权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ALDH Inhibition as Modulator of Tumor Immunobiology

ALDH 抑制作为肿瘤免疫生物学的调节剂

基本信息

批准号：
10392913
负责人：
Ronald J Buckanovich
金额：
$ 43.18万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
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：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392913
关键词：
American Anabolism Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cancer Vaccines Cell Death Cell Proliferation Cell physiology Cells Cellular biology Cessation of life Clinical Data Dendritic Cells Disease Down-Regulation Enzyme Inhibitor Drugs Enzymes FOXP3 gene Family Family member Generations Genetic Transcription Goals Human Immune Immune Cell Suppression Immune Tolerance Immune system Immunity Immunobiology Immunocompetent Immunomodulators Immunotherapeutic agent Immunotherapy In Vitro Incidence Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-12 Knock-out LacZ Genes Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Molecular Mucin 1 protein Mus NR4A1 gene Necrosis Nuclear Receptors Patients Pattern Pharmacology Phenotype Production RXR RXRA gene Regulatory T-Lymphocyte Reporter Resistance Retinoic Acid Receptor Role Signal Transduction T cell differentiation T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Transgenic Mice Tretinoin Tumor Antigens Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Up-Regulation Vaccines Woman aldehyde dehydrogenases cancer cell cancer immunotherapy cancer therapy cell type checkpoint therapy cytokine exhaustion immune checkpoint blockade in vivo inhibitor knock-down mortality neoplasm immunotherapy neoplastic cell new therapeutic target novel novel strategies novel therapeutics ovarian neoplasm receptor response stemness therapeutic target therapy resistant transcription factor transcriptome sequencing transdifferentiation tumor

项目摘要

Ovarian cancer (OvCa) is a deadly disease ranking 5th in cancer deaths in women, with the 3rd highest mortality to incidence ratio of all cancers. With patient overall survival not significantly changed for several decades, there is a clear unmet clinical need to develop new therapies for OvCa. Aldehyde dehydrogenase-1A enzymes (ALDH1A) represent a therapeutic target for OvCa. ALDH1A enzymes are upregulated in ovarian cancer initiating cells (CIC) and mediate the biosynthesis of retinoic acid (RA), to regulate numerous cellular processes. We recently identified a novel ALDH1A family inhibitor (ALDHi). Our preliminary data indicate that ALDHi treatment of cancer cells and immune cells have opposite effects, both of which could promote anti- tumor immunity. ALDHi treatment of CIC induces an RA and transcription- dependent necroptotic cell death, potentially related to altered function of the RA transcription partner NR4A1. This ALDHi-induced CIC death is associated with the release of Damage Associated Molecular Patterns (DAMPs) and other inflammatory mediators. In contrast, ALDHi treatment is associated with enhanced proliferative response of both dendritic cells (DC) and CD8+ T cells. Our overarching hypothesis is that ALDHi can act as an immune modulator and can be used to enhance immunotherapeutic approaches in OvCa. To test our hypotheses, we propose the following specific aims: SA1: To identify the RA receptors and downstream factors that drive ALDHi induced CIC necrosis and to determine whether ALDHi-induced CIC necroptosis is inflammatory cell death. We propose to test the role of individual RA receptors RAR/RXR and NR4A1 co-receptor in ALDHi-mediated CIC death and evaluate the impact of ALDHi/NR4A1 on CIC release of inflammatory mediators and this stimulation of an anti- tumor T cell response. Next, we will, in SA2: Assess the impact of ALDHi on host DC and T cells. As RA can regulate the differentiation of T cells and DC, we will use reporter mice to evaluate the role of ALDHi on disruption of RA/NR4A1 signaling and DC and T cell biology in vitro and in vivo. We will evaluate the capacity of DC to differentiate into IL-12 producing DC1, and CD4 T helper cell subsets differentiation with focus on the Th17/Treg trans-differentiation. Finally, our preliminary data suggest ALDHi may enhance anti- tumor immunity both via actions on the tumor cell and immune cells. We therefore propose SA3: To determine the ability of ALDHi to enhance immunotherapy in OvCa. To test this hypothesis, we will use several immune competent models of OvCa to determine the ability of ALDHi to enhance checkpoint inhibitor therapy and antitumor vaccines. IMPACT: While immune therapy has demonstrated significant benefit in many cancers, the impact in OvCa has been limited. The studies proposed here will define the role for a novel therapeutic ALDHi in immunotherapy in OvCa. Given ALDH is broadly linked with therapeutic resistance in cancer, these studies will have far-reaching implications for cancer therapy.

卵巢癌是一种致命疾病，在妇女癌症死亡中排名第五，死亡率第三高