Optimizing radiation therapy through the manipulation of glutamine metabolism

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PROJECT SUMMARY Up to 50% of patients with locally advanced cervical cancer treated with the current standard of care will fail this treatment, and there is currently no cure for recurrent or metastatic disease. As a result of our recently completed studies of the connection between cervical cancer metabolism and radiation resistance, we have found that cervical cancer is highly dependent upon glutamine. Recent data has also demonstrated that targeting glutamine metabolism not only limits tumor cell growth, but also improves anti-tumor immunity by reprogramming macrophages in the tumor microenvironment (TME) towards a more pro-inflammatory phenotype. Given that radiation therapy (RT) has also been shown to promote anti-tumor immunity, these findings suggest that the combination of targeting glutamine metabolism and RT may synergize to enhance anti-tumor immunity and achieve long term tumor control. The purpose of this renewal R01 application is to perform preclinical mechanistic studies and a corresponding investigator-initiated clinical trial to support targeting glutamine metabolism with radiation therapy as a novel therapeutic strategy for radiation-resistant cervical cancers. Our working hypothesis is that inhibition of glutamine metabolism enhances radiation sensitivity through synergistic metabolic effects on tumor cells and immune cells within the TME. In Specific Aim 1, we will test whether the combination of the glutaminase inhibitor, CB-839, and chemoradiation improves anti-tumor immune responses using paired human tumor specimens collected in the context of an investigator initiated Phase I/II clinical trial. In Specific Aim 2, using 2D and 3D co-culture systems, we will determine whether the cytotoxic effects of inhibition of glutamine metabolism are mediated primarily through metabolic effects on tumor cells versus the combined effects on tumor cells and macrophages. In Specific Aim 3, using a patient derived xenograft (PDX) library and a novel genetically engineered mouse model (GEMM), we will determine whether the radiation modifying properties of CB-839 are dependent upon metabolic editing of the tumor microenvironment, and test new therapy combinations that will support future clinical trials. This work will generate a mechanistic rationale and test predictive biomarkers for the inhibition of glutamine metabolism and RT, and in so doing complete the first-in-human trial of CB-839 + chemoradiation in cervical cancer. This clinical trial is unique in that it includes an investigational new drug, CB-839, administered with both conventionally fractionated external beam RT as well as high dose rate hypofractionated brachytherapy. This design will provide valuable data in humans regarding the effects of RT dose and fractionation on chemoradiation and CB-839 associated changes in the TME.