PI3K/mTOR Inhibitor Demonstrates Efficacy in Some Uterine Sarcomas

Leiomyosarcomas account for 30% of all uterine sarcomas and are difficult to treat.
Leiomyosarcomas account for 30% of all uterine sarcomas and are difficult to treat.

The protein P-S6S240 is a potential a biomarker for poor prognosis in patients with leiomyosarcoma, a type of uterine sarcoma that is difficult to treat, a study published in Clinical Cancer Reserch has shown. In addition, the findings suggest that tumors with P-S6S240 may respond to PI3K/mTOR inhibitors.1

Uterine sarcomas make up 2% to 5% of all uterine malignancies. Leiomyosarcomas account for 30% of all uterine sarcomas. In patients with localized disease, the 5-year survival rate is approximately 50%. In patients with metastatic disease, however, 5-year survival rate drops to 10% to 30%.

In this study, the researchers examined whether any targetable proteins could serve as biomarkers in predicting outcomes.

"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," explained Frédéric Amant, MD, PhD, a professor at the Leuven Cancer Institute in Belgium and at the Netherlands Cancer Institute in Amsterdam, Netherlands, and a senior investigator in the study.

"Identifying biomarkers is crucial because novel treatments are expensive, underscoring the importance of patient selection."

Researchers examined 5 proteins of potential interest in 288 samples from uterine sarcomas. Of these samples, 157 were from leiomyosarcomas, 52 from benign uterine stromal tumors, and 41 from normal uterine tissues. The remaining samples were from endometrial sarcomas, adenosarcomas, and undifferentiated uterine sarcomas.

Results indicated that P-S6S240 was present more frequently in high-grade tumors (32%) than in low-grade tumors (9%). The presence of this protein also correlated with shorter progression-free survival and disease-specific survival in the patients with leiomyosarcoma from whom the samples had come.

P-S6S240 acts in PI3K/mTOR signaling, which is a signaling pathway involved in cancer proliferation.

Next, the researchers used a mouse xenograft model to implant 5 leiomyosarcoma samples from patients. They treated the mice with an investigational PI3K/mTOR inhibitor.

Two tumors shrank, 1 tumor remained stable, 1 tumor decreased growth, and 1 tumor did not respond to treatment. The tumor that did not respond did not have detectable P-S6S240. All the tumors that did respond to treatment had P-S6S240.

"We used a new-generation dual PI3K/mTOR inhibitor [BEZ235; dactolisib] in our preclinical study and were mostly surprised by the efficacy. Such a strong treatment response is rarely seen in leiomyosarcomas," Armant reported.

Xenograft mouse models do not have immune systems such that immune-related treatment responses and side effects cannot be assessed in the models.

Reference

1. Cuppens T, Annibali D, Coosemans A, et al. Potential targets' analysis reveals dual PI3K/mTOR pathway inhibition as a promising therapeutic strategy for uterine leiomyosarcomas — an ENITEC Group Initiative. Clin Cancer Res. 2017 Feb 23. doi: 10.1158/1078-0432.CCR-16-2149 [Epub ahead of print]

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