Use of senolytics to enhance chemotherapeutic efficacy in lung cancer

使用 senolytics 增强肺癌化疗效果

• 批准号: 10599636
• 负责人: David A. Gewirtz
• 金额: $ 5.64万
• 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/10599636
• 关键词: Address; Animals; Antigens; Apoptosis; Apoptotic; BCL1 Oncogene; BCL2 gene; BCL2L1 gene; CD8-Positive T-Lymphocytes; Cell Aging; Cell Culture Techniques; Cell Death; Cells; Characteristics; Chemotherapy and/or radiation; Cross Presentation; Disease; Dose; Family; Goals; Growth; Human; Immune; Immune system; Immunocompetent; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Mus; Non-Small-Cell Lung Carcinoma; Patients; Population; Predisposition; Property; Protein Family; Recovery; Recurrence; Recurrent disease; Residual Tumors; Residual state; Role; Schedule; Site; Sorting - Cell Movement; Sum; TP53 gene; Testing; Therapeutic; Therapeutic Agents; cancer recurrence; cell killing; clinically relevant; design; experimental study; inhibitor; lung cancer cell; mortality; mouse model; neoplastic cell; parent grant; prevent; response; 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 growtharrested 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 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： 化疗和放疗往往会导致肺癌进入长时间的生长停滞状态， 衰老的特征。衰老样状态也是残存肿瘤细胞存活的特征 在化疗和/或放疗已经消除了大部分肿瘤细胞群体之后。肿瘤细胞存活 治疗诱导的衰老（TIS）具有恢复增殖能力的能力， 长时间的生长停滞肿瘤细胞从这种生长停滞状态的恢复和重新出现， 有助于疾病复发后数月或数年的病人显然已经治愈的原发性 疾病许多药剂最近已被鉴定为具有衰老清除特性。鉴于这种疾病 复发和随之而来的癌症死亡率通常与增殖性肿瘤的再次出现有关， 肿瘤细胞无论是在原发性疾病部位或转移部位，该项目的主要目标将是测试 假设衰老清除剂可以消除衰老样肺肿瘤细胞，以防止或至少 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状态的细胞。本 最后，我们将进行分选，专门分离衰老的人类和小鼠非小细胞肺癌。 （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抑制剂的敏感性，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细胞在不存在的情况下诱导抗原交叉递呈和CD 8 T细胞引发的能力 和ABT-263的存在。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BCL-XL和/或BCL-W作为ABT-263靶点的作用，评估它们之间的相互作用， 在BCL-2家族蛋白中，确定p53是否是凋亡细胞致敏所必需的 TIS细胞死亡。目的3将检验衰老清除剂如ABT-263将增强衰老的假设。 在免疫缺陷和免疫活性小鼠模型中对化疗和/或放疗的反应。 为了检验这一假设，我们将使用小鼠刘易斯肺癌NSCLC肿瘤模型来：（i）研究肿瘤细胞如何在肿瘤细胞中表达。 免疫系统响应TIS细胞;（ii）确定初级治疗的耐受给药方案， 诱导衰老，然后进行衰老清除处理;（iii）确定衰老清除剂如何改变细胞的非衰老状态， 对化疗和放疗的自主反应。这些实验的总和将（i）建立 化疗诱导肿瘤细胞衰老的细胞非自主反应的参与， 在不存在和存在衰老清除剂的情况下进行辐射;以及（ii）建立针对衰老清除剂的治疗策略。 消除可能导致疾病复发的NSCLC细胞。