Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 9154244
• 负责人: James Mitchell
• 金额: $ 67.78万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9154244
• 关键词: Animals; Attention; CDK4 gene; Cancer Cell Growth; Cell Aging; Cell Line; Clinical; Clinical Trials; DNA Repair; Dose; Fibrosis; Functional Imaging; Glutamine; Goals; Head and Neck Squamous Cell Carcinoma; Heat-Shock Proteins 90; Human; Hypoxia; In Vitro; Ionizing radiation; Lactate Dehydrogenase; Lung; Malignant Epithelial Cell; Metabolic; Metabolism; Modification; Molecular; Normal tissue morphology; Pharmaceutical Preparations; Physiology; Process; Production; Publishing; Radiation; Radiation Induced DNA Damage; Radiation Oncology; Radiation therapy; Radiation-Protective Agents; Radiation-Sensitizing Agents; Radiosensitization; Research; Research Design; Sirolimus; Stem cells; Testing; Therapeutic; Toxic effect; Translating; Work; Xenograft procedure; cancer therapy; chemotherapy; imaging platform; improved; in vivo; inhibitor/antagonist; interest; mTOR Inhibitor; novel; pre-clinical; pre-clinical research; preclinical study; prevent; radiation effect; radiation response; radioresistant; repaired; response; treatment response; tumor; tumor microenvironment

In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. We have completed and published a study evaluating a PI3K/mTOR inhibitor in human head/neck carcinoma cells lines. Impressive radiosensitization by the inhibitor is observed in vitro and in vivo. No toxicity of the combination was observed in vivo. The mechanism of action of the inhibitor was found to be inhibition of radiation-induced DNA damage repair. The results of this pre-clinical study will provide the necessary information to consider a clinical human trial with this agent as a radiation sensitizer. We have demonstrated that a novel HSP90 inhibitor is a radiation sensitizer (in vitro and in vivo). Significant in vitro radiation dose modification factors have been observed with this agent and xenograft studies are ongoing. This agent also has potential of being translated into human clinical trials. We have initiated preliminary in vitro studies evaluating a CDK4/6 inhibitor, which demonstrates significant radiosensitization. We continue to evaluate a number of metabolic inhibitors as radiation modifiers under the working hypothesis that inhibition of metabolism (for example, decreased ATP production) will diminish the repair of radiation-induced DNA damage. We are currently evaluating a novel lactate dehydrogenase inhibitor with and without a glutamine inhibitor as potential radiation modifiers of cancer cell growth. With respect to normal tissue response to radiation, we completed a study demonstrating that rapamycin supplied in the animal's chow protects against radiation-induced lung fibrosis in part by preventing radiation induced stem cell senescence. We continue to develop an test novel functional imaging platforms to better understand the contribution of tumor hypoxia and metabolism on radiation and drug induced tumor response in tumor-bearing animals. Collectively we have identified a number of pre-clinical approaches to initiate human radiation oncology clinical trials for modulation of radiation effects on tumors and normal tissues.

为了提高癌症的治疗水平，辐射损伤的修饰受到了极大的关注。各种化疗和/或分子靶向药物与辐射的相互作用正在研究中，以确定是否可以使肿瘤更敏感，或使正常组织对放射治疗更具抵抗力。中心目标是确定将导致净治疗收益的方法，从而改善癌症的放射治疗。该项目的目标之一是定义和更好地了解肿瘤生理学的这些方面，包括细胞和分子过程以及肿瘤微环境对治疗反应的影响。增强肿瘤对辐射的反应，而不增强给定治疗范围内的正常组织的能力是可取的。我们已经完成并发表了一项研究，评估了一种PI3K/mTOR抑制剂在人头颈部癌细胞系中的作用。在体外和体内观察到该抑制剂具有令人印象深刻的放射增敏作用。在体内未观察到该组合的毒性。其作用机制可能与抑制辐射诱导的DNA损伤修复有关。这项临床前研究的结果将为考虑将该制剂作为辐射增敏剂进行临床人体试验提供必要的信息。我们已经证明了一种新型的HSP90抑制剂是一种辐射增敏剂(在体外和体内)。用这种试剂观察到了显著的体外辐射剂量调节因子，异种移植研究正在进行中。这种药物也有可能被转化为人体临床试验。我们已经开始了初步的体外研究，评估了一种CDK4/6抑制剂，它显示了显著的放射增敏作用。我们继续评估一些代谢抑制剂作为辐射调节剂的工作假设，即抑制新陈代谢(例如，减少ATP产生)将削弱辐射诱导的DNA损伤的修复。我们目前正在评估一种新的乳酸脱氢酶抑制剂，包括谷氨酰胺抑制剂和不含谷氨酰胺抑制剂，作为潜在的肿瘤细胞生长的辐射调节剂。关于正常组织对辐射的反应，我们完成了一项研究，证明在动物的食物中供应的雷帕霉素可以部分地通过防止辐射诱导的干细胞衰老来预防辐射诱导的肺纤维化。我们继续开发一种测试新型功能成像平台，以更好地了解肿瘤缺氧和代谢对荷瘤动物辐射和药物诱导的肿瘤反应的贡献。总体而言，我们已经确定了一些临床前方法来启动人类放射肿瘤学临床试验，以调节肿瘤和正常组织的辐射效应。