Preclinical Study of PI3K/mTOR Inhibitors in Uterine Leiomyosarcomas


Key Points

  • The protein P-S6S240, which plays a role in the PI3K/mTOR cell-signaling pathway, was present more frequently in high-grade uterine tumors (32%) than in low-grade tumors (9%). And its presence correlated with shorter progression-free and disease-specific survival in leiomyosarcomas.
  • Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and P-S6S240 expression is a potential biomarker for response to treatment. 

According to the National Cancer Institute, uterine sarcomas are rare gynecologic malignancies comprising between 2% and 5% of all uterine malignancies. Leiomyosarcomas, which arise from myometrial muscle, account for 30% of all uterine sarcomas. These aggressive, rare cancers are characterized by high mortality rates and limited treatment options.

Now, a laboratory study investigating the expression of potential therapeutic targets in a large cohort of different human uterine sarcomas has found that dual PI3K/mTOR inhibition is a promising therapeutic strategy in uterine leiomyosarcoma. The study also found that the P-S6S240 protein is a potential predictive biomarker for response to the treatment. The study by Cuppens et al was published in Clinical Cancer Research.

Study Methodology

The study was an international collaboration within the European Network for Individualized Treatment for Endometrial Cancer (ENITEC). The study researchers investigated the expression of several druggable targets in 288 human uterine sarcoma samples, including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential; 52 benign uterine stromal tumors; and 41 normal uterine tissues. The potential therapeutic value of the most promising target, P-S6S240, was tested in patient-driven xenograft leiomyosarcoma models.

Study Findings

The researchers found that in uterine sarcomas and smooth muscle tumors of uncertain malignant potential, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with a higher grade (P = .001) and recurrence (P = .019), as shown by logistic regression. In addition, P-S6S240 correlated with shorter progression-free survival (P = .034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in four of five leiomyosarcoma patient-driven xenograft models, with tumor shrinkage in two models. Remarkably, the four responding models showed basal P-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for P-S6S240 in response prediction to PI3K/mTOR inhibition.

Potential Prognostic Marker

“Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and P-S6S240 expression is a potential predictive biomarker for response to treatment,” concluded the researchers.

In a statement on the study results, coauthor Frédéric Amant, MD, PhD, a professor at the Leuven Cancer Institute in Belgium and at the Netherlands Cancer Institute in Amsterdam, said, “Uterine sarcomas have generally been underexplored due to their rareness. Nevertheless, they behave aggressively and are difficult to treat, resulting in a high clinical need. Leiomyosarcoma is a neglected field, and we now have solid data offering a rationale for testing PI3K/mTOR inhibitors against this disease in clinical trials. Patient participation in such studies is also strongly hoped for.”

Funding for this study was provided by Prague’s biobanking grant project; the Swedish Labour Market Insurance and Swedish Medical Research Council; the Western Norway Regional Health Authority; the Norwegian Cancer Society; and the Norwegian Research Council.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.