Targeting Aldehyde Dehydrogenase for Cancer Prevention

以醛脱氢酶为靶点预防癌症

• 批准号: 9973328
• 负责人: SHANTU G AMIN
• 金额: $ 64.13万
• 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/9973328
• 关键词: Aldehydes; Animals; Antibodies; Biological Response Modifiers; CD8-Positive T-Lymphocytes; Carboxylic Acids; Cell Line; Cell Survival; Cell physiology; Cells; Characteristics; Cultured Cells; Data; Dendritic Cells; Development; Disease Resistance; Drug Combinations; Drug Targeting; Drug resistance; Effector Cell; Enzymes; Exhibits; Family member; Flow Cytometry; Genetic; Immune; Immune response; Immunosuppression; Immunotherapy; Individual; Isatin; Knock-out; Lethal Dose 50; Link; Malignant Neoplasms; Measures; Mediating; Modeling; Mus; Natural Killer Cells; Natural Products; Neoplasm Metastasis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Process; Protein Family; Protein Isoforms; Proteins; Recurrence; Regulatory T-Lymphocyte; Research; Resistance; Resistance development; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Tretinoin; Tumor-Derived; Tumor-infiltrating immune cells; Validation; Vertebral column; aldehyde dehydrogenases; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; antibody immunotherapy; base; cancer cell; cancer prevention; cancer stem cell; cell type; chemotherapy; clinical translation; clinically relevant; drug development; efficacy testing; enzyme activity; genetic approach; immune function; immunogenic cell death; immunoregulation; improved; inhibitor/antagonist; innovation; melanoma; mortality; mouse model; nanoparticle; neoplastic cell; novel; pre-clinical; preclinical efficacy; prevent; response; stem cell population; stem cells; stem-like cell; targeted agent; tumor; tumor microenvironment; tumor-immune system interactions

ABSTRACT: In cancer, aldehyde dehydrogenase (ALDH) enzyme activity is high in dendritic cells and regulatory T-cells, hypothesized to modulate the immune response and also in cancer stem cells (CSCs) to aid the development of recurrent resistant disease. It is therefore surprising that drugs targeting ALDH have not been developed to modulate these processes in cancer. To investigate this issue, we tested the efficacy of existing isoform-specific and broad-spectrum ALDH inhibitors on cultured cells and found that none were very effective at modulating cell survival. Furthermore, we predicted that a broad-spectrum inhibitor would be needed due to the overlapping functions of the ALDH family members. These observations provided the rationale to develop a non-toxic broad- spectrum ALDH inhibitor, which would kill ALDH+ CSCs to prevent recurrent resistant disease, and improve immunotherapy of melanoma. Thus, the central hypothesis is that a non-toxic ALDH inhibitor can be developed to reduce recurrent resistant disease development mediated by ALDH+ CSCs and improve the efficacy of existing immunotherapies by reducing immune suppression. Preliminary data show development of a potent non-toxic ALDH inhibitor built on the backbone of the Isatin natural product. This agent eliminates CSCs with high ALDH activity, preventing increases in ALDH+ cells typically seen with traditional drug treatments. Finally, the inhibitor improves the preclinical efficacy of anti-PD1 immunotherapy in a syngeneic mouse melanoma model where this approach alone is not effective. Based on these hypothesis-supporting preliminary data, the following Specific Aims are proposed. First, determine how effectively a non-toxic broad-spectrum ALDH inhibitor eliminates the melanoma ALDH+ CSC population that expands when treating with traditional chemotherapy. Furthermore, determine its potency when combined with traditional chemotherapy to prevent recurrent resistant disease development. This will be achieved by isolating ALDH+ and ALDH- cell populations from cell lines and patient derived (PDX) tumors and determining inhibitor efficacy for preventing recurrent resistant disease development when provided in combination with current clinically relevant chemotherapy. Finally, the mechanistic basis for inhibition of resistance by the agent combination will be identified. Second, determine the efficacy of a non-toxic broad-spectrum ALDH inhibitor on immune regulatory and effector cells in the tumor microenvironment, alone and when combined with anti-PD1 antibody immunotherapy. Specific targeting of ALDH in melanoma tumor cells and in host cells on therapeutic efficacy will be tested. Mechanisms leading to enhanced immune response will be identified by defining the impact of the inhibitor and antibody combinations on immune cell composition and function within the tumors, assessing the relative ALDH levels in the immune cell populations, and using transient and genetic approaches to target the modulating immune cells. These significant discoveries would demonstrate the efficacy of targeting ALDH enzymes in cancer for modulating resistance and immune cell function, providing needed preclinical validation necessary for clinical translation.

抽象的： 在癌症中，树突状细胞和调节性 T 细胞中的乙醛脱氢酶 (ALDH) 酶活性很高， 假设可以调节免疫反应，也可以在癌症干细胞 (CSC) 中帮助发展 复发性耐药性疾病。因此，令人惊讶的是，针对 ALDH 的药物尚未开发出来 调节癌症中的这些过程。为了研究这个问题，我们测试了现有异构体特异性的功效 和广谱 ALDH 抑制剂对培养细胞的影响，发现没有一种对调节细胞非常有效 生存。此外，我们预测由于重叠，将需要一种广谱抑制剂 ALDH 家族成员的功能。这些观察结果为开发无毒的广泛用途提供了理论依据。 谱 ALDH 抑制剂，可杀死 ALDH+ CSC，以防止耐药性疾病复发，并改善 黑色素瘤的免疫治疗。因此，中心假设是可以开发一种无毒的 ALDH 抑制剂 减少由 ALDH+ CSC 介导的复发性耐药性疾病的发展并提高疗效 通过减少免疫抑制来改善现有的免疫疗法。初步数据显示，正在开发一种有效的 以靛红天然产物为基础的无毒 ALDH 抑制剂。该试剂可消除 CSC 高 ALDH 活性，防止传统药物治疗中常见的 ALDH+ 细胞增加。最后， 该抑制剂提高了同基因小鼠黑色素瘤模型中抗 PD1 免疫疗法的临床前疗效 仅此方法无效的地方。基于这些支持假设的初步数据，以下 提出了具体目标。首先，确定无毒广谱 ALDH 抑制剂的有效性 消除传统化疗时扩大的黑色素瘤 ALDH+ CSC 群体。 此外，确定其与传统化疗联合使用时预防耐药复发的效力 疾病的发展。这将通过从细胞系中分离 ALDH+ 和 ALDH- 细胞群来实现， 患者源性 (PDX) 肿瘤并确定抑制剂预防复发性耐药疾病的功效 与当前临床相关化疗结合使用时的发展。最后， 将确定药剂组合抑制耐药性的机制基础。其次，确定 无毒广谱 ALDH 抑制剂对肿瘤免疫调节细胞和效应细胞的功效 单独使用以及与抗 PD1 抗体免疫疗法联合使用时的微环境。具体目标 ALDH 在黑色素瘤肿瘤细胞和宿主细胞中的治疗功效将得到测试。导致的机制 通过定义抑制剂和抗体组合的影响来识别增强的免疫反应 评估肿瘤内免疫细胞的组成和功能，评估免疫细胞中的相对 ALDH 水平 细胞群，并使用瞬时和遗传方法来靶向调节免疫细胞。这些 重大发现将证明靶向 ALDH 酶在癌症中调节的功效 耐药性和免疫细胞功能，为临床转化提供所需的临床前验证。