Cuppens, Tine, Annibali, Daniela ORCID: 0000-0001-8413-7669, Coosemans, An ORCID: 0000-0002-7321-4339, Trovik, Jone, ter Haar, Natalja, Colas, Eva, Garcia-Jimenez, Angel ORCID: 0000-0002-7635-3174, Van de Vijver, Koen ORCID: 0000-0002-2026-9790, Kruitwagen, Roy P. M., Brinkhuis, Mariel, Zikan, Michal ORCID: 0000-0001-5266-8895, Dundr, Pavel ORCID: 0000-0002-8940-6124, Huvila, Jutta, Carpen, Olli, Haybaeck, Johannes, Moinfar, Farid, Salvesen, Helga B., Stukan, Maciej ORCID: 0000-0003-2376-4663, Mestdagh, Carole, Zweemer, Ronald P., Massuger, Leonardus F., Mallmann, Michael R., Wardelmann, Eva, Mints, Miriam, Verbist, Godelieve, Thomas, Debby ORCID: 0000-0003-3075-9846, Gomme, Ellen, Hermans, Els, Moerman, Philippe, Bosse, Tjalling and Amant, Frederic ORCID: 0000-0002-5452-4905 (2017). Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative. Clin. Cancer Res., 23 (5). S. 1274 - 1286. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Cuppens, TineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Annibali, DanielaUNSPECIFIEDorcid.org/0000-0001-8413-7669UNSPECIFIED
Coosemans, AnUNSPECIFIEDorcid.org/0000-0002-7321-4339UNSPECIFIED
Trovik, JoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ter Haar, NataljaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colas, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Jimenez, AngelUNSPECIFIEDorcid.org/0000-0002-7635-3174UNSPECIFIED
Van de Vijver, KoenUNSPECIFIEDorcid.org/0000-0002-2026-9790UNSPECIFIED
Kruitwagen, Roy P. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkhuis, MarielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zikan, MichalUNSPECIFIEDorcid.org/0000-0001-5266-8895UNSPECIFIED
Dundr, PavelUNSPECIFIEDorcid.org/0000-0002-8940-6124UNSPECIFIED
Huvila, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carpen, OlliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haybaeck, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moinfar, FaridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salvesen, Helga B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stukan, MaciejUNSPECIFIEDorcid.org/0000-0003-2376-4663UNSPECIFIED
Mestdagh, CaroleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zweemer, Ronald P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massuger, Leonardus F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mallmann, Michael R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wardelmann, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mints, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verbist, GodelieveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, DebbyUNSPECIFIEDorcid.org/0000-0003-3075-9846UNSPECIFIED
Gomme, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hermans, ElsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moerman, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bosse, TjallingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amant, FredericUNSPECIFIEDorcid.org/0000-0002-5452-4905UNSPECIFIED
URN: urn:nbn:de:hbz:38-238568
DOI: 10.1158/1078-0432.CCR-16-2149
Journal or Publication Title: Clin. Cancer Res.
Volume: 23
Number: 5
Page Range: S. 1274 - 1286
Date: 2017
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SOFT-TISSUE SARCOMA; GROWTH-FACTOR RECEPTOR; AKT-MTOR PATHWAY; MAMMALIAN TARGET; BREAST-CANCER; CYCLIN D1; EXPRESSION; TUMORS; RIDAFOROLIMUS; DOXORUBICINMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23856

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