Grant: CIHR - ICR / Cancer Research Society Partnership - Research Grants

Chemotherapy, such as doxorubicin, is often used to treat advanced or metastatic breast cancer. These aggressive breast cancers often metastasize to bone and/or spine. Doxorubicin is an anthracycline that can inhibit DNA synthesis through intercalation or topoisomerase inhibition, which triggers cell senescence and apoptosis. This drug has also been shown to induce cellular senescence in surrounding normal cells and tissues. Senescence is a phenomenon where cells stop dividing and take on distinct cellular changes in gene expression, metabolism and DNA organization. Senescent cells adopt a state called senescence-associated secretory phenotype (SASP), with the secretion of pro-inflammatory and pro-tumorigenic factors, as well as immune suppression. While chemotherapy can induce cancer cells to become senescent (originally thought be good), senescence in surrounding cells/tissues and tumor itself has been linked to advanced cancer growth and metastasis through SASP secretion. Chemotherapy-induced senescence in unrelated tissues also accelerates ageing and degenerative pathways. Senolytics specifically target senescent cells and induce apoptosis by various mechanisms. Here we test whether combining senolytics and chemotherapeutics targeting senescence will help to prevent cancer migration, decrease SASP, improve overall therapeutic efficacy, and decrease negative effects of senescence in other tissues. The overall goal is to develop new treatments to improve outcomes.