Investigating the chromatin remodeling complex PBAF in small cell lung cancer

About This Grant

Small cell lung cancer (SCLC) is a highly aggressive, recalcitrant neuroendocrine carcinoma associated with a dismal prognosis. Despite recent progress, the molecular mechanisms that promote the development of SCLC remain incompletely delineated and there is an urgent need for refined, more effective therapies. Our long-term goal is to elucidate the chromatin, epigenetic and transcriptional mechanisms that promote and are required for SCLC, and to translate these mechanistic findings to the clinic. We have recently identified recurrent inactivating mutations in genes that encode for subunits of the polybromo-associated BAF (PBAF), a SWI/SNF chromatin remodeling complex. Yet, the functional consequences, underlying mechanisms and therapeutic targets associated with PBAF inactivation are unknown. Our project is based on the following preliminary findings: 1) Genomic analyses of ~1200 SCLC patient samples reveal recurrent loss of function mutations in PBAF. 2) PBAF exerts tumor suppressor functions in cellular models. 3) PBAF-deficiency leads to a marked acceleration of SCLC development and a stark reduction in overall survival. 4) PBAF-deficient SCLC models exhibit increased chromatin accessibility and an upregulation of pro-growth, pro-metastatic gene expression programs. 5) PBAFdeficient SCLCs are reliant on residual SWI/SNF complexes for growth. Altogether, our results pinpoint a critical function for PBAF in SCLC. Our central hypothesis is that PBAF-deficiency promotes SCLC development by altering chromatin structure, transcription factor binding and gene expression programs, and that such alterations lead to the development of SCLCs with unique biological features and therapeutic vulnerabilities. To test these hypotheses, we will pursue the following three aims: 1) Establish the functional importance of PBAF during SCLC initiation, progression, and metastasis. 2) Elucidate the transcriptional and epigenetic mechanisms underlying PBAF-deficient SCLCs. 3) Evaluate SWI/SNF inhibition as a therapeutic strategy for PBAF mutant SCLCs. This project is significant because it focuses on understanding the function of a recurrently mutated chromatin remodeling complex in SCLC and will guide future translational efforts for the most aggressive form of lung cancer. It is conceptually and mechanistically innovative because it leverages the first PBAF-deficient mouse model of SCLC. Our investigations require the use of these innovative animal models to study the functions of PBAF during SCLC initiation, progression and metastasis, which is currently not possible with any other model. While there is no equivalent non-animal alternative that allows us to effectively perform the proposed investigations, the animal studies will be complemented, when suitable, with human centric models such as ex vivo human systems, patient derived xenograft models (PDXs) and human SCLC specimens. Finally, our study is technically innovative as it implements state-of-the-art epigenomic profiling techniques. Collectively, our research will improve the understanding of SCLC biology and reveal new therapeutic avenues for patients.