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Published on: July 25, 2020
Precision medicine for ovarian clear cell carcinoma based on gene alterations
Takafumi Kuroda1,2, Takashi Kohno3
1Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
Abstract:
Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian carcinoma prevalent in Asians. No clear therapeutic selection based on molecular profile has been implemented for this disease. Oncogenic PIK3CA mutation, which activates the PIK3CA/AKT/mTOR signaling pathway, is a promising druggable alteration in OCCC. Recent studies by our group and others have identified the ARID1A mutation as another alteration linked to therapeutic selection based on synthetic lethality: deleterious ARID1A mutations, resulting in ARID1A deficiency, make OCCC cells sensitive to drugs targeting poly (ADP-ribose) polymerase and EZH2, as well as to glutathione inhibitors. In addition, we recently obtained evidence that ARID1A-deficient OCCC could benefit from gemcitabine treatment. Precision medicine based on gene alteration profiling might improve the prognosis of OCCC patients.
Insights
Ovarian clear cell carcinoma (OCCC) shows promise for targeted therapies. ARID1A-deficient OCCC may respond to specific drugs, including gemcitabine, improving patient outcomes through precision medicine.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Ovarian clear cell carcinoma (OCCC) is a distinct histological subtype of epithelial ovarian carcinoma, disproportionately affecting Asian populations.
- Current therapeutic strategies for OCCC lack specific molecular guidance, highlighting an unmet clinical need.
- Key molecular alterations, including PIK3CA and ARID1A mutations, are implicated in OCCC pathogenesis and present potential therapeutic targets.
Purpose of the Study:
- To explore the therapeutic implications of specific molecular alterations in OCCC.
- To identify potential drug sensitivities associated with ARID1A deficiency in OCCC.
- To advocate for precision medicine approaches in OCCC treatment based on genetic profiling.
Main Methods:
- Review of recent studies identifying oncogenic PIK3CA mutations and their role in the PIK3CA/AKT/mTOR pathway.
- Analysis of research linking ARID1A mutations and deficiency to synthetic lethality vulnerabilities.
- Evaluation of evidence supporting gemcitabine efficacy in ARID1A-deficient OCCC models.
Main Results:
- PIK3CA mutations represent a druggable target in OCCC by activating the PIK3CA/AKT/mTOR pathway.
- ARID1A-deficient OCCC exhibits sensitivity to poly (ADP-ribose) polymerase inhibitors, EZH2 inhibitors, and glutathione inhibitors.
- Preliminary evidence suggests that ARID1A-deficient OCCC can benefit from gemcitabine treatment.
Conclusions:
- Targeting PIK3CA offers a potential therapeutic avenue for OCCC.
- ARID1A deficiency creates vulnerabilities exploitable by specific targeted therapies and gemcitabine.
- Precision medicine strategies, guided by molecular profiling, hold promise for improving OCCC patient prognosis.
