Abstract
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.
Highlights
The first line of therapy for most gynecologic cancers includes surgery, followed by chemotherapy and radiation [1]
ALDH1A1 expression was higher in residual tumors after the first round of chemotherapy compared to tumors from untreated patients [86], demonstrating enrichment of ovarian cancer stem cells (OCSCs) post-treatment
A co-crystal structure of CM039 with ALDH1A1 yielded two compounds with high selectivity towards ALDH1A1 over ALDH2 isoform, named 13g and 13h [112] (Table 2). Both compounds significantly reduced the proliferation of ALDHhigh CD133+ OCSC population in high grade serous ovarian cancer (HGSOC) cell lines and showed excellent in vivo efficacy (i.p. administration) [112] and 13h synergized with cisplatin in a patient-derived ovarian cancer (OC) spheroid model [112]
Summary
The first line of therapy for most gynecologic cancers includes surgery, followed by chemotherapy and radiation [1]. In the majority of cases, these conventional therapies do not completely eliminate the malignant cells. The primary reason for high mortality is recurrence and subsequent metastasis caused by the residual population of cancer cells [2,3]. The cells that survive after the first line of treatment and contribute to cancer recurrence are known as CSCs [4,5]. The CSC theory states that the tumor is a heterogeneous mass, and within the tumor exists a hierarchy of cells, with CSCs at the apex [6]. CSCs have since been reported in gynecologic malignancies (Table 1)
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