醛脱氢酶（ALDH）酶活性是许多肿瘤类型中癌症起始细胞（CIC）的标志物。我们的研究组和其他研究发现，ALDH1A家族抑制剂（ALDHi）可以优先诱导已建立的卵巢癌中的CIC死亡。我们试图确定ALDHi是否可以作为卵巢癌的化学预防药物，通过在肿瘤起始时靶向CIC。由于BRCA1/2突变携带者代表一个可能从卵巢癌化学预防中受益的人群，我们将重点放在BRCA突变相关的肿瘤细胞系和小鼠肿瘤模型上进行研究。我们发现，与BRCA野生型细胞相比，BRCA突变的卵巢癌细胞对ALDHi673A更敏感。同样地，虽然对野生型输卵管上皮（FTE）细胞的673A处理是无毒的，但673A在BRCA1敲除的FTE细胞中引起细胞死亡。通过使用卵巢癌发生的小鼠输卵管器官样体模型，我们发现673A降低了器官样体的复杂性，并显著减少了BRCA突变细胞的集落形成。在673A处理后仍然存在的器官样体主要是BRCA1 wt，但NF1突变，暗示存在一种耐药机制。最后，通过使用tubo-ovarian癌BPRN（Brca1，Trp53，Rb1，Nf1灭活）小鼠模型，我们评估了间歇性673A治疗对癌症发生的影响。673A治疗导致丝状输卵管上皮内癌（STIC）病变和癌症显著减少。总体而言，这些发现表明，如673A所示，ALDHi可能作为BRCA1/2突变携带者的化学预防剂。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers.Copyright © 2023 Elsevier Inc. All rights reserved.