Exploring sarcoma functional genomics to identify disease-specific vulnerabilities

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Matthew Hemming, MD, PhD,  Dana-Farber Cancer Institute
Recipient of the: Race to Cure Sarcoma Research Award

Sarcomas are uncommon and poorly understood malignancies of mesenchymal tissues. Their histologic diversity and diagnostic complexity bring tremendous challenge to optimal clinical management. The lack of understanding of the biological underpinnings of sarcoma development and neoplastic drivers is underscored by both the frequency of misdiagnosis and lack of targeted therapies. Strategies that shed light on the development of these tumors may offer means of better diagnosis and identify sarcoma subtype-specific tumor dependencies that represent therapeutic targets. Sarcomas are uncommon and poorly understood malignancies of mesenchymal tissues. Their histologic diversity and diagnostic complexity bring tremendous challenge to optimal clinical management. The lack of understanding of the biological underpinnings of sarcoma development and neoplastic drivers is underscored by both the frequency of misdiagnosis and lack of targeted therapies. Strategies that shed light on the development of these tumors may offer means of better diagnosis and identify sarcoma subtype-specific tumor dependencies that represent therapeutic targets.  Using chromatin-immunoprecipitation and next-generation sequencing (ChIP-seq), the enhancer landscape utilized by tumor cells may be exposed. Large enhancer domains regulate the expression of key oncogenes required for tumorigenesis and are useful in identifying tumor-specific patterns of gene regulation and expression. Together with RNA-seq, these experimental approaches enable a detailed ‘functional genomics’ exploration of a tumor subtype. As opposed to other genomic or proteomic approaches, functional genomics better affords the ability to discern a tumor’s cell-of-origin from knowledge of tissue- and cell-type-specific enhancer patterns, which holds particular diagnostic value to sarcoma. Taken together, this approach holds tremendous potential to better define sarcoma subtypes and reveal tumor vulnerabilities, both of which represent urgent challenges to advancing sarcoma patient care.  I propose to define and collate the enhancer and transcriptional landscape of sarcoma tumors and cell lines in Aim 1. Functional genomic profiles can be compared within and between sarcoma subtypes to generate a clearer understanding of genes that uniquely support a tumor’s identity and growth. Preliminary analysis of these tumor-specific oncogenic programs has identified a characteristic enhancer and transcriptional pattern in GIST and leiomyosarcoma. These results have led to the follow-up studies outlined in Aims 2 and 3, in which I will explore a novel transcriptional dependency in metastatic GIST and the toxic synergistic effects of tyrosine kinase and BET-bromodomain inhibitors on the GIST-specific epigenetic and transcriptional program. This novel drug combination represents an exciting translational opportunity in this disease, with drugs with independent mechanisms of action converging on a conserved tumor dependency.  Upon completion, this project will provide a framework for functionally stratifying sarcoma subtypes. This may provide a key for the development of additional diagnostic biomarkers and to better classify undifferentiated sarcomas. The identification of tumor vulnerabilities by these methods may also lead to therapeutic insights, as shown in preliminary data using BET bromodomain inhibitors to target the KIT enhancer in GIST. As these compounds are now in clinical trials, this work will serve as the basis for future clinical translation in GIST.

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