Abstract 3554: Targeting chromatin remodeling complex in pediatric cancers

Abstract

Abstract Chromatin accessibility plays critical roles in maintaining normal gene regulatory programs in healthy tissue. Aberrant chromatin accessibility triggered by abnormal activity of a variety of chromatin remodeling complexes is known to activate and maintain tumor proliferation. The most widely known of these complexes is the SWI/SNF (also called BAF) complex. Studies have shown that BAF regulates chromatin accessibility in a more global manner and its long-term inhibition or functional loss may lead to non-specific downstream effects in both tumor and normal tissue. Thus, there is a need to further probe understudied complexes, such as the Imitation Switch (ISWI) family of chromatin remodelers, to find more cancer specific functions that can provide mechanistic insights that pave the way for novel therapeutic discoveries. We have examined the functions of these chromatin complex in different type of pediatric cancers to estsablish the pre-clinical rationale for potential novel pediatric cancer therapy. We discovered that fusion protein positive rhabdomyosarcoma (FP-RMS), an aggressive sub-type of RMS characterized by chromosomal translocations resulting in gene fusions between PAX3/7 and FOXO1 is highly dependent on chromatin accessibility. This aggressive subtype exhibits a significant vulnerability in its dependence on the oncogenic transcription factor PAX3-FOXO1, yet like many other TFs, PAX3-FOXO1 is currently not considered a viable therapeutic candidate. We have then carefully examined the effect of chemical inhibition and chemical degradation of BAF complex function in FP-RMS and discovered that BAF complex globally regulates chromatin accessibility, is not specifically regulating FP function. We next examined the function of other chromatin remodeling complexes that might regulate FP function specifically in FP-RMS. We identified that some of other chromatin remodeling complex, such as Nuclear Remodeling Factor (NURF) complex, a member of the ISWI chromatin remodeling complex family, interacts with a critical fusion protein, PAX3/7-FOXO1, in FP-RMS. There is limited understanding surrounding the functions of NURF complex, particularly in pediatric cancer. Here, we then studied the key functions of FP regulated by variety of chromatin remodeling complex utilizing combined chemistry and biology method to elaborate the essential functions of PAX3/7-FOXO1 fusion protein. We have developed variety of chemical strategies to target these complexes, and utilize these tool compounds to delineate the chromatin remodeling complex regulated FP functions. This study showcased our approach to advance cancer research by combining the power of chemistry, chemical biology, structural biology, computational biology and cellular biology to identify novel mechanistic understanding as well as novel therapeutic approach for pediatric cancers. Citation Format: Jun Qi. Targeting chromatin remodeling complex in pediatric cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3554.