Selectively Targeting Non-Proliferating Cancer Cells

ASPIRE Award (2020-Present)

René Bernards, PhD, Netherlands Cancer Institute (Principal); Anthony Letai, MD, PhD, Dana-Farber Cancer Institute

Senescent cells exist in a state of permanent proliferative arrest; they no longer reproduce, and are resistant to apoptosis (programmed cell death). In normal cells, the acquisition of cancer-causing mutations can induce senescence, which acts as a fail-safe mechanism to prevent transformation and tumor outgrowth. Established tumor cells can become senescent after treatment with chemotherapy or other cancer therapies. Senescence in cancer is a double-edged sword: although senescence stops proliferation and slows tumor growth, senescent cells can also remodel the surrounding microenvironment to a pro-tumorigenic state and contribute to a chronic inflammatory response that accelerates cancer metastasis. Senescent cancer cells are markedly different from proliferating cells in terms of gene expression, metabolism, cell morphology, and many other properties, potentially presenting unique opportunities to target these cells. Researchers in the Bernards and Letai labs are seeking to harness this unique biology to develop drugs known as senolytics that selectively kill senescent cancer cells. Toward that aim, they will leverage their previously validated in vitro senescence induction system to run small-molecule and genetic screens in multiple cancer cell lines to identify senolytic compounds and targets.  The small-molecule screen will use a library of drugs that have already been tested in clinical trials, so potent hits could potentially be moved quickly into patients for testing.  In parallel, these groups will use BH3 profiling, a technique developed by the Letai lab, on a large panel of cancer cell lines to identify the molecular pathways protecting senescent cancer cells from apoptosis. A deeper understanding of this biology could help develop new strategies to push senescent cancer cells toward death, thereby complementing findings from the small molecule and genetic screens. The ultimate goal of this research is to develop a powerful “one–two punch” sequential combination therapy that would stop cancer cell proliferation and kill residual senescent cells, while avoiding the toxicity often seen when combination therapies are given simultaneously.