Targeting colorectal cancer stem cells with ALDH1B1 antagonists

使用 ALDH1B1 拮抗剂靶向结直肠癌干细胞

基本信息

批准号：
10640894
负责人：
JAMES K CHEN
金额：
$ 43.19万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640894
关键词：
Adherent Culture Aftercare Angiogenesis Inhibitors Antimitotic Agents Biochemical Biochemistry Biological Assay Cancer Biology Cancer Etiology Cancer Model Cell Line Cell Maintenance Cell model Cells Cellular biology Cessation of life Chemicals Chemoresistance Clinical Clustered Regularly Interspaced Short Palindromic Repeats Colon Carcinoma Colorectal Cancer Complement Complex Development Diagnosis Differentiation and Growth Disease Drug Targeting Enzymes Epidermal Growth Factor Receptor Exhibits Gastroenterology Genes Goals Guanidines Immunodeficient Mouse Immunotherapy In Vitro Incidence Individual Intestines Investigation Investigational Drugs Knock-out Lead Life Style Lipid Peroxidation Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Mus Mutagenesis Neoplasm Metastasis Normal tissue morphology Oncogenic Operative Surgical Procedures Outcome Pathway interactions Patients Periodicity Pharmaceutical Chemistry Population Preventive screening Property Protein Isoforms Relapse Reporting Research Resected Retina Roentgen Rays Role Signal Transduction Structure Survival Rate Synthesis Chemistry Therapeutic Time Tretinoin Tumor Promotion Tumorigenicity Work Xenograft Model Xenograft procedure absorption aldehyde dehydrogenases antagonist cancer cell cancer stem cell cancer subtypes cancer therapy chemotherapeutic agent chemotherapy colon cancer cell line colon cancer patients colon growth colorectal cancer progression colorectal cancer treatment effective therapy improved in vivo inhibitor insight lipid metabolism metastatic colorectal molecular subtypes neoplastic cell new therapeutic target oxidation pharmacologic pre-clinical response scaffold self renewing cell stem cell biology stem cell biomarkers stem cell function stem cell population stem cell survival stem cells stemness structural biology therapeutic target tool transcriptome transcriptomic profiling tumor tumor growth tumor xenograft tumorigenesis western diet young adult

项目摘要

Colorectal cancer is the third most common malignancy in the world, with approximately 1.4 million new cases and 700,000 deaths each year. Global incidence rates are expected to escalate 60% by 2030 as Western diets and lifestyles become more common, and colorectal cancer is afflicting increasing numbers of young adults. Despite preventative screening and surveillance, approximately 20% of colorectal cancer patients have metastatic disease at the time of diagnosis, and 40-50% of early-stage patients will relapse after treatment. Unfortunately standard colorectal cancer therapies such as anti-mitotic agents, epidermal growth factor receptor antagonists, and angiogenesis inhibitors are largely ineffectual against late-stage disease. As a result, the 5-year survival rates for these patients is only 12%. It is now widely believed that eliminating cancer stem cells (CSCs) is the key to durable clinical responses, as these self-renewing cells drive tumor relapse, chemoresistance, and metastasis. Our project strives to achieve this goal by investigating and pharmacologically targeting metabolic pathways that are unique to colorectal cancer CSCs. Our work builds on recent reports that aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed in intestinal stem cell and required for the growth of colon cancer-derived spheroid cultures and xenografts. Our findings support a role for ALDH1B1 in colorectal CSC maintenance, and we have developed the first known ALDH1B1-selective antagonists. We have also solved the first X-ray crystal structures of ALDH1B1 and ALDH1B1-inhibitor complexes, uncovering the molecular basis of antagonist action and gaining insights for further compound development. Our latest lead compounds can inhibit the viability of colorectal cancer spheroids, with minimal effects on adherent cultures or non- cancerous cells. In addition, our preliminary studies indicate that ALDH1B1 inhibitors can suppress the growth of colon cancer xenografts in mice. We are now investigating the mechanisms by which ALDH1B1 promotes colorectal cancer (Aim 1). We will explore the potential roles of this mitochondrial enzyme in colorectal CSC maintenance, chemoresistance, and invasiveness, using cell lines that are representative of various colorectal cancer subtypes. We will also determine whether oncogenic ALDH1B1 function involves the oxidation of retinal and/or lipid peroxidation products, and we will elucidate the ALDH1B1-dependent transcriptome. In parallel with these mechanistic studies, we will use medicinal chemistry, biochemical assays, and cellular models to develop ALDH1B1 inhibitors with optimized potency, selectivity, and pharmacological properties (Aim 2). We will then evaluate the activities of ALDH1B1 inhibitors in colorectal cancer xenograft models (Aim 3). Together, these investigations will deepen our understanding of ALDH1B1 function and colorectal CSC biology. They will also generate new chemical tools for studying ALDH1B1-dependent pathways, reveal the therapeutic potential of pharmacological ALDH1B1 inhibition, and provide valuable leads for the development of ALDH1B1-targeting drugs.

大肠癌是世界上第三大常见的恶性肿瘤，大约有140万例新病例每年70万人死亡。预计到2030年，全球发病率将升级为60％，因为西方饮食和生活方式变得越来越普遍，大肠癌正在困扰着越来越多的年轻人。尽管预防性筛查和监视，大约20％的结直肠癌患者患有转移性疾病诊断时间和40-50％的早期患者将在治疗后复发。不幸的是标准结肠直肠癌症疗法，例如抗隔离剂，表皮生长因子受体拮抗剂和血管生成抑制剂在很大程度上针对晚期疾病无效。结果，这些患者的5年生存率仅为12％。现在，人们普遍认为消除癌症干细胞（CSC）是持久临床反应的关键，因为这些自我更新细胞驱动肿瘤复发，化学抗性和转移。我们的项目努力实现这一目标通过研究和靶向大肠癌CSC独有的代谢途径的目标。我们的工作基于最近的报道，即醛脱氢酶1B1（ALDH1B1）在肠道干细胞中表达结肠癌衍生的球体培养物和异种移植物的生长所必需。我们的发现支持结直肠CSC维护中的ALDH1B1，我们开发了第一个已知的ALDH1B1选择性拮抗剂。我们还解决了ALDH1B1和ALDH1B1抑制剂配合物的第一个X射线晶体结构，发现了拮抗作用的分子基础，并获得进一步的复合发展的见解。我们的最新线索化合物可以抑制大肠癌球体的生存能力，对依从性培养或非 - 癌细胞。此外，我们的初步研究表明ALDH1B1抑制剂可以抑制结肠的生长小鼠的癌症异种移植物。我们现在正在研究ALDH1B1促进结直肠癌的机制（AIM 1）。我们将探索这种线粒体酶在结直肠CSC维持，化学耐药和化学上的潜在作用使用代表各种大肠癌亚型的细胞系的侵入性。我们还将确定致癌ALDH1B1功能是否涉及视网膜和/或脂质过氧化产物的氧化，我们将阐明依赖ALDH1B1的转录组。与这些机械研究并行，我们将使用药用化学，生化测定和细胞模型以优化的效力，选择性，和药理特性（AIM 2）。然后，我们将评估大肠癌中ALDH1B1抑制剂的活性异种移植模型（AIM 3）。这些调查一起将加深我们对Aldh1b1功能的理解和结直肠CSC生物学。他们还将生成用于研究ALDH1B1依赖途径的新化学工具，揭示药理学ALDH1B1抑制的治疗潜力，并为靶向ALDH1B1靶向药物的开发。