Use of senolytics to enhance chemotherapeutic efficacy in lung cancer

项目概要/摘要化疗和放疗常使肺癌进入迁延状态 具有衰老特征的生长停滞。衰老样状态也是残留的特征。 化疗和/或放疗后存活的肿瘤细胞已经消除了大部分肿瘤细胞群。 在治疗诱导的衰老（TIS）中存活的肿瘤细胞具有恢复增殖能力的能力 在其长时间生长停滞之后。肿瘤细胞从这种生长中恢复和重新出现- 停滞状态可能会导致患者在显然已经被治愈后数月或数年的疾病复发。 治愈了原发病。许多药剂最近已被鉴定为具有衰老清除特性。 鉴于疾病复发和随之而来的癌症死亡率往往与复发有关， 增殖性肿瘤细胞在原发性疾病部位或转移部位，该项目的主要目标将 是为了检验衰老清除剂可以消除衰老样肺肿瘤细胞的假设， 或至少显著抑制癌症复发。目的1将检验衰老清除剂 如促存活BCL-2家族抑制剂ABT-263将选择性地消除衰老样细胞中的细胞， 状态为此，我们将进行分选，专门分离衰老的人和小鼠非小细胞肺 通过临床相关疗法诱导的非小细胞肺癌（NSCLC）细胞，并建立其对衰老清除治疗的敏感性。 我们还将确定在衰老过程中是否改变了对衰老药物的敏感性，以及是否 在大部分肿瘤群体被治疗剂消除后存活的残余群体 特别地证明了对senolytics的细胞杀伤作用的敏感性。最后，离体研究将确定 TIS细胞诱导抗原交叉呈递和CD 8 T细胞引发的能力， ABT-263目的2探讨ABT-263诱导TIS细胞凋亡的机制。我们将研究 促存活BCL-XL和/或BCL-W作为ABT-263靶点的作用，评估BCL-2与ABT-263之间的相互作用， 家族蛋白，并确定是否需要p53敏化TIS细胞中的凋亡性细胞死亡。目标3 将检验衰老清除剂如ABT-263将增强对化疗反应的假设 和/或辐射。为了验证这个假设，我们将 使用小鼠刘易斯肺癌NSCLC肿瘤模型：（i）研究免疫系统如何响应TIS （ii）确定诱导衰老的初级疗法的耐受给药方案，随后进行衰老清除疗法， （iii）确定衰老清除剂如何改变细胞对化疗的非自主反应，以及 辐射这些实验的总和将（i）建立细胞非自主性（即免疫性）的参与， 系统介导的）对在缺乏化疗和放疗的情况下由化疗和放疗诱导的肿瘤细胞衰老的反应 和衰老清除剂的存在;和（ii）建立消除NSCLC细胞的治疗策略， 有可能导致疾病复发。

Project Summary/Abstract 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.