Targeting colorectal cancer stem cells with ALDH1B1 antagonists

结直肠癌是世界上第三种最常见的恶性肿瘤，约有140万新病例 每年有70万人死亡。到2030年，全球发病率预计将上升60%，因为西方饮食和 生活方式变得越来越普遍，结直肠癌正在困扰着越来越多的年轻人。尽管 预防性筛查和监测，大约20%的结直肠癌患者在 确诊时间短，40-50%的早期患者治疗后会复发。不幸的是，标准的结直肠 肿瘤治疗，如抗有丝分裂药、表皮生长因子受体拮抗剂和血管生成抑制剂 在很大程度上对晚期疾病无效。因此，这些患者的5年存活率仅为12%。 现在人们普遍认为，消除癌症干细胞(CSCs)是持久临床反应的关键，因为 这些自我更新的细胞驱动肿瘤复发、化疗耐药和转移。我们的项目致力于实现这一目标 目的通过研究和药理学靶向研究结直肠癌CSCs特有的代谢途径。 我们的工作基于最近的报道，即乙醛脱氢酶1b1(ALDH1B1)在肠道干细胞中表达 以及结肠癌来源的球形培养物和异种移植物的生长所必需的。我们的发现支持了 ALDH1B1在大肠CSC的维持中，我们已经开发出第一个已知的ALDH1B1选择性拮抗剂。 我们还解决了ALDH1B1和ALDH1B1-抑制剂络合物的第一个X射线晶体结构，揭示了 拮抗剂作用的分子基础，并为进一步的化合物开发获得见解。我们的最新线索 化合物可以抑制结直肠癌球体的活性，对贴壁培养或非贴壁培养的影响最小。 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 小鼠体内的异种肿瘤移植。 我们现在正在研究ALDH1B1促进结直肠癌的机制(目标1)。我们会 探讨这种线粒体酶在大肠CSC维持、化疗耐药和 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 致癌的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ALDH1B1依赖的转录组。在这些机械学研究的同时，我们将使用药物 化学，生化分析和细胞模型，以开发ALDH1B1抑制剂具有优化的效力，选择性， 和药理特性(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)。综上所述，这些研究将加深我们对ALDH1B1功能和 结直肠肿瘤干细胞生物学。他们还将产生新的化学工具来研究ALDH1B1依赖的途径， 揭示药物抑制ALDH1B1的治疗潜力，为临床治疗提供有价值的线索。 ALDH1B1靶向药物的开发。

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.