis therapy; cancer therapy; chemotherapeutic agent; chemotherapy; design; drug development; efficacy testing; improved; killings; mouse model; neovasculature; novel strategies; outcome forecast; preclinical study; public health relevance; research study; response; rho; rho GTP-Binding Proteins; tumor; tumor progression; vessel regression

DESCRIPTION (provided by applicant): The vasculature of solid tumors is highly defective, resulting in poor blood flow and hypoxia. These defects have profoundly negative consequences for the delivery of chemotherapeutic agents and also for the efficacy of radiation therapy that is oxygen-dependent. The broad long-term objectives of the proposed research are to improve the effectiveness of chemo- and radiation therapies by rectifying key defects in the tumor vasculature. Our recent work has suggested a novel strategy for improving dysfunctional tumor blood vessels with a panel of cytoskeleton-regulating drugs that rectify key defects in neovessels that would otherwise exhibit a pathological phenotype. To apply this new strategy towards improvement of cancer therapies, we propose the following Specific Aims: (1) In mouse models of cancer, employ cytoskeleton-regulating drugs that target Rho GTPase signaling pathways and calpain to rectify important functional defects in the tumor vasculature. Identify combinations of drugs that provide cumulative improvement of tumor vascular perfusion and reduction of hypoxia. (2) Test strategies identified in Aim 1 that maximally increase tumor vascular perfusion and increased tumor oxygenation for improved delivery and efficacy of representative chemotherapeutic agents and improved tumor radiotherapy. Experiments in Aim 1 will define the specific contributions of the various cytoskeleton-regulating drugs, identified in our preliminary studies, to enhance perfusion and oxygenation of important representative tumors and define the optimal dose response and time course for such alterations. Parameters to be measured are improvement of angio-architecture, improved blood flow, increased tumor perfusion, and reduced hypoxia. Depending on findings with each drug individually, we will conduct experiments with combinations of these drugs designed to achieve maximal improvement of tumor perfusion and oxygenation. Experiments in Aim 2 will test the efficacy of the optimal tumor vessel rectifying strategies identified in Aim 1 for improving tumor perfusion and tumor killing using representative chemotherapeutic agents. Experiments in Aim 2 also will test optimal strategies identified in Aim 1 that reduce tumor hypoxia for improved radiation therapy. Validation of this strategy in the proposed preclinical studies offers the prospect of rapid improvement in conventional chemo- and radiation therapies for cancer patients. This is because the several classes of drugs to be used here for stable normalization of pathological tumor blood vessels are actively being pursued as potential therapeutics for other disorders. Thus, implementation of this strategy would not require the extended time and expense typically associated with new drug development. PUBLIC HEALTH RELEVANCE: The goals of this research are to identify and develop new strategies for improving conventional cancer therapies. The blood vessels of tumors are highly abnormal, resulting in poor delivery of chemotherapeutic agents and impaired sensitivity to radiation therapy. Our proposed strategy is to achieve drug-mediated correction of these blood vessel defects in order to increase effectiveness of chemo- and radiation therapies and thereby improve cancer patient survival.

描述（申请人提供）：实体瘤的血管系统高度缺陷，导致血流不畅，缺氧。这些缺陷对化疗药物的输送和依赖氧的放射治疗的疗效有深远的负面影响。该研究的长期目标是通过纠正肿瘤血管中的关键缺陷来提高化疗和放疗的有效性。我们最近的工作提出了一种新的策略，通过一组细胞骨架调节药物来改善功能失调的肿瘤血管，这种药物可以纠正新血管中的关键缺陷，否则这些缺陷会表现出病理表型。为了将这一新策略应用于改善癌症治疗，我们提出以下具体目标：(1)在小鼠癌症模型中，使用靶向Rho GTPase信号通路和钙蛋白酶的细胞骨架调节药物来纠正肿瘤血管系统中的重要功能缺陷。确定可累积改善肿瘤血管灌注和减少缺氧的药物组合。(2) Aim 1中确定的测试策略，最大限度地增加肿瘤血管灌注和肿瘤氧合，以改善代表性化疗药物的递送和疗效，并改善肿瘤放疗。Aim 1的实验将确定我们在初步研究中确定的各种细胞骨架调节药物对增强重要代表性肿瘤的灌注和氧合的具体贡献，并确定这种改变的最佳剂量反应和时间过程。测量的参数包括血管结构改善、血流改善、肿瘤灌注增加和缺氧减少。根据每种药物的结果，我们将进行这些药物的联合实验，以最大限度地改善肿瘤灌注和氧合。Aim 2中的实验将测试Aim 1中确定的最佳肿瘤血管矫正策略在使用代表性化疗药物改善肿瘤灌注和肿瘤杀伤方面的功效。Aim 2的实验也将测试Aim 1中确定的减少肿瘤缺氧以改善放射治疗的最佳策略。在拟议的临床前研究中验证这一策略，为癌症患者的常规化疗和放疗提供了快速改善的前景。这是因为用于病理肿瘤血管稳定正常化的几类药物正被积极地用作其他疾病的潜在治疗药物。因此，这一策略的实施将不需要延长时间和费用，通常与新药开发相关。公共卫生相关性：本研究的目标是确定和开发改进传统癌症治疗的新策略。肿瘤的血管高度异常，导致化疗药物的输送不良和对放射治疗的敏感性受损。我们提出的策略是实现药物介导的血管缺陷矫正，以提高化疗和放疗的有效性，从而提高癌症患者的生存率。