[R01] Targeting SEC61 complex to overcome resistance to immunotherapy in GBM
Ente: National Cancer Institute
Scadenza: 2029-12-31
Importo max: 519.870 EUR
Paese: US
Descrizione
Glioblastoma (GBM) is an incurable brain tumor with a median overall survival of less than 15 months. The recent
success of immunotherapy in extracranial malignancies has translated into trials for GBM. Despite its promise,
immunotherapy's clinical efficacy has yet to be shown for GBM. The resistance to immunotherapy in GBM is
multifactorial. To uncover the targets and pathways contributing to resistance in GBM, we designed and
performed an unbiased, genome-wide CRIPR-Cas9 knockout screen screening in a glioma cell line under a
cytotoxic T-cell mediated selection pressure. This screen identified SEC61subunit gamma (SEC61G) as a gene
involved in immunotherapeutic resistance in GBM. SEC61G is a component of the SEC61 translocon complex
in the endoplasmic reticulum. Our data shows that SEC61G is highly expressed in GBM, with genomic
amplification seen in up to 30-40% of GBM patients. Knocking out SEC61G sensitized glioma cells to T cell-
mediated therapy in vitro. Proteomic analysis of SEC61G knockout cells revealed an interplay of SEC61G
expression with the activation of the MAPK pathway in glioma cells. The proposed pre-clinical investigation aims
to understand the role SEC61G in immunotherapeutic resistance in GBM and to evaluate SEC61G as a
therapeutic target in combination with immunotherapy. We hypothesize that SEC61G confers resistance to T
cell-mediated immunotherapy in GBM and that targeting SEC61G can significantly enhance the response
of GBM to immunotherapy. This hypothesis will be tested in three Specific Aims. SA1 will investigate how
SEC61G overexpression interconnects with the MAPK pathway and contributes to the T cell-mediated
therapeutic resistance in glioma cells. SA2 will determine the contribution of SEC61G to the immunosuppressive
tumor microenvironment impeding the responses of T cells in GBM. SA3 will investigate SEC61G treatment
regimens in combination with T-cell mediated therapies using murine and human models of GBM. Upon
completing these studies, we will understand the mechanisms underlying SEC61G-mediated immunotherapeutic
resistance, characterize SEC61G as a therapeutic target, and yield translational results for the treatment of GBM
and potentially other solid tumors.
Istituzione: NORTHWESTERN UNIVERSITY AT CHICAGO
PI: Irina V Balyasnikova
Progetto: 5R01CA290737-02
Settori: National Cancer Institute
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