Targeting Ovarian Cancer Stem Cells Through Selective Inhibition of ALDH1A1

通过选择性抑制 ALDH1A1 靶向卵巢癌干细胞

• 批准号: 8958378
• 负责人: THOMAS D. HURLEY
• 金额: $ 20.34万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958378
• 关键词: Address; Animal Model; Biochemistry; Cancer Biology; Cancer Model; Cancer cell line; Carboplatin; Cell Proliferation; Cells; Characteristics; Chemicals; Clinic; Clinical; Coin; Data; Development; Disease; Disease remission; Drug Kinetics; Enzymes; Evolution; Goals; Hand; Human; In Vitro; Laboratories; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Membrane; Metabolic Diseases; Modeling; Names; Natural regeneration; Outcome; Ovarian; Physiology; Platinum; Population; Property; Protein Isoforms; Proteins; Recurrence; Relapse; Research; Resistance; Specificity; Staging; Stem cells; Testing; Therapeutic; Therapeutic Agents; Time; Tumor Debulking; Xenograft procedure; aldehyde dehydrogenases; analog; base; biochemical tools; cancer cell; cancer recurrence; cancer stem cell; cancer therapy; cancer type; chemotherapy; clinical application; cytotoxic; improved; in vivo; inhibitor/antagonist; innovation; malignant ascites; neoplastic cell; novel; ovarian neoplasm; prevent; programs; public health relevance; response; self-renewal; small molecule; targeted treatment; transcription factor; treatment strategy; tumor; tumor eradication; tumorigenic

 DESCRIPTION (provided by applicant): Cancer recurrence after tumor eradication by chemotherapy portends poor outcome. Recent data point to persistence of quiescent cancer cells not eliminated by chemotherapy and able to re-generate tumors as the main contributor to tumor relapse. Such cells have been recognized as cancer stem cells (CSCs) and are programmed to self-renew or to differentiate into progenitor cells, generating new tumors. CSCs are characterized by expression of membrane efflux proteins that render them highly chemotherapy resistant. Several markers have been proposed for CSCs' identification, of which activity of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), either alone, or in combination with other proteins, is a robust identifier that has been validated by several groups in different cancer types, including ovarian. Over the past 20 years, our laboratory has developed the biochemical tools to study the functions of aldehyde dehydrogenases in normal physiology and in metabolic disorders. Equipped with unique expertise in this field, we have recently identified highly potent and specific small molecule inhibitors for ALDH1A1 that block the enzyme at nM concentrations. Here we propose to optimize and validate the lead inhibitor for the first time in a cancer model, focusing on inhibiting the functions of ALDH1A1+ ovarian CSCs. We will determine the lead inhibitor's target specificity and its cytotoxic activity in ALDH1A1+ ovarian cancer cells and will measure its anti-cancer activity in an animal model that replicates tumor recurrence after chemotherapy. The application is highly responsive to the current RFA (PA-12-145) seeking to support new and developmental concepts in cancer therapy. Successful completion of our studies will strongly support a novel CSC targeting strategy and will permit transition of this innovative concept to the clinic.

 描述(申请人提供)：化疗根治肿瘤后肿瘤复发预示着不良预后。最近的数据表明，静止的癌细胞持续存在，不能被化疗消除，并能够重新生成肿瘤，成为肿瘤复发的主要原因。这类细胞被认为是癌症干细胞(CSCs)，并被编程为自我更新或分化为祖细胞，从而产生新的肿瘤。CSCs的特征是表达膜外排蛋白，使其对化疗具有高度耐药性。已经提出了几个标记来鉴定CSCs，其中乙醛脱氢酶异构体1A1(ALDH1A1)的活性，无论是单独的，还是与其他蛋白质结合在一起，都是一个强大的标记，已经在包括卵巢在内的不同类型的癌症中得到了几个小组的验证。在过去的20年里，我们的实验室开发了生化工具来研究乙醛脱氢酶在正常生理和代谢紊乱中的功能。凭借在这一领域的独特专业知识，我们最近发现了ALDH1A1的高度有效和特定的小分子抑制剂，它们可以在NM浓度下阻断酶。在这里，我们建议首次优化和验证铅抑制剂 肿瘤模型，重点抑制ALDH1A1+卵巢CSCs的功能。我们将确定先导抑制物在ALDH1A1+卵巢癌细胞中的靶向性和细胞毒活性，并将在复制化疗后肿瘤复发的动物模型中测量其抗癌活性。该应用程序高度响应当前的RFA(PA-12-145)，寻求支持癌症治疗中的新的和发展的概念。成功完成我们的研究将有力地支持一种新的CSC靶向策略，并将使这一创新概念过渡到临床。