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：
10299142
负责人：
JAMES K CHEN
金额：
$ 41.18万
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/10299142
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 Crystallization 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 Pharmaceutical Chemistry Pharmacology Population Preventive screening Property Protein Isoforms Relapse Reporting Research Resected Retina Roentgen Rays Role Signal Transduction Structure Survival Rate Synthesis Chemistry Therapeutic Time Tretinoin Tumorigenicity Work Xenograft Model Xenograft procedure absorption aldehyde dehydrogenases base 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/antagonist insight lipid metabolism metastatic colorectal molecular subtypes neoplastic cell new therapeutic target oxidation 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 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.

结直肠癌是世界上第三大常见恶性肿瘤，约有 140 万新发病例每年有 70 万人死亡。随着西方饮食和生活方式的改变，到 2030 年全球发病率预计将上升 60% 生活方式变得更加普遍，结直肠癌正在困扰着越来越多的年轻人。尽管通过预防性筛查和监测，大约 20% 的结直肠癌患者在诊断时，40-50%的早期患者治疗后会复发。不幸的是标准结直肠癌症疗法，例如抗有丝分裂剂、表皮生长因子受体拮抗剂和血管生成抑制剂对晚期疾病基本上无效。因此，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，因为这些自我更新的细胞会导致肿瘤复发、化疗耐药和转移。我们的项目致力于实现这一目标通过研究和药理学靶向结直肠癌 CSC 特有的代谢途径来实现这一目标。我们的工作建立在最近的报告基础上，即乙醛脱氢酶 1B1 (ALDH1B1) 在肠干细胞中表达以及结肠癌衍生球体培养物和异种移植物生长所需的。我们的研究结果支持以下作用： ALDH1B1 在结直肠 CSC 维持中的作用，我们开发了第一个已知的 ALDH1B1 选择性拮抗剂。我们还解析了 ALDH1B1 和 ALDH1B1 抑制剂复合物的第一个 X 射线晶体结构，揭示了拮抗剂作用的分子基础，并获得进一步化合物开发的见解。我们的最新线索化合物可以抑制结直肠癌球体的活力，对贴壁培养物或非癌细胞。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体内的癌症异种移植物。我们现在正在研究 ALDH1B1 促进结直肠癌的机制（目标 1）。我们将探索这种线粒体酶在结直肠 CSC 维持、化疗耐药性和侵袭性，使用代表各种结直肠癌亚型的细胞系。我们还将确定致癌 ALDH1B1 功能是否涉及视网膜氧化和/或脂质过氧化产物，我们将阐明 ALDH1B1 依赖性转录组。在进行这些机制研究的同时，我们将使用药物化学、生化测定和细胞模型，用于开发具有优化效力、选择性、和药理学特性（目标 2）。然后我们将评估 ALDH1B1 抑制剂在结直肠癌中的活性异种移植模型（目标 3）。总之，这些研究将加深我们对 ALDH1B1 功能和结直肠 CSC 生物学。他们还将开发新的化学工具来研究 ALDH1B1 依赖性途径，揭示药理学 ALDH1B1 抑制的治疗潜力，并为 ALDH1B1靶向药物的开发。