Lung cancer prevention and treatment by targeting ALDH1 and CD44 expressing putative lung cancer stem cells

通过靶向表达 ALDH1 和 CD44 的假定肺癌干细胞来预防和治疗肺癌

• 批准号: 10227075
• 负责人: Fekadu Kassie
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227075
• 关键词: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; Affect; Biological Availability; CD44 gene; Cancer Etiology; Carcinogens; Cells; Cessation of life; Chemoprevention; Cystine; Cytotoxic T-Lymphocytes; Data; Development; Disulfiram; Dose; Drug Modulation; Encapsulated; Epigenetic Process; Erinaceidae; Exhibits; Frequencies; Generations; Genetic; Genotype; Glutamates; Immune; Immune checkpoint inhibitor; Immunosuppression; Immunotherapy; K-ras Gene; KRAS2 gene; Literature; Longevity; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oxidative Stress; Pharmaceutical Preparations; Pharmacology; Population; Property; Proteins; Reporting; Role; Serum; Signal Pathway; Small Interfering RNA; Solid; Sulfasalazine; Testing; Tobacco smoke; Treatment Efficacy; Tumor Burden; United States; aldehyde dehydrogenase 1; anti-cancer; antitumor effect; cancer stem cell; cancer therapy; combinatorial; drug repurposing; immune checkpoint; immunoregulation; lipid nanoparticle; lung cancer cell; lung cancer prevention; lung development; lung tumorigenesis; member; mutant; nano; neoplastic cell; overexpression; prevent; programmed cell death ligand 1; self-renewal; smoothened signaling pathway; stem cell genes; stem cell population; stem cells; tumor; tumorigenesis; tumorigenic

PROJECT SUMMARY Lung cancer is the leading cause of cancer-related death in the United States. About 90% of lung cancer cases are associated with genetic/epigenetic changes induced by tobacco smoke (TS). Although all types of lung cells could be affected by TS, the effect on stem cells is particularly alarming owing to their longevity and propensity for transformation. Therefore, selective targeting of altered stem cells known as cancer stem cells (CSCs) could prevent the development of lung cancer. In this application, we will test the hypothesis that targeting of uniquely tumorigenic putative CSCs expressing high levels of aldehyde dehydrogenase 1(ALDH1H) and CD44 (CD44H) with the combination of the repurposed drugs disulfiram (DSF) and sulfasalazine (SAS) which are nano-formulated to enhance bioavailability will suppress the development and progression of carcinogen-induced and spontaneous lung tumor in mice. These hypotheses will be tested by the following three specific aims: Specific Aim 1: Determine the efficacy of SLN-DSF, SLN-SAS and SLN-DSF+SAS to suppress NNK- or mutant K-ras induced lung tumorigenesis by targeting ALDH1HCD44H subpopulations of lung cells. In this aim, mice treated with NNK or harboring mutations in K-ras gene will be given the drugs and modulation of tumor burden, frequency of ALDH1HCD44H lung tumor cells and CSC-associated proteins will be analyzed. Specific Aim 2: Determine the immunosuppressive effects of ALDH1HCD44H putative LCSCs and whether the anti-cancer effects of SLN-DSF-SAS are mediated, at least in part, via immunomodulatory mechanism and its potential to enhance the therapeutic efficacy of anti-PD-L1 immune checkpoint inhibitors. Hypothesis: Overexpression of PD-L1 by ALDH1HCD44H lung tumor cells endows them immunosuppressive properties and modulation of these properties by SLN-DSF-SAS could potentiate anti-PD-L1-induced rescuing of dysfunctional cytotoxic T cells and tumor destruction. Specific Aim 3: Determine the role of common NSCLC genetic alterations in the generation, proliferation, self- renewal, and tumor propagating efficiency of ALDH1HCD44H putative CSCs and if these effects are modulated by SLN-DSF+SAS. Hypothesis: The genotype of transformed lung cells could be an important determinant of the self-renewal and tumor-propagating potential of ALDH1H CD44H fractions. Impact: Targeting ALDH1H CD44H putative CSCs is a new paradigm shift in lung cancer prevention and treatment as these cells are believed to be the cell of origin of cancer.

项目概要 肺癌是美国癌症相关死亡的主要原因。约90%的肺癌病例 与烟草烟雾（TS）引起的遗传/表观遗传变化有关。尽管所有类型的肺 细胞可能会受到 TS 的影响，对干细胞的影响尤其令人担忧，因为它们的寿命很长，而且 转变的倾向。因此，选择性靶向改变的干细胞（称为癌症干细胞） （CSC）可以预防肺癌的发展。在此应用中，我们将测试以下假设： 靶向表达高水平乙醛脱氢酶 1 (ALDH1H) 的独特致瘤推定 CSC 和 CD44 (CD44H) 与重新利用的药物双硫仑 (DSF) 和柳氮磺吡啶 (SAS) 的组合 纳米制剂可提高生物利用度，抑制疾病的发展和进展 致癌物诱发的小鼠自发性肺肿瘤。这些假设将通过以下方面进行检验 三个具体目标： 具体目标 1：确定 SLN-DSF、SLN-SAS 和 SLN-DSF+SAS 抑制 NNK- 或 突变型 K-​​ras 通过靶向肺细胞的 ALDH1HCD44H 亚群诱导肺肿瘤发生。为了这个目标， 接受 NNK 治疗或携带 K-ras 基因突变的小鼠将接受药物和肿瘤调节 将分析 ALDH1HCD44H 肺肿瘤细胞和 CSC 相关蛋白的负担、频率。 具体目标 2：确定 ALDH1HCD44H 假定的 LCSC 的免疫抑制作用以及是否 SLN-DSF-SAS 的抗癌作用至少部分是通过免疫调节机制及其 增强抗PD-L1免疫检查点抑制剂治疗效果的潜力。假设： ALDH1HCD44H 肺肿瘤细胞过度表达 PD-L1 赋予其免疫抑制特性 SLN-DSF-SAS 对这些特性的调节可以增强抗 PD-L1 诱导的拯救 功能失调的细胞毒性 T 细胞和肿瘤破坏。 具体目标 3：确定常见 NSCLC 基因改变在生成、增殖、自我修复中的作用 ALDH1HCD44H 推定 CSC 的更新和肿瘤增殖效率以及这些效应是否受到调节 通过 SLN-DSF+SAS。假设：转化肺细胞的基因型可能是重要的决定因素 ALDH1H CD44H 片段的自我更新和肿瘤增殖潜力。 影响：靶向 ALDH1H CD44H 推定 CSC 是肺癌预防和治疗的新范式转变 治疗，因为这些细胞被认为是癌症的起源细胞。