Author:

Keywords:

Uterine sarcoma, Leiomyosarcoma, Immunohistochemistry, PI3K/mTOR pathway, Patient-derived xenograft models, Science & Technology, Life Sciences & Biomedicine, Oncology, GROWTH-FACTOR RECEPTOR, AKT-MTOR PATHWAY, MAMMALIAN TARGET, BREAST-CANCER, CYCLIN D1, SARCOMAS, EXPRESSION, TUMORS, RIDAFOROLIMUS, DOWNSTREAM, Animals, Biomarkers, Tumor, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Molecular Targeted Therapy, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Prognosis, Ribosomal Protein S6, Signal Transduction, TOR Serine-Threonine Kinases, Uterine Neoplasms, Xenograft Model Antitumor Assays, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

Abstract:

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6(S240) ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), 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 (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6(S240), was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6(S240) phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6(S240) correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6(S240) expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6(S240) in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6(S240) expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1-12. ©2017 AACR.