Use of senolytics to enhance chemotherapeutic efficacy in lung cancer

项目摘要/摘要化疗和放射治疗往往会导致肺癌进入长期状态 以衰老为特征的生长停滞。类衰老状态也是残留物的特征 在化疗和/或放疗后存活的肿瘤细胞已经消除了大部分肿瘤细胞。 在治疗诱导衰老(TIS)中存活的肿瘤细胞具有恢复增殖能力的能力 在他们长期的增长停滞之后。从这种生长中恢复和重新出现肿瘤细胞- 停滞状态可能会导致疾病复发，在患者显然已经 治愈了原发病。最近，许多试剂被鉴定为具有感光特性。 鉴于疾病复发和随之而来的癌症死亡往往与复发有关。 无论是在原发疾病部位还是在转移部位，该项目的一个主要目标是 是为了验证这样一种假设，即增感剂可以消除衰老的类肺癌细胞，以防止， 或者至少显著抑制癌症复发。目标1将检验这样一种假设：感觉剂 如促存活的bcl-2家族抑制剂ABT-263将选择性地消除细胞中的衰老样 州政府。为此，我们将进行分选，以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癌症(NSCLC)细胞，并确定其对感受性治疗的敏感性。 我们还将确定在衰老过程中是否改变了对衰老剂的敏感性，以及 大部分肿瘤种群被治疗剂消除后存活的剩余种群 特别展示了对感觉剂的细胞杀伤作用的敏感性。最后，体外研究将确定 TIS细胞诱导抗原交叉递呈和CD8T细胞在缺失和存在时的激发能力 ABT-263。目的2探讨ABT-263诱导TIS细胞凋亡的机制。我们将研究 促生存的bclxl和/或bclW作为ABT-263靶点的作用，评价bcl2之间的相互作用 并确定是否需要P53对TIS细胞中的凋亡性细胞死亡敏感。目标3 将检验ABT-263等促感觉剂将增强对化疗反应的假设 和/或辐射在免疫缺陷和免疫能力正常的小鼠模型中。为了检验这一假设，我们将 利用小鼠Lewis肺癌NSCLC肿瘤模型：(I)研究免疫系统对TIS的反应 细胞；(2)确定可耐受的主要治疗方法的剂量计划，以诱导衰老，然后进行衰老溶解 治疗；(Iii)确定感觉剂如何改变细胞对化疗和 辐射。这些实验的总和将(I)确定细胞非自主(即免疫)的参与 系统介导的)对化疗和放射诱导的肿瘤细胞衰老的反应 以及(Ii)建立消除非小细胞肺癌细胞的治疗策略， 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.