Modulation of Therapeutic Response

为了改善癌症治疗，相当多的注意力已经放在辐射损伤的修饰上。正在研究各种化疗和/或分子靶向药物与放射的相互作用，以确定是否可以使肿瘤对放射治疗更敏感或使正常组织对放射治疗更耐受。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。该项目的一个目标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。增强肿瘤对辐射的响应而不增强给定治疗区域内的正常组织的能力是期望的。我们完成了一种新的HSP 90抑制剂和一种CDK 4/6抑制剂作为辐射增敏剂的临床前研究（体外和体内）。两种药物和异种移植物研究均观察到显著的体外辐射剂量调整因子，表明药物与分次辐射的组合导致放射敏感性增强。此外，我们已经确定了分子生物标志物，这将有助于评估两种药物的治疗效果。这两种药物都有可能转化为人体临床试验。我们继续评估一些代谢抑制剂作为辐射改性剂的工作假设下，抑制代谢（例如，减少ATP的生产）将减少辐射诱导的DNA损伤的修复。体外研究表明，一种新的乳酸脱氢酶抑制剂（LDHAi）可增强人胰腺癌细胞的放射敏感性。初步的异种移植研究表明，单独使用该药物可显著延迟肿瘤生长，但不会增强放射反应。我们目前正在探索不同的药物输送途径，以确定这是否可能提供放射敏感性的增强。我们已经启动了将LDHAi与丙酮酸脱氢酶抑制剂相结合的研究。初步研究表明，显着增强体外放射敏感性。计划将这两种药物与放射相结合的异种移植研究以及使用13 C-丙酮酸盐的功能性异种移植代谢成像研究，以确定特定的生化途径是否被阻断。这些临床前研究将提供必要的信息，以考虑在肿瘤放射增敏的临床人体试验中使用这些药物。去年进行的研究表明，动物食物中的雷帕霉素部分通过防止辐射诱导的干细胞衰老来防止辐射诱导的肺纤维化。这一发现促使我们研究辐射诱导的人类肿瘤细胞衰老。高剂量的辐射导致大部分细胞衰老。随着衰老清除剂的最新发展，其可以杀死衰老的人类癌细胞，我们已经进行了异种移植研究，其中肿瘤接受大剂量的辐射，并随后在辐射后用衰老清除剂进行治疗。我们已经发现，一类新的分子靶向药物，即CDK 4/6抑制剂是有效的辐射增敏剂在体外和体内。有趣的是，这些药物还抑制放射治疗后的肿瘤血管形成（血管发生），进一步增加治疗相关的肿瘤生长延迟。今后的研究重点将放在确定血管生成抑制的机制上。总的来说，我们已经确定了许多临床前方法，以启动人类放射肿瘤学临床试验，以调节辐射对肿瘤的影响。

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 finished pre-clinical studies of a novel HSP90 inhibitor and a CDK4/6 inhibitor as a radiation sensitizers (in vitro and in vivo). Significant in vitro radiation dose modification factors have been observed with both agents and xenograft studies indicate that the combination of the drug with fractionated radiation results in enhanced radiosensitivity. Further we have identified molecular biomarkers that will be helpful in assessing treatment efficacy for both agents. Both agents have potential of being translated into human clinical trials. 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. In vitro studies have shown that a novel lactate dehydrogenase inhibitor (LDHAi) enhances the radiosensitivity of human pancreatic carcinoma cells. Preliminary xenograft studies with this agent have shown a significant tumor growth delay with drug alone, but no enhancement of the radiation response. We are currently exploring different drug delivery routes to determine if this might provide enhancement of radiosensitivity. We have initiated studies combining the LDHAi with an inhibitor of pyruvate dehydrogenase. Preliminary studies shown significant enhancement of radiosensitivity in vitro. Xenograft studies combining both agents with radiation are planned as well as functional xenograft metabolic imaging studies using 13C-pyruvate to determine if particular biochemical pathways are blocked. These pre-clinical studies will provide the necessary information to consider these agents in a clinical human trial for tumor radiosensitization. Studies conducted last year demonstrating that rapamycin supplied in the animal's chow protected against radiation-induced lung fibrosis in part by preventing radiation-induced stem cell senescence. This finding has prompted us to study radiation-induced senescence in human tumor cells. High doses of radiation result in a large percentage of cells becoming senescent. With the recent development of senolytic agents, which can kill senescent human cancer cells, we have conducted xenograft studies where tumors receive large doses of radiation and are subsequently treated after radiation with senolytic agents. We have found that a new class of molecularly targeted agents, namely, CDK4/6 inhibitors are potent radiation sensitizers both in vitro and in vivo. Interestingly, these agents also inhibit tumor blood vessel formation (vasculogenesis) post-radiation treatment further increasing treatment related tumor growth delay. A major emphasis will be placed on determining the mechanism of vasculogenesis inhibition in future studies. Collectively, we have identified a number of pre-clinical approaches to initiate human radiation oncology clinical trials for modulation of radiation effects on tumors.