Thursday, May 2, 2024
5/2/2024
PROJECT SUMMARY The loss of the tumor suppressor gene SMARCB1, a core member of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, defines a group of malignancies characterized by a particularly aggressive clinical course and prominent metastatic behavior. Renal medullary carcinoma (RMC) is the most commonly diagnosed SMARCB1-deficient renal malignancy and predominantly afflicts young individuals of African descent carrying the sickle cell trait. SMARCB1-deficient renal malignancies are extremely challenging diseases that fail to respond to standard-of-care therapeutic regimens used for other renal tumors. In our recent work, we found that SMARCB1-deficient renal malignancies such as RMC are characterized by a highly inflamed phenotype, yet demonstrate accelerated tumor progression (hyperprogression) in response to standard immune checkpoint inhibition (ICI). Our preliminary data in prospectively collected tissue specimens and immunocompetent genetically engineered mouse models (GEMMs) of RMC suggest that this hyperprogression following ICI is due to the engagement of myeloid-affiliated transcriptional programs in tumor cells. Our overarching hypothesis is that the hijacking of myeloid-affiliated transcriptional circuits by SMARCB1-deficient renal malignancies is the major mechanism driving ICI-induced hyperprogression, which can be prevented by targeting master myeloid regulators such as S100A9 and the CEBPB/p300 complex. In the first aim, we will perform immunogenomic profiling studies at the single-cell level in our clinical trial tissue specimens and immunocompetent GEMMs to determine how ICIs, using anti-PD-1 alone or in combination with either anti- CTLA-4 or anti-LAG-3, modulate the tumor immune microenvironment to drive hyperprogression via the engagement of myeloid-affiliated transcriptional pathways. In the second aim, we will perform translational genomic and pharmacologic experiments in our GEMMs of RMC to determine whether targeting S100A9 or the CEBPB/p300 complex can induce sensitivity to ICIs in SMARCB1-deficient renal malignancies. In the third aim, we will utilize a first-in-class technology that enables the retrieval of ICI therapy-resistant clones to investigate clonal dynamics in our GEMMs and determine the role of SMARCB1 loss in the engagement of myeloid-related transcriptional pathways and subsequent hyperprogression of tumor cells following ICI treatment. This project is realistic and feasible within the proposed timeline and budget because it utilizes technology, tissue samples, and models of SMARCB1-deficient renal malignancies already available to the multidisciplinary research team of experts and a dedicated translational pipeline led by the PI, Dr. Pavlos Msaouel. Our approach can provide fundamental information about the mechanisms of ICI-induced hyperprogression in SMARCB1-deficient renal malignancies, which will substantially improve our understanding of how to optimally elicit antitumor immune responses and thus will open new therapeutic avenues for these and other diseases driven by loss of SMARCB1 or of other subunits of the SWI/SNF chromatin remodeling complex.
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