Chemotherapy and radiation can induce breast tumors to enter a prolonged state of growth arrest with characteristics of senescence. A senescent-like state is also characteristic of residual tumor cells that survive after chemotherapy and/or radiation have eliminated the bulk of a tumor cell population. Tumor cells surviving therapy-induced senescence have the capacity to recover proliferative capacity subsequent to their prolonged growth arrest. Recovery and re-emergence of tumor cells from this growth-arrested state could contribute to disease recurrence months or years after the patient has apparently been cured of the primary disease. Several agents have recently been identified as having senolytic properties [e.g. ABT-263 (navitoclax)] which can selectively kill senescent cells. Given that disease recurrence and consequent cancer mortality is frequently associated with the re-emergence of proliferative tumor cells either at the primary disease site or metastatic sites, a primary goal of this project will be to test the hypothesis that senolytic agents can eliminate therapy induced senescent breast tumor cells to prevent, or at least significantly suppress, cancer recurrence.
Aim 1 will examine the hypothesis that the senolytic agent, ABT-263, can efficiently eliminate cells induced into senescence by chemotherapy or radiation when used sequentially (and potentially, repeatedly) after the initial therapy. Sensitivity to senolytics will be assessed in senescence-sorted breast tumor cells, prior to senescence and during the course of recovery, and in residual populations surviving after the bulk of the tumor population has been eliminated by therapeutic agents. The effectiveness of a sequential treatment schedule will also be assessed in vivo using xenograft and PDX tumor models.
Aim 2 will interrogate the mechanisms whereby the senolytic ABT-263 promotes cell death in senescent breast tumor cells, with a focus on the contributions of pro- and anti-apoptotic BCL-2 family proteins.
Aim 3 will examine the immune response to therapy-induced senescent cells alone and after treatment with senolytics. A phenotypic assessment of tumor infiltrating immune cells and studies with selective immune cell depletion in mouse models will define the nature (adaptive and innate) of the antitumor immune response. Ex vivo studies will further determine NK- and T cell-mediated lysis of senescent cells in the absence or presence of ABT-263. The ability of senolytics to induce immunogenic cell death will be a focus. Toxicity to the host will be compared for exposure to senolytics concomitant with chemotherapy (i.e. prior to entry into senescence) and subsequent to induction of senescence.
Statement This project is designed to evaluate the capacity of senolytic agents to eliminate breast tumor cells induced into senescence by chemotherapy and radiation, with studies in both cell culture and tumor bearing animals, and to identify the contribution(s) of the immune system to the effectiveness of this therapeutic strategy.
