Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative

Tine Cuppens, Daniela Annibali, An Coosemans, Jone Trovik, Natalja ter Haar, Eva Colas, Angel Garcia-Jimenez, Koen Van de Vijver, Roy P. M. Kruitwagen, Mariel Brinkhuis, Michal Zikan, Pavel Dundr, Jutta Huvila, Olli Carpen, Johannes Haybaeck, Farid Moinfar, Helga B. Salvesen, Maciej Stukan, Carole Mestdagh, Ronald P. ZweemerLeonardus F. Massuger, Michael R. Mallmann, Eva Wardelmann, Miriam Mints, Godelieve Verbist, Debby Thomas, Ellen Gomme, Els Hermans, Philippe Moerman, Tjalling Bosse, Frederic Amant*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Web of Science)

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-alpha, 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, S6S240 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. (C)2017 AACR.

Original languageEnglish
Pages (from-to)1274-1285
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number5
DOIs
Publication statusPublished - 1 Mar 2017

Keywords

  • ENDOMETRIAL STROMAL SARCOMA
  • SOFT-TISSUE SARCOMA
  • GROWTH-FACTOR RECEPTOR
  • AKT-MTOR PATHWAY
  • MAMMALIAN TARGET
  • BREAST-CANCER
  • CYCLIN D1
  • EXPRESSION
  • TUMORS
  • TRIAL

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