Mitigating Uterine Sarcomas With PI3K/mTOR Inhibitors

Researchers have identified a protein that may respond to PI3K/mTOR inhibitors for patients with a specific type of uterine sarcoma. Broadly, these make up approximately 2% to 5% of all uterine malignancies, and leiomyosarcomas account for 30% of all uterine sarcomas, according to the National Cancer Institute. Patients with localized disease of leiomyosarcomas have a 5-year survival rate of around 50%, which declines to 10% to 30% for those with metastatic disease. Leiomyosarcomas are particularly challenging to treat and this new option looks promising.

The PI3K/mTOR (phosphoinositide 3-kinase/mammalian target of rapamycin) pathway is stimulated by growth factors and their receptors. It regulates cell metabolism, cell growth, cell survival, cell proliferation, cell motility, and angiogenesis. The PI3K/AKT/mTOR pathway is considered one of the most frequently mutated pathways in cancer leading to cancer progression and resistance to existing treatments.

Preclinical data of the protein P-S6S240 demonstrates that patients whose tumors have this protein may respond to PI3K/mTOR inhibitors. Frédéric Amant, MD, PhD, a professor at the Leuven Cancer Institute in Belgium and at the Netherlands Cancer Institute in Amsterdam, and his team identified this protein which may indicate a poor prognosis for patients with leiomyosarcoma. This was first published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).

“We wanted to generate a clear view on the presence of targetable proteins in all subtypes of uterine sarcomas, with the aim of improving treatment options for these patients,” Amant said in a news release.

His team also investigated whether any of the targetable proteins might be potential biomarkers for predicting clinical outcomes. They studied five proteins of interest in 288 uterine sarcoma samples, which included 157 leiomyosarcomas, 52 benign uterine stromal tumors, and 41 normal uterine tissues; the rest were endometrial sarcomas, adenosarcomas, and other undifferentiated types of uterine sarcoma.

The researchers found that one of the proteins studied, the activated S6 ribosomal protein P-S6S240, was present more frequently in high-grade tumors (32%) than in low-grade tumors (9%). The presence of this protein was also associated with shorter progression-free survival and disease-specific survival in patients with leiomyosarcoma.

P-S6S240 plays a role in the PI3K/mTOR cell-signaling pathway, a cellular process that stimulates cancer growth and they concluded that patients with uterine leiomyosarcoma with activated S6 protein relapses faster, suggesting that P-S6S240 may serve as a prognostic marker.

Earlier versions of mTOR inhibitors that targeted only one of the two active mTOR complexes only achieved mild responses in patients and also had substantial toxicity in patients with uterine sarcomas, and so the US Food and Drug Administration denied approval for sarcoma.