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 肺癌是美国癌症相关死亡的主要原因。大约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 细胞可能受到TS的影响，对干细胞的影响特别令人担忧，因为它们的寿命长， 转化的倾向。因此，选择性靶向被称为癌症干细胞的改变的干细胞， （CSCs）可以预防肺癌的发展。在本申请中，我们将检验以下假设： 靶向表达高水平醛脱氢酶1（ALDH 1H）的独特致瘤性推定CSC 和CD 44（CD 44 H）与再利用药物双硫仑（DSF）和柳氮磺胺吡啶（SAS）的组合 其被纳米配制以提高生物利用度， 致癌物诱导的和自发的小鼠肺肿瘤。这些假设将通过以下方式进行检验： 三个具体目标： 具体目的1：确定SLN-DSF、SLN-SAS和SLN-DSF+SAS抑制NNK-或 突变K-ras通过靶向肺细胞的ALDH 1HCD 44 H亚群诱导肺肿瘤发生。在这一目标下， 用NNK或K-ras基因突变处理的小鼠将被给予药物和肿瘤的调节， 将分析ALDH 1HCD 44 H肺肿瘤细胞和CSC相关蛋白的负荷、频率。 具体目的2：确定ALDH 1HCD 44 H推定的LCSC的免疫抑制作用，以及ALDH 1HCD 44 H是否抑制LCSC的免疫抑制作用。 SLN-DSF-SAS的抗癌作用至少部分地通过免疫调节机制介导， 增强抗PD-L1免疫检查点抑制剂的治疗功效的潜力。假设： ALDH 1HCD 44 H肺肿瘤细胞过表达PD-L1赋予它们免疫抑制特性， SLN-DSF-SAS对这些特性的调节可以增强抗PD-L1诱导的 功能失调的细胞毒性T细胞和肿瘤破坏。 具体目标3：确定常见的NSCLC遗传变异在NSCLC的生成、增殖、自身免疫应答和预后中的作用。 更新和肿瘤增殖效率，以及如果这些作用被调节， 通过SLN-DSF+SAS。假设：转化的肺细胞的基因型可能是一个重要的决定因素， ALDH 1H CD 44 H组分的自我更新和肿瘤增殖潜力。 影响：靶向ALDH 1H CD 44 H推定的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。