Targeting Ovarian Cancer Stem Cells Through Selective Inhibition of ALDH1A1

 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局。最近的数据表明，化疗不能消除的静止癌细胞的持续存在，并且能够再生肿瘤，这是肿瘤复发的主要原因。这些细胞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。CSC的特征是表达膜外排蛋白，使其具有高度化疗耐药性。已经提出了几种标记物用于CSC的鉴定，其中醛脱氢酶同种型1A 1（ALDH 1A 1）的活性，无论是单独的，还是与其他蛋白质组合的，都是一种稳健的鉴定物，已经在不同的癌症类型（包括卵巢癌）中被几个小组验证。在过去的20年里，我们的实验室已经开发了生物化学工具来研究乙醛脱氢酶在正常生理和代谢紊乱中的功能。凭借在该领域的独特专业知识，我们最近发现了ALDH 1A 1的高效特异性小分子抑制剂，可在nM浓度下阻断该酶。在这里，我们提出了优化和验证的铅抑制剂首次在一个 癌症模型，重点是抑制ALDH 1A 1+卵巢CSC的功能。我们将确定先导抑制剂在ALDH 1A 1+卵巢癌细胞中的靶向特异性及其细胞毒性活性，并将在化疗后复制肿瘤复发的动物模型中测量其抗癌活性。该应用程序对当前旨在支持癌症治疗新概念和发展概念的RFA（PA-12-145）做出了高度响应。我们的研究的成功完成将有力地支持一种新的CSC靶向策略，并将允许这种创新概念过渡到临床。

 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.