Targeting Aldehyde Dehydrogenase for Cancer Prevention

以醛脱氢酶为靶点预防癌症

• 批准号: 10369718
• 负责人: SHANTU G AMIN
• 金额: $ 60.05万
• 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/10369718
• 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; improved; inhibitor; innovation; melanoma; mortality; mouse model; nanoparticle; neoplastic cell; novel; pre-clinical; preclinical efficacy; prevent; response; stem cell biomarkers; stem cell population; 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.

摘要： 在癌症中，醛脱氢酶（ALDH）酶活性在树突细胞和调节性T细胞中很高， 假设调节免疫反应，也在癌症干细胞（CSC）中，以帮助发展 复发性抗性疾病。因此，令人惊讶的是，靶向ALDH的药物尚未被开发出来， 调节癌症中的这些过程。为了研究这个问题，我们测试了现有的异构体特异性 和广谱ALDH抑制剂对培养的细胞，发现没有一个是非常有效的调节细胞， 生存此外，我们预测，由于重叠，需要一种广谱抑制剂。 ALDH家族成员的功能。这些观察结果提供了开发无毒广泛的 谱ALDH抑制剂，其将杀死ALDH+ CSC以防止复发性抗性疾病，并改善 黑色素瘤的免疫治疗因此，中心假设是可以开发无毒ALDH抑制剂 减少由ALDH+ CSC介导的复发性抗性疾病的发展，并提高 现有的免疫疗法通过减少免疫抑制。初步数据显示， 无毒ALDH抑制剂建立在靛红天然产物的骨架上。该药剂可消除CSC， 高ALDH活性，防止ALDH+细胞的增加，这在传统药物治疗中是常见的。最后， 该抑制剂改善了抗PD 1免疫疗法在同基因小鼠黑色素瘤模型中的临床前功效 仅靠这种方法是无效的。根据这些支持假设的初步数据， 提出了具体目标。首先，确定无毒广谱ALDH抑制剂 消除了在用传统化疗治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复发性耐药的效力 疾病发展。这将通过从细胞系中分离ALDH+和ALDH-细胞群来实现， 患者来源的（PDX）肿瘤和确定抑制剂功效以预防复发性耐药疾病 当与当前临床相关化疗联合使用时，最后 将鉴定通过药剂组合抑制抗性的机理基础。第二，确定 无毒广谱ALDH抑制剂对肿瘤中免疫调节和效应细胞的功效 单独使用和与抗PD 1抗体免疫疗法联合使用时，可以改善微环境。特异性靶向 将测试ALDH在黑色素瘤肿瘤细胞和宿主细胞中的治疗功效。机制导致 通过确定抑制剂和抗体组合的影响， 对肿瘤内免疫细胞组成和功能的影响，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 重要的发现将证明靶向癌症中的ALDH酶用于调节癌症的有效性。 抗性和免疫细胞功能，提供临床转化所需的临床前验证。