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Pancreatic Neoplasms: HELP
Articles by Cyril H. Benes
Based on 5 articles published since 2010
(Why 5 articles?)
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Between 2010 and 2020, Cyril H. Benes wrote the following 5 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. 2019

Ligorio, Matteo / Sil, Srinjoy / Malagon-Lopez, Jose / Nieman, Linda T / Misale, Sandra / Di Pilato, Mauro / Ebright, Richard Y / Karabacak, Murat N / Kulkarni, Anupriya S / Liu, Ann / Vincent Jordan, Nicole / Franses, Joseph W / Philipp, Julia / Kreuzer, Johannes / Desai, Niyati / Arora, Kshitij S / Rajurkar, Mihir / Horwitz, Elad / Neyaz, Azfar / Tai, Eric / Magnus, Neelima K C / Vo, Kevin D / Yashaswini, Chittampalli N / Marangoni, Francesco / Boukhali, Myriam / Fatherree, Jackson P / Damon, Leah J / Xega, Kristina / Desai, Rushil / Choz, Melissa / Bersani, Francesca / Langenbucher, Adam / Thapar, Vishal / Morris, Robert / Wellner, Ulrich F / Schilling, Oliver / Lawrence, Michael S / Liss, Andrew S / Rivera, Miguel N / Deshpande, Vikram / Benes, Cyril H / Maheswaran, Shyamala / Haber, Daniel A / Fernandez-Del-Castillo, Carlos / Ferrone, Cristina R / Haas, Wilhelm / Aryee, Martin J / Ting, David T. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Clinic of Surgery, UKSH Campus Lübeck, Germany. · Institute of Pathology, University Medical Center Freiburg, Germany. · Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aryee.martin@mgh.harvard.edu. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu. ·Cell · Pubmed #31155233.

ABSTRACT: Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

2 Article Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. 2017

Lev, Avital / Lulla, Amriti R / Wagner, Jessica / Ralff, Marie D / Kiehl, Joshua B / Zhou, Yan / Benes, Cyril H / Prabhu, Varun V / Oster, Wolfgang / Astsaturov, Igor / Dicker, David T / El-Deiry, Wafik S. ·Department of Hematology/Oncology, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA. · Biostatistics Department, Fox Chase Cancer Center, Philadelphia, PA, USA. · Massachusetts General Hospital, Boston, MA, USA. · Oncoceutics, Inc., Philadelphia, PA, USA. · Department of Hematology/Oncology, Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA. ·Oncotarget · Pubmed #29137221.

ABSTRACT: Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines (

3 Article Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. 2015

Alagesan, Brinda / Contino, Gianmarco / Guimaraes, Alex R / Corcoran, Ryan B / Deshpande, Vikram / Wojtkiewicz, Gregory R / Hezel, Aram F / Wong, Kwok-Kin / Loda, Massimo / Weissleder, Ralph / Benes, Cyril H / Engelman, Jeffrey / Bardeesy, Nabeel. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114. · Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA 02114. · Department of Radiology, Harvard Medical School, Boston, MA 02115. · Department of Medicine, Harvard Medical School, Boston, MA 02115. · Department of Pathology, Massachusetts General Hospital, Boston, MA 02114. · Department of Pathology, Harvard Medical School, Boston, MA 02115. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02215. · Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115. ·Clin Cancer Res · Pubmed #25348516.

ABSTRACT: PURPOSE: Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM). EXPERIMENTAL DESIGN: We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC. RESULTS: In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. CONCLUSIONS: Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR.

4 Article CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. 2014

Heilmann, Andreas M / Perera, Rushika M / Ecker, Veronika / Nicolay, Brandon N / Bardeesy, Nabeel / Benes, Cyril H / Dyson, Nicholas J. ·Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts. · Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts dyson@helix.mgh.harvard.edu. ·Cancer Res · Pubmed #24986516.

ABSTRACT: Loss-of-function mutations in p16(INK4A) (CDKN2A) occur in approximately 80% of sporadic pancreatic ductal adenocarcinoma (PDAC), contributing to its early progression. Although this loss activates the cell-cycle-dependent kinases CDK4/6, which have been considered as drug targets for many years, p16(INK4A)-deficient PDAC cells are inherently resistant to CDK4/6 inhibitors. This study searched for targeted therapies that might synergize with CDK4/6 inhibition in this setting. We report that the IGF1R/IR inhibitor BMS-754807 cooperated with the CDK4/6 inhibitor PD-0332991 to strongly block proliferation of p16(INK4A)-deficient PDAC cells in vitro and in vivo. Sensitivity to this drug combination correlated with reduced activity of the master cell growth regulator mTORC1. Accordingly, replacing the IGF1R/IR inhibitor with the rapalog inhibitor temsirolimus broadened the sensitivity of PDAC cells to CDK4/6 inhibition. Our results establish targeted therapy combinations with robust cytostatic activity in p16(INK4A)-deficient PDAC cells and possible implications for improving treatment of a broad spectrum of human cancers characterized by p16(INK4A) loss.

5 Article STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. 2011

Corcoran, Ryan B / Contino, Gianmarco / Deshpande, Vikram / Tzatsos, Alexandros / Conrad, Claudius / Benes, Cyril H / Levy, David E / Settleman, Jeffrey / Engelman, Jeffrey A / Bardeesy, Nabeel. ·Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. ·Cancer Res · Pubmed #21586612.

ABSTRACT: The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors.