Executive Summary : | GLOBOCAN reported 834,860 cases of Head and Neck Cancers (HNCs) in 2018, resulting in over 431,000 deaths worldwide. In India, about one-third of all cases are HNCs, with 90% being squamous cell carcinomas (HNSCCs). Despite advancements in cancer therapy, many patients with HNSCCs do not benefit from available treatments. New therapeutic strategies tailored for molecularly selected patient populations are needed. Targeting epigenetic molecules offers a novel treatment approach for solid tumors. HNSCCs show mutations in several components of active histone mark regulators, such as NSD1, KMT2D, and EP300, CREBP, encouraging the search for other potential epigenetic changes with synthetic lethal consequences.
This project aims to test epigenetic drug-based treatment combinations in molecularly defined HNSCC subtypes. The study proposes investigating druggable vulnerabilities associated with mutations in two histone methyltransferases, NSD1 and KMT2D, present in 17% and 20% of HNSCCs. Genetic alterations in both genes are associated with chromatin changes at cis-regulatory elements and elevation of repressive histone mark, H3K27me3. EZH2 inhibitors like Tazemetostat are under clinical evaluation in cancers like ARID1A or BAP1 mutated malignancies. The proposed study will look for synthetic lethal consequences following drug-induced inhibition of EZH2 in NSD1 or KMT2D deficient HNSCCs. Bioinformatically analyzing published chromatin and expression data will identify commonly affected genes in HNSCCs, hypothesizing that these regulatory regions could play a central role in HNSCC pathogenesis and serve as effective biomarkers or actionable targets for effective treatment. |