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Identifying new targeted senescence therapies using screening and mouse modeling approaches

There are currently thousands of FDA-approved drugs to treat a wide variety of cancers; however, the mechanism of action of many of these drugs have not been fully elucidated. Interestingly, many commonly used treatments, including conventional chemo- and radiation therapy, have been shown to induce cellular senescence in certain contexts, and it is likely that other anti-cancer agents may also activate senescence.

In order to identify new senescence-inducing therapies in a targeted fashion, we are developing senescence reporters to read out different aspects of the senescence and SASP phenotypes. We are then applying small molecule and genetic screening (e.g. CRISPR-based) approaches to our suite of genetically curated cancer cell lines to uncover new pro-senescence targets in a cancer and genotype-specific manner. Once identified we will then validate these targets in our mouse model platforms to understand how these senescence-inducing agents impact the surrounding microenvironment and in particular the immune system and immunotherapy efficacy in tumor types where they are currently ineffective.

Our hope is to develop this as a pipeline to translate new combinations of senescence-inducing targeted therapies and immunotherapies as treatments for cancer patients.