Targeting Aldehyde Dehydrogenase for Cancer Prevention

以醛脱氢酶为靶点预防癌症

• 批准号: 10327368
• 负责人: SHANTU G AMIN
• 金额: $ 12.5万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327368
• 关键词: Administrative Supplement; Aldehydes; Award; BRAF gene; Biological Markers; Carboxylic Acids; Cell Count; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical; Collaborations; Development; Disease Progression; Disease Resistance; Drug Combinations; Drug Exposure; Drug Targeting; Drug resistance; Drug usage; Effectiveness; Enzymes; Epigenetic Process; Equilibrium; Evaluation; Exposure to; Family; Gene Expression; Goals; Institutes; MEK inhibition; MEKs; Malignant Neoplasms; Mediating; Metabolism; Mitogen-Activated Protein Kinases; Modeling; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Population Sizes; Recurrence; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Site; Solid; Solid Neoplasm; Target Populations; Testing; The Wistar Institute; Translating; Treatment Efficacy; Work; aldehyde dehydrogenases; base; cancer cell; cancer drug resistance; cancer prevention; cancer type; clinically significant; drug development; drug efficacy; drug-sensitive; effective therapy; inhibitor/antagonist; innovation; interest; leukemia; melanoma; new therapeutic target; novel; patient derived xenograft model; pre-clinical; predict responsiveness; prevent; research clinical testing; response; therapeutic target; therapy development; tumor; tumor progression

PROJECT SUMMARY: This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-009 to establish a collaboration between the parent 1 R01 CA241148-01A1 and the NCI-supported PDX Development and Trial Centers Research Network (PDXNet)-Wistar Institute site. The project focuses on a unique form of cancer cell drug resistance identified in the parent R01 mediated by the Aldehyde Dehydrogenase (ALDH) expressing cellular subpopulations present in tumors. The ALDH family of enzymes convert toxic aldehydes generated during cellular metabolism into corresponding less toxic carboxylic acids that can be excreted and removed. ALDH expression and activity increases during tumor progression with a corresponding higher positive (ALDH+) subpopulation. In the parent R01, we have found that changing the size of the ALDH+ and negative (ALDH-) cell subpopulations, which occurs during drug treatment and resistance development, performs an important role in maintaining tumor ROS levels in an optimal range needed for the development of this novel type of drug resistance. This supplement proposes a collaboration to use melanoma PDXs developed by Dr. Meenhard Herlyn at the Wistar Institute to identify the most effective approach to prevent this novel form of cancer cell resistance. The goal will be to target the ALDH+ cells using DIMATE (under clinical evaluation for leukemia) in combination with a clinically used BRAF and MEK inhibitor combination targeting the ALDH- subpopulation. The evaluation would be undertaken in PDX models naïve or resistant to the BRAF/MEK drug combination. In the parent R01, we have discovered that ALDH+ and ALDH- cell subpopulations, cooperate to promote survival and achieve drug resistance. Furthermore, we have discovered in cultured cell line-based models that this cooperation can best be prevented by therapeutically targeting both populations. The ALDH cell number and/or the related ROS pathway signaling can be used as biomarkers to assess treatment efficacy in the PDX models. Therefore, we have formulated a novel central hypothesis that drug resistance can be prevented in cancer by targeting the ALDH positive cell population with DIMATE and the negative population by targeting the MAP kinase pathways through BRAF and MEK inhibition in PDX tumors resistant to MAP kinase inhibition. To test this hypothesis, we will determine the most effective consecutive or simultaneous targeting approach to prevent resistance in PDX melanoma models naïve or resistant to BRAF/MEK inhibition using DIMATE. PDX models used would have developed resistant to MAP kinase pathway inhibition through different mechanisms. The effectiveness of DIMATE will be compared to nanoKS100 (a preclinical agent developed in the Parent R01 Award), which we have found is effective at preventing resistance when combined with MAP kinase pathway targeting. The clinical significance of this project is that if successful, these discoveries could provide a solid rationale for testing this approach in the clinic.

项目摘要： 该申请是为了响应特殊利益通知（NOSI）而提交 21-009建立父母1 R01 CA241148-01A1与NCI支持的PDX之间的合作 开发和试验中心研究网络（PDXNET） - 威斯塔尔研究所站点。该项目着重于 由醛脱氢酶介导的母体R01鉴定的癌细胞耐药性的独特形式 （ALDH）表达肿瘤中存在的细胞亚群。酶的ALDH家族转化有毒 在细胞代谢期间产生的醛成像相应的毒性羧酸相应的醛 排出并去除。 ALDH表达和活性在肿瘤进展过程中增加 较高的阳性（ALDH+）亚群。在父r01中，我们发现更改ALDH+的大小 以及在药物治疗和耐药性发展期间发生的阴性（ALDH-）细胞亚群 在维持肿瘤ROS水平的最佳范围内发挥所需的最佳范围内发挥重要作用 这种新型的耐药性。这项补充提案是使用黑色素瘤PDXS开发的合作 Wistar Institute的Meenhard Herlyn博士撰写，以确定防止这种新颖形式的最有效方法 癌细胞耐药性。目的是使用Dimate靶向ALDH+细胞（在临床评估下 白血病）与针对ALDH-的临床使用的BRAF和MEK抑制剂组合结合 亚种群。该评估将在PDX模型中对BRAF/MEK药物具有抗性 组合。在父r01中，我们发现Aldh+和Aldh-细胞亚群合作 促进生存并获得耐药性。此外，我们在基于培养的细胞系中发现了 可以通过热靶向两个人群来最好地预防这种合作的模型。 Aldh 细胞数和/或相关的ROS途径信号传导可用作评估治疗效率的生物标志物 在PDX模型中。因此，我们提出了一个新的中心假设，即耐药性可以是 通过将ALDH阳性细胞群靶向具有Dimate的ALDH阳性细胞群和负人数，从而阻止癌症 通过BRAF和MEK抑制PDX肿瘤的靶向MAP激酶的靶向MAP激酶途径 抑制。为了检验这一假设，我们将确定最有效的保守或简单定位 防止PDX黑色素瘤模型幼稚或对BRAF/MEK抑制具有耐药性的方法 dimate。所使用的PDX模型将通过不同 机制。 Dimate的有效性将与Nanoks100进行比较（在 父母R01奖），我们发现，与MAP结合使用时，该奖项可有效预防阻力 激酶途径靶向。该项目的临床意义是，如果成功，这些发现可以 为在诊所中测试这种方法提供了坚实的理由。