We speculate that the same mutations that confer proliferative and growth advantages to cancer cells also incur a biological cost. We want to exploit these vulnerabilities to make new cancer therapeutics. Specifically, we analyze the cellular and molecular effects of key driver mutations in lymphoma. We use biochemical and biological experiments to understand the biological benefits and costs to the cancer of these mutations.
Examples include:
- The frequent mutations in immune receptor genes (HVEM, BTLA, EPHA7, beta-2 micro-globulin) that control lymphoma cell growth and shape the local immune environment. Notably, these receptors act on the cell surface and they are readily accessible to antibody conjugates and ligand-producing CAR T cell “micro-pharmacies.”
- Abnormal RNA translation in lymphoma and other cancers is required to support tumor growth and key translation factors, such as the eIF4A RNA helicase, drive the translation of oncogenic RNAs such as MYC and others. Natural compounds block the eIF4A helicase and we found that synthetic analogues are powerful cancer drugs. Surprisingly, RNA viruses such as SARS-CoV2 also depend on host cell eIF4A and we found that inhibitors can block viral replication.
- Cancer cell behavior reflects changes in gene expression that are controlled by epigenetic factors (e.g., KMT2D, CREBBP, EZH2) and by transcription factors such as MYC, NFkB, and NRF2. We don’t have pharmacological inhibitors for these factors, and therefore we use smart genetic screens to identify new ways of disrupting their function in cancer.