Modulation of Therapeutic Response

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。一项最初使用CDK4/6抑制剂(Abemaciclib)的新发现被证实与另一种完全不同的试剂HSP90抑制剂(AT13387)一起工作。当与放射联合使用时，这两种药物都会抑制肿瘤血管生成，这是放射后的一个过程，使肿瘤重新获得血管供应，从而导致肿瘤再生。在过去的一年里，我们把重点放在了确定血管生成抑制的机制上，我们发现这两种药物都能抑制HIF-1α和SDF-1。我们目前正在进行研究，以确定这种抑制的机制，并进行研究，评估药物治疗联合放射治疗后的肿瘤血流。抑制血管生成应该会导致治疗后肿瘤内的血流受阻。我们的初步数据表明，经治疗的肿瘤中的血流量确实减少了。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。体外研究表明，一种新型乳酸脱氢酶抑制剂(LDHAi)可增强人胰腺癌细胞的放射敏感性。使用该制剂的初步异种移植研究表明，单用药物可显著延缓肿瘤生长，但不能增强放射反应。我们还评估了一种氧化磷酸化抑制剂，将这两种药物(LDHAi和OxPhos抑制剂)与放射联合使用，以确定对肿瘤反应的影响。我们已经证明，当LDHAi和OxPhos抑制剂结合起来时，与单独使用辐射相比，提供了更多的辐射增敏作用。在过去的一年里，我们重点研究了两种KRAS突变抑制剂(AMG510，MRTD849)，它们使用了在KRAS中具有特定突变(G12C)的胰腺和肺癌细胞株。初步数据表明，这两种试剂都是有效的辐射敏感剂。我们还在使用13C-丙酮酸MRI对肿瘤代谢进行非侵入性监测，以评估肿瘤代谢的变化，以及研究肿瘤血流和缺氧状态的MRI研究。这些临床前研究将为在肿瘤放射增敏的临床人体试验中考虑这些药物提供必要的信息。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，以调节肿瘤的辐射效应。

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.