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

项目总结 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。虽然各型肺 细胞可能受到TS的影响，对干细胞的影响尤其令人担忧，因为它们的寿命和 转变的倾向。因此，选择性靶向改变的干细胞被称为癌症干细胞 (CSCs)可以预防肺癌的发展。在此应用程序中，我们将测试以下假设 靶向高水平表达乙醛脱氢酶1(ALDH1H)的独特致瘤CSCs 和CD44(CD44H)，与改用药物双硫兰(DSF)和柳氮磺胺吡啶(SAS)联合使用 它们是用来提高生物利用度的纳米配方，将抑制 致癌物诱发和自发的小鼠肺肿瘤。这些假说将通过以下方式进行检验 三个具体目标： 具体目标1：确定SLN-DSF、SLN-SAS和SLN-DSF+SAS抑制NNK-OR的疗效 突变型K-ras通过靶向肺细胞ALDH1HCD44H亚群诱导肺肿瘤发生。在这个目标中， 接受NNK治疗或K-ras基因突变的小鼠将被给予药物和肿瘤调节 将分析ALDH1HCD44H肺癌细胞的负荷、频率和CSC相关蛋白。 具体目标2：确定ALDH1HCD44H可能的免疫抑制作用，以及 SLN-DSF-SAS的抗癌作用至少部分是通过免疫调节机制和其 有可能提高抗PD-L1免疫检查点抑制剂的治疗效果。假设： ALDH1HCD44H肺癌细胞过表达PD-L1使其具有免疫抑制特性和 SLN-DSF-SAS对这些特性的调节可增强抗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：确定常见的非小细胞肺癌基因改变在肺癌的发生、增殖、自体发育中的作用 ALDH1HCD44H可能的CSCs的更新和肿瘤增殖效率以及这些作用是否被调节 采用SLN-DSF+SAS。假设：转化的肺细胞的基因可能是一个重要的决定因素 ALDH1H CD44H组分的自我更新和肿瘤增殖能力 影响：靶向ALDH1H CD44H假定的CSCs是肺癌预防和治疗领域的新范式转变 这些细胞的治疗被认为是癌症的起源细胞。

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.