Use of senolytics to enhance chemotherapeutic efficacy in lung cancer

使用 senolytics 增强肺癌化疗效果

• 批准号: 9765748
• 负责人: David A. Gewirtz
• 金额: $ 39.9万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765748
• 关键词: Address; Aftercare; Animals; Antigens; Antitumor Response; Apoptosis; Apoptotic; BCL1 Oncogene; BCL2 gene; CD8-Positive T-Lymphocytes; Cell Aging; Cell Culture Techniques; Cell Death; Cells; Characteristics; Clinical Trials; Cross Presentation; Data; Disease; Dose; Effectiveness; Exposure to; Family; Goals; Growth; Histone Deacetylase Inhibitor; Human; Immune; Immune response; Immune system; Immunization; In Vitro; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Mus; Non-Small-Cell Lung Carcinoma; Outcome Study; Patients; Population; Predisposition; Property; Protein Family; Protocols documentation; Radiation; Recovery; Recurrence; Recurrent disease; Residual Tumors; Residual state; Role; Schedule; Series; Site; Sorting - Cell Movement; Stable Disease; Sum; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tumor Immunity; Work; anti-tumor immune response; assault; base; cancer cell; cancer recurrence; cell growth; cell killing; chemotherapy; clinically relevant; defined contribution; design; experimental study; immunogenic; immunogenic cell death; in vitro Model; inhibitor/antagonist; mortality; mouse model; neoplastic cell; novel; pre-clinical; preclinical study; prevent; response; self-renewal; senescence; therapeutic effectiveness; tumor

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.

项目概要/摘要化疗和放疗常常导致肺癌进入长期状态 具有衰老特征的生长停滞。类衰老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）中幸存的肿瘤细胞有能力恢复增殖能力 在其长期生长停滞之后。肿瘤细胞从这种生长中恢复并重新出现- 逮捕状态可能会导致患者在明显被逮捕数月或数年后疾病复发。 原发病已治愈。最近已鉴定出许多药剂具有抗衰老特性。 鉴于疾病复发和随之而来的癌症死亡率通常与复发有关 该项目的主要目标是在原发疾病部位或转移部位增殖肿瘤细胞 是为了检验衰老药物可以消除衰老样肺肿瘤细胞以预防的假设， 或者至少显着抑制癌症复发。目标 1 将检验以下假设：衰老抑制剂 例如促生存BCL-2家族抑制剂ABT-263会选择性消除衰老样细胞 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 临床相关疗法诱导的癌症 (NSCLC) 细胞，并确定其对 senolytic 治疗的敏感性。 我们还将确定在衰老过程中对衰老药物的敏感性是否发生改变，以及是否 治疗药物消除大部分肿瘤群体后存活下来的剩余群体 特别证明对 senolytics 的细胞杀伤作用的敏感性。最后，离体研究将确定 TIS 细胞在不存在和存在的情况下诱导抗原交叉呈递和 CD8 T 细胞启动的能力 ABT-263。目标 2 将确定 ABT-263 在 TIS 细胞中诱导细胞凋亡的机制。我们将检查 促生存 BCL-XL 和/或 BCL-W 作为 ABT-263 靶标的作用，评估 BCL-2 之间的相互作用 家族蛋白并确定 p53 是否是 TIS 细胞对凋亡细胞死亡敏感所必需的。目标 3 将检验 ABT-263 等 senolytics 药物将增强化疗反应的假设 和/或免疫缺陷和免疫功能正常小鼠模型中的辐射。为了检验这个假设，我们将 使用小鼠 Lewis 肺癌 NSCLC 肿瘤模型来：(i) 研究免疫系统如何响应 TIS 细胞； (ii) 确定诱导衰老的主要疗法的耐受给药方案，然后进行衰老抑制剂 治疗; (iii) 确定衰老药物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）确定细胞非自主（即免疫）的参与 系统介导的）对化疗和放疗诱导的肿瘤细胞衰老的反应 和衰老剂的存在； (ii) 建立消除 NSCLC 细胞的治疗策略 有可能导致疾病复发。