Modulation of Therapeutic Response

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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. Both a CDK4/6 inhibitor (abemaciclib) and a HSP90 inhibitor (AT13387) was was shown to be potent radiation sensitizers of human cancer cells. Further, both agents inhibited tumor vasculogenesis, which is a process following radiation that resupplies the tumor with blood vessels resulting in tumor regrowth. We are in the process of determining the mechanism of vasculogenesis inhibition which we have found that both agents that inhibit HIF-1alpha and SDF-1. We are currently using evaluating several imaging approaches to determine 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 tumor growth delay with drug alone, but no enhancement of the radiation response. We have also found that an inhibitor of oxidative phosphorylation has little effects of in vitro radiosensitization, not significant radiosensitization in vivo. The OxPhos inhibitor clearly results in less oxygen consumption in tumors thereby decreasing the hypoxic fraction in tumors and hence radiation sensitization. We have expanded studies 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. These two agents also show in vitro and in vivo radiosensitization. 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. We have recently acquired three different inhibitors of G12C mutations for evaluation. 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.