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1. Supplementary methods from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

Abstract

Supplementary methods

Published
2023
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2. Supplementary figure 4 from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

Abstract

Combination of the mTORC1/2 inhibitor TAK-228 and the PI3K-α inhibitor alpelisib inhibits EMC041 tumor growth to the same extent as BEZ235

Published
2023
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3. Supplementary figure 2 from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

Abstract

Immunohistochemistry stainings of potential targets.

Published
2023
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4. Supplementary figure 3 from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

Abstract

High-grade endometrial stromal sarcoma with YMHAE/NUTM2A/B fusion and cyclin D1 expression.

Published
2023
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5. Data from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

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-S6S240 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-S6S240, 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-S6S240 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-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: 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. Clin Cancer Res; 23(5); 1274–85. ©2017 AACR.

Published
2023
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6. Supplementary data from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

Abstract

Supplementary tables and figure legends

Published
2023
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7. Supplementary figure 1 from Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Author

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

Abstract

Survival of uterine sarcoma patients according to tumor grade and histologic subtype.

Published
2023
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9. Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative

Author

Mariël Brinkhuis, Miriam Mints, Tjalling Bosse, Koen Van de Vijver, Debby Thomas, R.P.F.M. Kruitwagen, Ronald P. Zweemer, Helga B. Salvesen, Michal Zikan, Tine Cuppens, Carole Mestdagh, Jone Trovik, Ellen Gomme, Pavel Dundr, Philippe Moerman, Godelieve Verbist, Jutta Huvila, Michael R. Mallmann, Maciej Stukan, Natalja T. ter Haar, Farid Moinfar, Els Hermans, Daniela Annibali, Johannes Haybaeck, Angel Garcia-Jimenez, Frédéric Amant, Olli Carpén, An Coosemans, Eva Wardelmann, Eva Colas, Leonardus F. Massuger, Amsterdam Reproduction & Development (AR&D), Other departments, Medicum, Department of Pathology, Precision Cancer Pathology, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (9), MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology, and Obstetrie & Gynaecologie

Subjects
0301 basic medicine, Leiomyosarcoma, Cancer Research, Pathology, AKT-MTOR PATHWAY, ENDOMETRIAL STROMAL SARCOMA, Uterine sarcoma, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Molecular Targeted Therapy, Phosphorylation, CYCLIN D1, Phosphoinositide-3 Kinase Inhibitors, Ribosomal Protein S6, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], biology, Soft tissue sarcoma, TOR Serine-Threonine Kinases, Prognosis, Immunohistochemistry, TUMORS, Gene Expression Regulation, Neoplastic, PI3K/mTOR pathway, SOFT-TISSUE SARCOMA, Oncology, 030220 oncology & carcinogenesis, Uterine Neoplasms, TRIAL, Female, Signal Transduction, EXPRESSION, medicine.medical_specialty, Stromal cell, 3122 Cancers, Disease-Free Survival, 03 medical and health sciences, medicine, Biomarkers, Tumor, PTEN, BREAST-CANCER, Animals, Humans, PI3K/AKT/mTOR pathway, Endometrial stromal sarcoma, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, MAMMALIAN TARGET, Patient-derived xenograft models, Cancer research, biology.protein, business, GROWTH-FACTOR RECEPTOR
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-S6S240 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-S6S240, 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-S6S240 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-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition. Conclusions: 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. Clin Cancer Res; 23(5); 1274–85. ©2017 AACR.

Published
2017

10. Aggressive Angiomyxoma: Imaging Findings in 3 Cases With Clinicopathological Correlation and Review of the Literature

Author

Rosa Dominguez Oronoz, Pilar Lozano Arranz, Javier Miguez Gonzalez, Francesc Calaf Forn, Angel Garcia Jimenez, and Pedro Barrios Sanchez

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Clinicopathological correlation, Contrast Media, Gadolinium, Diagnosis, Differential, Aggressive angiomyxoma, Imaging, Three-Dimensional, Multidetector Computed Tomography, medicine, Soft tissue mass, Humans, Radiology, Nuclear Medicine and imaging, Aged, medicine.diagnostic_test, business.industry, Mesenchymal Tumor, Rectum, Myxoma, Magnetic resonance imaging, Image enhancement, Middle Aged, medicine.disease, Image Enhancement, Magnetic Resonance Imaging, Diffusion Magnetic Resonance Imaging, Vagina, Female, Differential diagnosis, business
Abstract

Aggressive angiomyxoma is a rare mesenchymal tumor with a typical presentation as a slowly growing perineal soft tissue mass in paravulvar and pararectal region in young adult women. We present 3 cases of aggressive angiomyxoma with clinicopathological correlation and describe their main imaging features with emphasis on magnetic resonance imaging, adding useful information about their behavior on dynamic contrast-enhanced sequences and diffusion-weighted imaging and including a comprehensive review of the existing literature.

Published
2015

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