TY - JOUR
T1 - Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative
AU - Cuppens, Tine
AU - Annibali, Daniela
AU - Coosemans, An
AU - Trovik, Jone
AU - ter Haar, Natalja
AU - Colas, Eva
AU - Garcia-Jimenez, Angel
AU - Van de Vijver, Koen
AU - Kruitwagen, Roy P. M.
AU - Brinkhuis, Mariel
AU - Zikan, Michal
AU - Dundr, Pavel
AU - Huvila, Jutta
AU - Carpen, Olli
AU - Haybaeck, Johannes
AU - Moinfar, Farid
AU - Salvesen, Helga B.
AU - Stukan, Maciej
AU - Mestdagh, Carole
AU - Zweemer, Ronald P.
AU - Massuger, Leonardus F.
AU - Mallmann, Michael R.
AU - Wardelmann, Eva
AU - Mints, Miriam
AU - Verbist, Godelieve
AU - Thomas, Debby
AU - Gomme, Ellen
AU - Hermans, Els
AU - Moerman, Philippe
AU - Bosse, Tjalling
AU - Amant, Frederic
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - ENDOMETRIAL STROMAL SARCOMA
KW - SOFT-TISSUE SARCOMA
KW - GROWTH-FACTOR RECEPTOR
KW - AKT-MTOR PATHWAY
KW - MAMMALIAN TARGET
KW - BREAST-CANCER
KW - CYCLIN D1
KW - EXPRESSION
KW - TUMORS
KW - TRIAL
U2 - 10.1158/1078-0432.CCR-16-2149
DO - 10.1158/1078-0432.CCR-16-2149
M3 - Article
C2 - 28232476
SN - 1078-0432
VL - 23
SP - 1274
EP - 1285
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -