Modulation of Therapeutic Response

为了改善癌症治疗， 对辐射损伤的修正各种化疗和/或化疗药物之间的相互作用 分子靶向药物与放射治疗正在研究中，以确定是否可以使肿瘤 更敏感或正常的组织对放射治疗更有抵抗力。中心目标是 确定将导致净治疗收益的方法，从而改善癌症 放射治疗。该项目的一个目标是定义和更好地理解这些 肿瘤生理学方面，包括细胞和分子过程以及 肿瘤微环境对治疗反应的影响。提高反应的能力， 在不增强给定治疗区域内的正常组织的情况下， 令人向往最初使用CDK 4/6抑制剂（abemaciclib）的新发现是 证实了与完全不同的代理，HSP 90抑制剂（AT 13387）的操作。 当与辐射结合时，两种药物都抑制肿瘤血管生成，这是一个过程， 在放射后，血管重新供应肿瘤，导致肿瘤再生。 过去的一年里，我们把重点放在确定血管发生的机制上 抑制，我们发现这两种药物都抑制HIF-1 α和SDF-1。我们目前正在 进行研究，以确定这种抑制的机制， 评价药物治疗联合放射治疗后的肿瘤血流。抑制 血管发生应导致治疗后肿瘤中血流受损。我们 初步数据表明，治疗的肿瘤中的血流确实减少。我们继续 评估一些代谢抑制剂作为辐射改性剂下的工作 假设代谢抑制（例如，ATP产生减少）将减少 修复辐射引起的DNA损伤体外研究表明， 脱氢酶抑制剂（LDHAi）增强人胰腺癌放射敏感性 细胞初步的异种移植研究表明，这种代理显着的肿瘤生长 单独使用药物延迟，但不增强辐射反应。我们还评估了 氧化磷酸化的抑制剂，同时使用两种试剂（LDHAi和OxPhos 抑制剂）与放射组合以确定对肿瘤反应的影响。我们已经表明 LDHAi和OxPhos抑制剂的组合在与辐射组合时提供 比单独使用每种试剂与辐射所观察到的放射增敏作用更强。我们重点 在过去的一年中，使用胰腺和肺的两种KRAS突变抑制剂（AMG 510，MRTD 849） 在KRAS中具有特定突变（G12 C）的癌细胞系。初步数据显示 这两种试剂都是有效的辐射敏化剂。我们还在进行非侵入性监测 使用13 C-丙酮酸盐MRI评估肿瘤代谢的变化， MRI研究，解决肿瘤血流和缺氧状态。这些临床前研究将 提供必要的信息，以考虑这些药物在临床人体试验的肿瘤 放射增敏总的来说，我们已经确定了一些临床前方法， 启动人类放射肿瘤学临床试验，以调节放射对 肿瘤的

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. A new discovery initially made using the CDK4/6 inhibitor (abemaciclib) was confirmed to be operational with a completely different agent, the HSP90 inhibitor (AT13387). When combined with radiation both agents inhibited tumor vasculogenesis, which is a process following radiation that resupplies the tumor with blood vessels resulting in tumor regrowth. We have placed a major emphasis this past year on defining the mechanism of vasculogenesis inhibition which we have found that both agents inhibit HIF-1alpha and SDF-1. We are currently conducting studies to determine the mechanism of this inhibition and conducting studies evaluating tumor blood flow following drug treatment combined with radiation. Inhibition of vasculogenesis should result in compromised blood flow in the tumor following treatment. Our preliminary data suggest that indeed blood flow in the treated tumor is reduced. 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 have also evaluated an inhibitor of oxidative phosphorylation with the idea of using both agents (LDHAi and OxPhos inhibitior) combined with radiation to determine the impact on tumor response. We have shown that the combination of LDHAi and the OxPhos inhibitor when combined with radiation provides more radiosensitization than is observed for each agent alone with radiation. We have focused this past year on two KRAS mutation inhibitors (AMG510, MRTD849) using pancreatic and lung cancer cell lines which have the specific mutations (G12C) in KRAS. Preliminary data indicate both agents are potent radiation sensitizers. We are also conducting non-invasive monitoring of tumor metabolism using 13C-pyruvate MRI to assess changes in tumor metabolism as well as MRI studies that address tumor blood flow and hypoxia status. These pre-clinical studies will provide the necessary information to consider these agents in a clinical human trial for tumor radiosensitization. Collectively, we have identified a number of pre-clinical approaches to initiate human radiation oncology clinical trials for modulation of radiation effects on tumors.