Induction of Senescence using Dexamethasone to re-sensitize NSCLC to anti-PD1 therapy

使用地塞米松诱导衰老使 NSCLC 对抗 PD1 疗法重新敏感

• 批准号: 10425223
• 负责人: NITHYA RAMNATH
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425223
• 关键词: Adenocarcinoma Cell; Affect; American; Blood; CCL2 gene; CCL4 gene; CXCL1 gene; CXCL2 gene; Cancer Etiology; Cell Cycle; Cell Cycle Arrest; Cell Line; Cells; Cessation of life; Chronic; Clinical; Clinical Trials Design; Complex; DNA Sequence Alteration; Data; Development; Dexamethasone; Diagnosis; Disease; Exposure to; FCGR3B gene; G1 Arrest; Genes; Glucocorticoid Receptor; Glucocorticoids; Growth; Health; Image; Immune; Immune checkpoint inhibitor; Immune system; Immuno-Chemotherapy; Immunotherapy; Infiltration; Lead; Lesion; Lung Adenocarcinoma; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modeling; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Outcome; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Population; Positron-Emission Tomography; Protein Isoforms; Proteins; Publishing; Quality of life; Recombinants; Research; Resistance; S Phase; Shapes; Signal Transduction; Steroids; Survival Rate; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transcriptional Activation; Veterans; War; Withdrawal; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; arm; base; cancer cell; chemokine; chemotherapy; cohort; docetaxel; effective therapy; fighting; glucocorticoid receptor alpha; immune activation; improved; mRNA Expression; monocyte; neoplastic cell; novel; novel strategies; overexpression; pembrolizumab; preclinical study; protein activation; protein expression; public health relevance; receptor expression; response; senescence; success; treatment duration; tumor; tumor growth; tumor-immune system interactions

Lung cancer accounts for 30% of all cancers among American war Veterans, and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung cancer (NSCLC), with a 2-year survival rate of 10%. Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer. However, given the modest response rates of 20-25%% to these ICIs and the desire to extend their benefits to more patients, there is a critical need for the development of novel approaches that can expand the benefit from ICIs and create more durable responses, prolonging survival from lung cancer. Our studies show that extended dexamethasone (Dex) treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor (GR) overexpressing lung adenocarcinoma cell populations. Further, following withdrawal of Dex, proteins associated with the senescence associated secretory phenotype (SASP), particularly CCL2, CCL4, CXCL1 and CXCL2 strongly attracted and expanded T-cells, NK cells and monocytes and stimulated tumor cell cytolytic activity of NK cells. Our overarching hypothesis is that in lung AC patients who are not on baseline steroids, pre-treatment with Dex will induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GRα and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to ICI following complete Dex withdrawal. We will test this hypothesis through the conduct of the following aims. Specific Aim 1: Use FLT-PET imaging and blood analysis to test whether a 7-14 day pre-treatment of lung AC patients with Dex followed by Dex withdrawal will induce persistent senescence related cell cycle arrest in ≥ 1 lesion in ≥ 60% of patients, (based on GRα expression) accompanied by release of SASP proteins and activation of T and NK cells. Specific Aim 2: Test whether a 7-14 day pre-treatment of lung AC patients with Dex followed by Dex withdrawal and subsequent re-challenge with pembrolizumab will yield an overall response rate (ORR) of ≥ 33% to pembrolizumab in association with tumor GR status, SASP and immune cell activation. These aims will be conducted through a Phase II clinical trial designed as a single-arm two-stage study in Veterans whose lung AC has progressed on ICI. Based on our preliminary data, we expect that Dex will induce tumor senescence in at least one lesion in ≥ 60% of patients and secondarily improve overall response to pembrolizumab by 33%. Success with these aims would inform a larger study that could potentially change the way we approach patients with primary or acquired resistance to ICIs with an off the shelf medication that could re-sensitize lung AC to ICIs. Our proposed research could substantially benefit Veterans with metastatic NSCLC, a group with the most genomically complex lung cancers and poor survival.

肺癌占美国退伍军人所有癌症的30%，仍然是美国退伍军人中最常见的癌症。 与癌症相关的死亡原因。所有肺癌的一半是转移性非小细胞肺癌（NSCLC）， 两年存活率为10%免疫检查点抑制剂（ICI）的免疫治疗已经成为一种新的治疗方法。 这是一种很有前途的治疗策略，旨在利用免疫系统对抗肺癌。但鉴于 对这些ICI的20- 25%的适度响应率以及将其益处扩展到更多患者的期望， 迫切需要开发新的方法来扩大ICI的益处， 产生更持久的反应，延长肺癌患者的生存期。 我们的研究表明，延长地塞米松（Dex）治疗诱导不可逆的细胞周期 通过糖皮质激素受体中p27 Kip 1基因的慢性激活阻断和衰老表型 (GR)过表达肺腺癌细胞群。此外，在停用Dex后，蛋白质 与衰老相关分泌表型（SASP）相关，特别是CCL 2、CCL 4、CXCL 1 CXCL 2对T细胞、NK细胞和单核细胞有强烈的吸引和扩增作用，并刺激肿瘤细胞增殖 NK细胞的细胞溶解活性。我们的总体假设是，在基线水平未达标的肺AC患者中， 类固醇，用Dex预处理将在肿瘤细胞亚群中诱导持续衰老表型 表达中/高水平的GRα和由衰老细胞产生的趋化因子， 动员宿主免疫细胞在完全Dex撤出后重新启动对ICI的反应。我们将测试这个 假设通过以下目的的行为。 具体目标1：使用FLT-PET成像和血液分析来测试7-14天的 Dex治疗后停药的AC患者肺组织中的Dex可诱导持续性衰老相关细胞 ≥ 60%的患者在≥ 1处病变中出现周期停滞（基于GRα表达），伴有 SASP蛋白与T和NK细胞的活化。 具体目标2：测试是否对肺部AC患者进行Dex预治疗7-14天，然后进行Dex 退出研究和随后的帕博利珠单抗再激发将产生总体缓解率（ORR） 与肿瘤GR状态、SASP和免疫细胞活化相关的Pembrolizumab的≥ 33%。 这些目标将通过设计为单臂两阶段研究的II期临床试验进行 在接受ICI治疗的肺AC进展的退伍军人中。根据我们的初步数据，我们预计德克斯将 在≥ 60%的患者中诱导至少一处病变的肿瘤衰老，其次改善总体缓解 pembrolizumab下降了33%这些目标的成功将为一项更大规模的研究提供信息， 我们用现成的药物治疗对ICI有原发性或获得性耐药的患者的方式， 可以使肺AC对ICI重新敏感。我们提出的研究可以大大有利于退伍军人转移 非小细胞肺癌，一组基因组最复杂的肺癌和生存率低。

项目成果

Contrasting genetic structure in two co-distributed species of old world fruit bat.

旧大陆果蝠两种共同分布物种的遗传结构对比

• DOI: 10.1371/journal.pone.0013903
• 发表时间: 2010-11-10
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chen J;Rossiter SJ;Flanders JR;Sun Y;Hua P;Miller-Butterworth C;Liu X;Rajan KE;Zhang S
• 通讯作者: Zhang S

Stability of an Electrodeposited Nanocrystalline Ni-Based Alloy Coating in Oil and Gas Wells with the Coexistence of H₂S and CO₂.

• DOI: 10.3390/ma10060632
• 发表时间: 2017-06-09
• 期刊: Materials (Basel, Switzerland)
• 作者: Sui Y;Sun C;Sun J;Pu B;Ren W;Zhao W
• 通讯作者: Zhao W