Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the ability to undergo self-renewal and clonal evolution, play a key role in tumor progression and drug resistance. Aldehyde dehydrogenases (ALDH) are a group of enzymes shown to be robust CSC markers in gynecologic and other malignancies. These enzymes also play functional roles in CSCs, including detoxification of aldehydes, scavenging of reactive oxygen species (ROS), and retinoic acid (RA) signaling, making ALDH an attractive therapeutic target in various clinical scenarios. In this review, we discuss the critical roles of the ALDH in driving stemness in different gynecologic malignancies. We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers. Many of these inhibitors have been shown to be effective in preclinical models of gynecologic malignancies, supporting further development in the clinic. Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth. Thus, ALDH-targeted therapies hold promise for improving patient outcomes in gynecologic malignancies

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with 974 significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with 974 revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that 974 inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation