From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer

Abstract

Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1β, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.

Keywords: ARID1A; Immunotherapy; Ovarian clear cell carcinoma; Synthetic lethality; Targeted therapies.

Fig. 1

Schematic overview of ovarian clear cell cancer carcinogenesis. A Ovarian Clear Cell Cancer Progression; B Genetic alterations; C Five main signalling pathway in carcinogenesis. Shed menstrual endometrium leaves the cavity and retrograde along the fallopian tube to the ovary. The microenvironment of ectopic endometrial cells contains a large amount of fragmented erythrocytes which in turn releases a large amount of ions leading to stronger oxidative stress and more IL-6 production, stimulating cellular. At the same time, there is a higher mutational burden compared to normal endometrial cells, with common mutations including ARID1A, PIK3CA, PTEN, and KRAS. The five major pathways involved in carcinogenesis to OCCC include: PI3K-AKT-mTOR pathway, HIF-1α-VEGF pathway, IL-6-STAT3 pathway and MAPK pathway and HNF-1β pathway. In addition, lymphatic, hematogenous, and peritoneal implantation metastasis are common metastatic pathways in advanced ovarian clear cell carcinoma

Fig. 2

Recent-known mechanism of chemoresistance. There are five mechanisms thought to be involved in the lack of response of colorectal adenocarcinoma to pharmacological treatment, including drug efflux (A), drug inactivation (B), nucleotide excision repair (C), growth-factor signaling (D) and cell-cycle control (E)

Fig. 3

Ovarian clear cell cancer treatment strategies. Abbreviation: FIGO, Federation International of Gynecology and Obstetrics; NCCN, National Comprehensive Cancer Network; ESMO, European Society for Medical Oncology-European Society of Gynaecological Oncology

Fig. 4

Recent-known novel therapies for ovarian clear cell cancer. Five major mechanisms of potential therapeutic target have been characterized in ovarian clear cell carcinoma, including immune checkpoint blockade (A), targeting angiogenesis (B), targeting HNF-1β (C), ferroptosis (D) and ARID1A synthetic lethal interaction (E)