Modulation of Therapeutic Response

为了改善癌症的治疗，人们对改变辐射损伤给予了相当大的关注。目前正在研究各种化疗和/或分子靶向药物与辐射的相互作用，以确定是否可以使肿瘤更敏感或正常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增益的方法，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。在给定的治疗范围内，增强肿瘤对辐射的反应而不增强正常组织的能力是可取的。我们完成了一种新型HSP90抑制剂和一种CDK4/6抑制剂作为辐射致敏剂的初步临床前研究（体外和体内）。在药物和异种移植物中都观察到显著的体外辐射剂量修饰因子，研究表明，药物与分次辐射的联合可增强放射敏感性。此外，我们已经确定了分子生物标志物，将有助于评估这两种药物的治疗效果。这两种药物都有可能被转化为人体临床试验。一项最初使用CDK4/6抑制剂（abemaciclib）的新发现被证实可以与完全不同的HSP90抑制剂（AT13387）一起使用。当与放疗联合使用时，这两种药物都抑制肿瘤血管生成，这是放疗后为肿瘤提供血管的过程，导致肿瘤再生。在过去的一年里，我们重点研究了血管生成抑制的机制，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。我们继续评估一些代谢抑制剂作为辐射调节剂，假设抑制代谢（例如，减少ATP的产生）会减少辐射诱导的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）增强了人胰腺癌细胞的放射敏感性。该药物的初步异种移植研究表明，单独使用该药物可显著延缓肿瘤生长，但没有增强放射反应。这一发现促使我们获得一种氧化磷酸化抑制剂，并考虑使用两种药物（LDHAi和OxPhos抑制剂）联合放疗来确定对肿瘤反应的影响。我们已经证明，LDHAi和OxPhos抑制剂与辐射联合使用时，比单独使用每种药物与辐射联合使用提供更多的放射致敏。我们还使用13c -丙酮酸MRI对肿瘤代谢进行无创监测，以评估肿瘤代谢的变化，以及针对肿瘤血流的MRI研究。这些临床前研究将提供必要的信息，以考虑在肿瘤放射致敏的临床人体试验中使用这些药物。总的来说，我们已经确定了一些临床前方法来启动人体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 initial 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. 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. 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. This finding has prompted us to obtain 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 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. 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.