Lung cancer is a devastating disease that remains the top cause of cancer mortality and accounts for a quarter of all cancer related deaths. Despite improvements in molecularly targeted therapies and immunotherapies, the majority of patients with lung cancer still lack effective treatment options. The recent introduction of immunotherapy has led to a paradigm shift in the treatment of lung cancer patients. Unfortunately, only a subset of patients respond to currently approved immunotherapies and many patients develop resistance after initial response. Hence, new immunotherapies and drugs that synergize with immunotherapy are urgently needed to further help patients. This proposal is based on...

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Lung cancer is a devastating disease that remains the top cause of cancer mortality and accounts for a quarter of all cancer related deaths. Despite improvements in molecularly targeted therapies and immunotherapies, the majority of patients with lung cancer still lack effective treatment options. The recent introduction of immunotherapy has led to a paradigm shift in the treatment of lung cancer patients. Unfortunately, only a subset of patients respond to currently approved immunotherapies and many patients develop resistance after initial response. Hence, new immunotherapies and drugs that synergize with immunotherapy are urgently needed to further help patients. This proposal is based on intriguing recent clinical observations that reported that patients on immunotherapy who concomitantly received a type of steroid hormone called glucocorticoids had poorer outcomes. This is in line with prior knowledge of the immunosuppressive effects of glucocorticoid hormones in other diseases. Hence, we hypothesized that drugs that inhibit glucocorticoid signaling could work together with immunotherapy to increase treatment response rate. To test this hypothesis, we recently developed drug-like molecules that induce the destruction of glucocorticoid receptor by utilizing a new technology that sends cancer-causing proteins to the cell's waste disposal system. We call these molecules GR PROTACs (Glucocorticoid Receptor PROteolysis TArgeting Chimeras). The overarching goal of this proposal is to investigate the utility of GR PROTACs to synergize with immunotherapy and enhance anti-tumor immunity in lung cancer using mouse models. If successful, our study will provide a new therapeutic modality in lung cancer and further ignite excitement in this new research area of targeted protein degradation as a new cancer treatment modality.

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