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（由申请人提供）：通过化疗根除肿瘤后癌症复发预示着不良结果，最近的数据表明，未通过化疗消除且能够再生肿瘤的静止癌细胞是导致肿瘤复发的主要因素。被认为是癌症干细胞 (CSC)，并被编程为自我更新或分化为祖细胞，产生新的肿瘤，其特点是表达膜流出蛋白，使其具有高度化疗耐药性。已提出用于 CSC 鉴定的标记物，其中乙醛脱氢酶同工型 1A1 (ALDH1A1) 的活性，无论是单独使用还是与其他蛋白质组合，都是一种强有力的标识符，已在包括卵巢癌在内的不同癌症类型中得到多个研究组的验证。在过去的 20 年里，我们的实验室开发了生化工具来研究醛脱氢酶在正常生理和代谢紊乱中的功能，并在这方面拥有独特的专业知识。在该领域，我们最近发现了 ALDH1A1 的高效且特异性的小分子抑制剂，可以在 nM 浓度下阻断该酶。在此，我们建议首次对先导抑制剂进行优化和验证。 癌症模型，重点是抑制 ALDH1A1+ 卵巢 CSC 的功能。我们将确定先导抑制剂在 ALDH1A1+ 卵巢癌细胞中的靶点特异性及其细胞毒活性，并在化疗后复制肿瘤复发的动物模型中测量其抗癌活性。对当前寻求支持癌症治疗新发展概念的 RFA (PA-12-145) 高度敏感，成功完成我们的研究将有力支持新型 CSC 靶向治疗。战略并将允许将这一创新概念转化为临床。