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Pancreatic Neoplasms: HELP
Articles by Masaya Jimbo
Based on 8 articles published since 2009
(Why 8 articles?)
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Between 2009 and 2019, M. Jimbo wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial. 2018

Tatarian, Talar / Jiang, Wei / Leiby, Benjamin E / Grigoli, Amanda / Jimbo, Masaya / Dabbish, Nooreen / Neoptolemos, John P / Greenhalf, William / Costello, Eithne / Ghaneh, Paula / Halloran, Christopher / Palmer, Daniel / Buchler, Markus / Yeo, Charles J / Winter, Jordan M / Brody, Jonathan R. ·Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. · Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. · Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. · Institute of Translational Medicine, Cancer Research UK Liverpool Cancer Trials Unit, Liverpool, UK. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Ann Surg · Pubmed #27893535.

ABSTRACT: OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3-36.4 vs 10.9 months, CI: 7.5-14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6-14.6 vs GEM, 12.9 months, CI: 11.2-15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.

2 Article Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells. 2017

Zarei, Mahsa / Lal, Shruti / Parker, Seth J / Nevler, Avinoam / Vaziri-Gohar, Ali / Dukleska, Katerina / Mambelli-Lisboa, Nicole C / Moffat, Cynthia / Blanco, Fernando F / Chand, Saswati N / Jimbo, Masaya / Cozzitorto, Joseph A / Jiang, Wei / Yeo, Charles J / Londin, Eric R / Seifert, Erin L / Metallo, Christian M / Brody, Jonathan R / Winter, Jordan M. ·Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Bioengineering, University of California, San Diego, La Jolla, California. · MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania. · Computational Medicine Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Moores Cancer Center, University of California, San Diego, La Jolla, California. · Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. jordan.winter@jefferson.edu. ·Cancer Res · Pubmed #28652247.

ABSTRACT: Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (

3 Article GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR. 2016

Zhou, H / Telonis, A G / Jing, Y / Xia, N L / Biederman, L / Jimbo, M / Blanco, F / Londin, E / Brody, J R / Rigoutsos, I. ·Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street Philadelphia, PA 19107, USA. · Department of Neuroscience and The Farber Institute for Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA. · Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. · Department of Surgery, The Jefferson Biliary and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA. ·Cell Death Dis · Pubmed #27415424.

ABSTRACT: GPRC5A is an orphan G-protein coupled receptor with an intriguing dual behavior, acting as an oncogene in some cancers and as a tumor suppressor in other cancers. In the pancreatic cancer context, very little is known about GPRC5A. By analyzing messenger RNA (mRNA) expression data from 675 human cancer cell lines and 10 609 samples from The Cancer Genome Atlas (TCGA) we found that GPRC5A's abundance in pancreatic cancer is highest (cell lines) or second highest (TCGA) among all tissues and cancer types. Further analyses of an independent set of 252 pancreatic normal and cancer samples showed GPRC5A mRNA to be more than twofold upregulated in primary tumor samples compared with normal pancreas (P-value<10(-5)), and even further upregulated in pancreatic cancer metastases to various organs (P-value=0.0021). Immunostaining of 208 cores (103 samples) of a tissue microarray showed generally low expression of GPRC5A protein in normal pancreatic ductal cells; on the other hand, in primary and metastatic samples, GPRC5A protein levels were dramatically increased in pancreatic ductal cells. In vitro studies of multiple pancreatic cancer cell lines showed that an increase in GPRC5A protein levels promoted pancreatic cancer cell growth and migration. Unexpectedly, when we treated pancreatic cancer cell lines with gemcitabine (2',2'-difluorodeoxycytidine), we observed an increase in GPRC5A protein abundance. On the other hand, when we knocked down GPRC5A we sensitized pancreatic cancer cells to gemcitabine. Through further experimentation we showed that the monotonic increase in GPRC5A protein levels that we observe for the first 18 h following gemcitabine treatment results from interactions between GPRC5A's mRNA and the RNA-binding protein HuR, which is an established key mediator of gemcitabine's efficacy in cancer cells. As we discovered, the interaction between GPRC5A and HuR is mediated by at least one HuR-binding site in GPRC5A's mRNA. Our findings indicate that GPRC5A is part of a complex molecular axis that involves gemcitabine and HuR, and, possibly, other genes. Further work is warranted before it can be established unequivocally that GPRC5A is an oncogene in the pancreatic cancer context.

4 Article The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells. 2016

Blanco, F F / Jimbo, M / Wulfkuhle, J / Gallagher, I / Deng, J / Enyenihi, L / Meisner-Kober, N / Londin, E / Rigoutsos, I / Sawicki, J A / Risbud, M V / Witkiewicz, A K / McCue, P A / Jiang, W / Rui, H / Yeo, C J / Petricoin, E / Winter, J M / Brody, J R. ·Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. · Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason University, Manassas, VA, USA. · Novartis Institutes for Biomedical Research, Novartis, Switzerland. · Center for Computational Medicine, Thomas Jefferson University, Philadelphia, PA, USA. · Lankenau Institute for Medical Research, Philadelphia, PA, USA. · Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. · Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA. ·Oncogene · Pubmed #26387536.

ABSTRACT: Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3'-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR's regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

5 Article Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells. 2015

Jimbo, Masaya / Blanco, Fernando F / Huang, Yu-Hung / Telonis, Aristeidis G / Screnci, Brad A / Cosma, Gabriela L / Alexeev, Vitali / Gonye, Gregory E / Yeo, Charles J / Sawicki, Janet A / Winter, Jordan M / Brody, Jonathan R. ·Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Pharmacology & Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA. · Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Dermatology, Thomas Jefferson University, Philadelphia, PA, USA. · NanoString Technologies, Seattle, WA, USA. · Lankenau Institute for Medical Research, Wynnewood, PA, USA. ·Oncotarget · Pubmed #26314962.

ABSTRACT: Post-transcriptional regulation is a powerful mediator of gene expression, and can rapidly alter the expression of numerous transcripts involved in tumorigenesis. We have previously shown that the mRNA-binding protein HuR (ELAVL1) is elevated in human pancreatic ductal adenocarcinoma (PDA) specimens compared to normal pancreatic tissues, and its cytoplasmic localization is associated with increased tumor stage. To gain a better insight into HuR's role in PDA biology and to assess it as a candidate therapeutic target, we altered HuR expression in PDA cell lines and characterized the resulting phenotype in preclinical models. HuR silencing by short hairpin and small interfering RNAs significantly decreased cell proliferation and anchorage-independent growth, as well as impaired migration and invasion. In comparison, HuR overexpression increased migration and invasion, but had no significant effects on cell proliferation and anchorage-independent growth. Importantly, two distinct targeted approaches to HuR silencing showed marked impairment in tumor growth in mouse xenografts. NanoString nCounter® analyses demonstrated that HuR regulates core biological processes, highlighting that HuR inhibition likely thwarts PDA viability through post-transcriptional regulation of diverse signaling pathways (e.g. cell cycle, apoptosis, DNA repair). Taken together, our study suggests that targeted inhibition of HuR may be a novel, promising approach to the treatment of PDA.

6 Article MUC1 Promoter-Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer. 2015

Tholey, Renee M / Lal, Shruti / Jimbo, Masaya / Burkhart, Richard A / Blanco, Fernando F / Cozzitorto, Joseph A / Eisenberg, Josh D / Jiang, Wei / Iacobuzio-Donahue, Christine A / Witkiewicz, Agnieszka K / Glbert, Melissa / Yeo, Charles J / Brody, Jonathan R / Sawicki, Janet A / Winter, Jordan M. ·Department of Surgery and the Jefferson Pancreas, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pathology and the David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, UT Southwestern Medical Center; Dallas, Texas. · Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. jordan.winter@jefferson.edu SawickiJ@MLHS.org. · Department of Surgery and the Jefferson Pancreas, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. jordan.winter@jefferson.edu SawickiJ@MLHS.org. ·Mol Cancer Res · Pubmed #25336517.

ABSTRACT: IMPLICATIONS: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter-driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs.

7 Article dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: a dual-institutional follow-up with the RTOG 9704 trial. 2014

McAllister, Florencia / Pineda, Danielle M / Jimbo, Masaya / Lal, Shruti / Burkhart, Richard A / Moughan, Jennifer / Winter, Kathryn A / Abdelmohsen, Kotb / Gorospe, Myriam / Acosta, Ana de Jesus / Lankapalli, Rachana H / Winter, Jordan M / Yeo, Charles J / Witkiewicz, Agnieska K / Iacobuzio-Donahue, Christine A / Laheru, Daniel / Brody, Jonathan R. ·Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA; Department of Medicine; Division of Clinical Pharmacology; Johns Hopkins University; Baltimore, MD USA. · Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA. · RTOG Statistical Center; Philadelphia, PA USA. · Laboratory of Genetics; National Institute on Aging Intramural Research Program; National Institutes of Health; Baltimore, MD USA. · Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA. · Department of Pathology; The University of Texas Southwestern Medical Center; Dallas, TX USA. ·Cancer Biol Ther · Pubmed #24618665.

ABSTRACT: Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47-0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33-0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR's regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.

8 Article HuR posttranscriptionally regulates WEE1: implications for the DNA damage response in pancreatic cancer cells. 2014

Lal, Shruti / Burkhart, Richard A / Beeharry, Neil / Bhattacharjee, Vikram / Londin, Eric R / Cozzitorto, Joseph A / Romeo, Carmella / Jimbo, Masaya / Norris, Zoë A / Yeo, Charles J / Sawicki, Janet A / Winter, Jordan M / Rigoutsos, Isidore / Yen, Timothy J / Brody, Jonathan R. ·Authors' Affiliations: Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Jefferson Medical College; Computational Medicine Center; Kimmel Cancer Center, Thomas Jefferson University; Fox Chase Cancer Center, Philadelphia; and Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. ·Cancer Res · Pubmed #24536047.

ABSTRACT: HuR (ELAV1), an RNA-binding protein abundant in cancer cells, primarily resides in the nucleus, but under specific stress (e.g., gemcitabine), HuR translocates to the cytoplasm in which it tightly modulates the expression of mRNA survival cargo. Here, we demonstrate for the first time that stressing pancreatic ductal adenocarcinoma (PDA) cells by treatment with DNA-damaging anticancer agents (mitomycin C, oxaliplatin, cisplatin, carboplatin, and a PARP inhibitor) results in HuR's translocation from the nucleus to the cytoplasm. Importantly, silencing HuR in PDA cells sensitized the cells to these agents, whereas overexpressing HuR caused resistance. HuR's role in the efficacy of DNA-damaging agents in PDA cells was, in part, attributed to the acute upregulation of WEE1 by HuR. WEE1, a mitotic inhibitor kinase, regulates the DNA damage repair pathway, and therapeutic inhibition of WEE1 in combination with chemotherapy is currently in early phase trials for the treatment of cancer. We validate WEE1 as a HuR target in vitro and in vivo by demonstrating (i) direct binding of HuR to WEE1's mRNA (a discrete 56-bp region residing in the 3' untranslated region) and (ii) HuR siRNA silencing and overexpression directly affects the protein levels of WEE1, especially after DNA damage. HuR's positive regulation of WEE1 increases γ-H2AX levels, induces Cdk1 phosphorylation, and promotes cell-cycle arrest at the G2-M transition. We describe a novel mechanism that PDA cells use to protect against DNA damage in which HuR posttranscriptionally regulates the expression and downstream function of WEE1 upon exposure to DNA-damaging agents.