Impact of local and systemic cellular senescence toward Triple Negative Breast Cancer growth and drug therapy

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ABSTRACT Triple negative breast cancer is considered one of the most aggressive forms of breast cancer and efficacious treatment options are lacking. A potential therapeutic avenue is related to senescent cells. Cellular senescence engages in important roles for many aspects of tissue homeostasis. As the natural process of aging occurs along with stresses and insults from the environment, cells in various organs and tissues of the body can undergo senescence, a phase of arrested growth and exit from the cell cycle that is established in order to prevent further propagation of damaged cells. A defining feature of senescent cells is their senescence- associated secretory phenotype (SASP), a group of cytokines, proteases, and growth factors, which are thought to recruit cells of the immune system to clear out damaged cells. Length of exposure to the SASP impacts what happens to the microenvironment. During embryonic development, wound healing, suppression of tumor growth, and recruitment of immune cells, short-lived, reversible senescence of defined cell populations and the resultant SASP promote optimal fitness for the organism. On the other hand, when senescent cells are present chronically, the SASP can have more negative effects, which include promoting an environment for tumorigenesis and metastasis. In terms of TNBC, no known studies have been carried out that assess how senescence and the SASP impact TNBC progression. In my preliminary studies, I have utilized the ATTAC mouse model (=Apoptosis through Activated Caspase 8). In this model, senescent cells express a drug-inducible suicide gene cassette under the control of p16Ink4a regulatory sequences. When given an inducing drug, AP20187, senescent cells expressing p16ink4a are eliminated by apoptosis. Thus, the first aim of my grant is to assess the effect of local and systemic senescent cells on growth and metastasis of the syngeneic TNBC cells in the ATTAC mice as hosts. The preliminary data suggest that continuous clearance of host senescent cells results in reduced tumor growth. Based on this, under a second aim I wish to analyze the impact that senolytics (drugs that eliminate senescent cells) have on the efficacy of cancer therapeutics (i.e. immune checkpoint inhibitors) towards TNBC. No known studies have yet been done that look at the relationship between immune checkpoint inhibitors and senescence towards TNBC. Thus, completion of these aims will provide not only insight on how TNBC growth is affected by both the microenvironment and the system as a whole, but also the possibility of discovering unique pharmacological targets for more effective TNBC treatments.