Using senolytic agents to suppress the toxicity of chemotherapy

ongoing

Many of the clinically used cancer chemotherapies have considerable short-term side effects, including fatigue, bone marrow suppression, nausea, diarrhea, and hair loss. Long-term side effects include cognitive impairment, organ dysfunction, and even secondary cancers. A body of evidence indicates that senescent cells induced by chemotherapy in non-cancerous tissues play a major part in these toxicities of chemotherapy. As part of the SENCAN grant, we have developed a cocktail of two drugs that is efficient in killing senescent cancer cells. This so-called senolytic cocktail synergizes strongly with chemotherapy in eradicating tumors in experimental animals. The senolytic cocktail acts independently of the genetic context of the cancer, thus demonstrating superior efficacy compared to other senolytic agents, which are context-dependent. We will test in this proof-of-concept grant whether this cocktail can also reduce the side effects of cancer chemotherapy by eliminating the senescent cells from non-cancerous tissues in mice. We use transgenic mice that carry a reporter gene that is activated in senescent cells and hence, tissues become luminescent when non-tumor-bearing animals are treated with chemotherapy. In pilot experiments, we have seen suppression of the luminescent signal when mice are treated with our senolytic cocktail post-chemotherapy. In this application, we plan to investigate the effect of the senolytic cocktail on vital organs that are often affected by chemotherapy: the bone marrow, the heart, and muscle (fatigue). If successful, the case for use of the senolytic cocktail in combination with cancer chemotherapy would become even stronger: not only have we already shown that the cocktail synergizes with chemotherapy in eradicating tumors in vivo in SENCAN, but the present work may also support the notion that the senolytic cocktail can suppress the toxicities that are invariably associated with cancer chemotherapy treatment.