Combination therapy with FDA-approved oxidative phosphorylation (OXPHOS) inhibitors and platelet-derived growth factor receptor (PDGFR) inhibitors may selectively target ovarian cancer stem cells and limit their enrichment by carcinoma-associated mesenchymal stem cells, according to a preclinical study published in NPJ Women’s Health.

Surgery remains the cornerstone of treatment for ovarian cancer.

Speaking with El Médico Interactivo, part of the Medscape Professional Network, Sara Pérez Ramírez, MD, clinical oncologist from the Hospital General Universitario Gregorio Marañón in Madrid, Spain, said, “In advanced epithelial ovarian cancer, the first consideration when planning treatment is whether optimal cytoreductive surgery can be performed without residual postoperative disease.”

If surgery is feasible, treatment begins with primary cytoreductive surgery followed by adjuvant chemotherapy, typically carboplatin plus paclitaxel. If upfront surgery is not feasible, patients usually receive neoadjuvant carboplatin plus paclitaxel to reduce the tumor burden before interval cytoreductive surgery.

Following surgery and chemotherapy, “patients continue maintenance treatment with an antiangiogenic agent (bevacizumab), a poly (ADP-ribose) polymerase inhibitor (olaparib, niraparib, or rucaparib), or a combination of both (bevacizumab plus olaparib),” Pérez Ramírez said.

Maintenance Treatment

According to Pérez Ramírez, selecting maintenance therapy requires assessing the homologous recombination deficiency status using tumor tissue.

“Tumors with positive homologous recombination deficiency status are commonly associated with mutations in homologous recombination genes, including BRCA1 and BRCA2. These patients should also be referred to genetic counseling to determine whether they have hereditary ovarian cancer.”

The study evaluated a strategy targeting two mechanisms implicated in ovarian cancer recurrence: OXPHOS-dependent oxidative metabolism in cancer stem cells and stromal support provided by mesenchymal stem cells through PDGFR signaling.

“The hypothesis is that blocking both mechanisms could reduce treatment resistance and tumor recurrence,” Pérez Ramírez said.

Study Model

According to Pérez Ramírez, the researchers used a three-dimensional tumoroid model comprising OVCAR3 high-grade serous ovarian carcinoma cells and human mesenchymal stem cells.

“The primary finding was that simultaneous inhibition of mitochondrial metabolism through OXPHOS- and PDGFR-mediated signaling reduced ovarian cancer tumoroid viability more than either treatment alone. However, the effect appeared to be additive rather than clearly synergistic.”

Among the OXPHOS inhibitors evaluated, atovaquone demonstrated the highest activity, whereas metformin showed limited efficacy. The combination of atovaquone with sunitinib or sorafenib produced the largest reduction in tumoroid viability.

Study Limitation

Pérez Ramírez emphasized that the limitation of the study is that all findings were generated in vitro.

“The study does not demonstrate a highly effective new therapy but rather provides preclinical proof of concept. Combining an OXPHOS inhibitor, particularly atovaquone, with a PDGFR inhibitor, such as sunitinib or sorafenib, produced greater antitumor activity than either drug alone in a three-dimensional ovarian cancer model. These findings support further in vivo studies and, ultimately, evaluation in clinical trials.”

Earlier Diagnosis

Pérez Ramírez said earlier diagnosis remains one of the greatest opportunities to improve long-term outcomes.

“Approximately 80% of ovarian cancers are diagnosed at an advanced stage because the tumor causes no symptoms while confined to the ovary. Most early-stage ovarian cancers are detected incidentally during investigations performed for other reasons.”

Ovarian cancer typically spreads throughout the peritoneal cavity, and peritoneal carcinomatosis often produces initial symptoms including abdominal distension, increasing abdominal girth, nausea, early satiety, abdominal pain, and constipation. Because these symptoms are nonspecific, they are frequently attributed initially to more common benign conditions, delaying diagnosis.

According to Pérez Ramírez, tumor stage remains one of the strongest prognostic factors.

“The more advanced the stage, the poorer the prognosis and the shorter the progression-free and overall survival. Even when treatment is intended to be curative, 70-80% of patients with advanced ovarian cancer experience recurrence within the first 2 years. Earlier detection would substantially improve prognosis, but this remains difficult because early-stage disease is usually asymptomatic. At present, screening is not recommended for the general population and is reserved for individuals carrying pathogenic variants associated with hereditary breast and ovarian cancer.”

Pérez Ramírez reported having no relevant conflicts of interest.

This article was translated from El Médico Interactivo, part of the Medscape Professional Network.