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.

项目摘要 肺癌是美国与癌症有关的主要原因。约90％的肺癌病例 与烟草烟雾（TS）诱导的遗传/表观遗传变化有关。虽然所有类型的肺 细胞可能会受到TS的影响，由于其寿命和 转化的倾向。因此，选择性靶向改变的干细胞称为癌症干细胞 （CSC）可以防止肺癌的发展。在此应用程序中，我们将测试以下假设 靶向唯一表达高水平醛脱氢酶1（ALDH1H）的唯一性肿瘤假定的CSC 和CD44（CD44H）与重新利用的二硫酸（DSF）和磺胺丙嗪（SAS）的组合 纳米形成以增强生物利用度将抑制 致癌物诱导的小鼠肺肿瘤和自发性肺肿瘤。这些假设将通过以下测试 三个具体目标： 特定目标1：确定SLN-DSF，SLN-SAS和SLN-DSF+SAS的功效以抑制NNK-或 突变K-RAS通过靶向肺细胞亚群的ALDH1HCD44H诱导肺肿瘤。在这个目标中 用NNK处理或在K-RAS基因中携带突变的小鼠将获得药物和肿瘤的调节 将分析负担，ALDH1HCD44H肺部肿瘤细胞和CSC相关蛋白的负担。 具体目的2：确定ALDH1HCD44H推定的LCSC的免疫抑制作用以及是否是否 SLN-DSF-SAS的抗癌作用至少部分通过免疫调节机制及其介导 增强抗PD-L1免疫检查点抑制剂的治疗功效的潜力。假设： ALDH1HCD44H肺部肿瘤细胞对PD-L1的过表达赋予它们免疫抑制特性和 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。 特定目的3：确定常见NSCLC遗传改变在发电，增殖，自我的作用 续订和肿瘤传播ALDH1HCD44H推定的CSC的效率，如果这些效应是调制的 由SLN-DSF+SAS。假设：转化的肺细胞的基因型可能是重要的决定因素 ALDH1H CD44H分数的自我更新和肿瘤的潜力。 影响：针对ALDH1H CD44H推定的CSC是预防肺癌和 由于这些细胞被认为是癌症起源细胞。