Chemotherapy and radiation often induce lung cancers to enter a prolonged state of growth arrest with characteristics of senescence. A senescence-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 (TIS) 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. A number of agents have recently been identified as having senolytic properties. 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 senescent-like lung tumor cells in order to prevent, or at least significantly suppress, cancer recurrence.
Aim 1 will examine the hypothesis that senolytic agents such as the pro-survival BCL-2 family inhibitor ABT-263 will selectively eliminate cells in the senescence-like state. To this end, we will perform sorting to isolate exclusively senescent human and mouse non-small cell lung cancer (NSCLC) cells induced by clinically relevant therapies and establish their sensitivity to senolytic treatment. We will also determine whether sensitivity to senolytics is altered during the course of senescence, and whether residual populations surviving after the bulk of the tumor population has been eliminated by therapeutic agents specifically demonstrate susceptibility to the cell killing effects of senolytics. Finally, ex vivo studies will determine the ability to TIS cells to induce antigen cross presentation and CD8 T cell priming in the absence and presence of ABT-263.
Aim 2 will determine the mechanisms of apoptosis induced by ABT-263 in TIS cells. We will examine the role of pro-survival BCL-XL and/or BCL-W as targets of ABT-263, evaluate the interaction among the BCL-2 family proteins and determine whether p53 is required for sensitization to apoptotic cell death in TIS cells.
Aim 3 will examine the hypothesis that senolytic agents such as ABT-263 will enhance the response to chemotherapy and/or radiation in both immune-deficient and immune-competent mouse models. To test this hypothesis we will use the mouse Lewis lung cancer NSCLC tumor model to: (i) study how the immune system responds to TIS cells; (ii) determine a tolerated dosing schedule for primary therapies to induce senescence followed by senolytic treatment; (iii) determine how senolytic agents alter the cell non-autonomous response to chemotherapy and radiation. The sum of these experiments will (i) establish the involvement of cell non-autonomous (i.e. immune system mediated) responses to tumor cell senescence induced by chemotherapy and radiation in the absence and presence of senolytic agents; and (ii) establish a therapeutic strategy for the elimination of NSCLC cells that have the potential to contribute to recurrent disease.
Statement This project is designed to address the problem of cancer recurrence by evaluating the capacity of senolytic agents to eliminate non-small cell lung cancer cells induced into senescence by chemotherapy and radiation. Studies both in cell culture and in tumor bearing animals will also identify the contribution(s) of the immune system to the effectiveness of this therapeutic strategy.