Targeting Aldehyde Dehydrogenase for Cancer Prevention

以醛脱氢酶为靶点预防癌症

基本信息

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
项目类别：
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

项目摘要

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细胞中的醛脱氢酶（ALDH）酶的活性很高，假设可以调节免疫反应以及在癌症干细胞（CSC）中的发展复发性抗性疾病。因此，令人惊讶的是，针对ALDH的药物尚未开发调节癌症的这些过程。为了调查此问题，我们测试了现有同工型特异性的功效和培养细胞的广谱ALDH抑制剂，发现没有一个在调节细胞方面非常有效生存。此外，我们预测由于重叠而需要广谱抑制剂 ALDH家庭成员的功能。这些观察结果为发展无毒的广泛性提供了理由光谱ALDH抑制剂将杀死ALDH+ CSC以防止复发性抗性疾病，并改善黑色素瘤的免疫疗法。因此，中心假设是可以开发出无毒的ALDH抑制剂减少ALDH+ CSC介导的复发性抗性疾病发展，并提高通过减少免疫抑制，现有的免疫疗法。初步数据显示了有效的发展非毒性ALDH抑制剂建立在Isatin天然产物的骨架上。该代理消除了CSC 高ALDH活性，可防止通常通过传统药物治疗观察到的ALDH+细胞的增加。最后，抑制剂提高了抗PD1免疫疗法在合成小鼠黑色素瘤模型中的临床前功效仅这种方法是无效的。基于这些假设支持的初步数据，以下提出了具体目标。首先，确定如何有效地无毒的广谱ALDH抑制剂消除了使用传统化学疗法治疗时扩展的黑色素瘤ALDH+ CSC种群。此外，与传统化学疗法结合使用以防止复发性抗性时确定其效力疾病发展。这将通过从细胞系和患者衍生（PDX）肿瘤并确定抑制剂的功效，以防止复发性抗性疾病与当前相关的化学疗法相结合提供的开发。最后，将确定抑制剂组合抑制抗性的机理基础。其次，确定无毒的广谱ALDH抑制剂对肿瘤中免疫调节和效应细胞的功效单独的微环境，并与抗PD1抗体免疫疗法结合使用。特定的目标将测试黑色素瘤肿瘤细胞和宿主细胞中治疗功效的ALDH。导致的机制通过定义抑制剂和抗体组合的影响，将确定免疫反应增强在肿瘤内的免疫细胞组成和功能上，评估免疫中的相对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酶在癌症调节中的功效抗性和免疫细胞功能，提供临床翻译所需的临床前验证。