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Murray Korc, MD

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Endocrinology

Professor of Medicine
Myles Brand Professor of Cancer Research, IUSM
Professor, Department of Medicine, Division of Endocrinology, IUSM
Director, IUPUI Pancreatic Cancer Signature Center
Co-director, Tumor Microenvironment and Metastases research program, IU Simon Cancer Center

Academic Office

Joseph E. Walther Hall, Room C528E
980 W. Walnut St.
Indianapolis IN 46202 Map

Contact Information

Phone: (317) 278-6410
Email:

Education and Training

Medicine (M.D.) Albany Medical College
Biology, General Brooklyn College Of Cuny

Publications (19)¹

Response to le large et Al.
Journal: The American journal of gastroenterology
Authors: Cote GA; Gore AJ; McElyea SD; Xu H; Sherman S; Korc M;
Publication Date: 2015 May
TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis.
Journal: Oncotarget
Authors: Gore J; Craven KE; Wilson JL; Cote GA; Cheng M; Nguyen HV; Cramer HM; Sherman S; Korc M;
Publication Date: 2015 Feb 25

Abstract

Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-ß signaling and STAT3. Inhibition of the type I TGF-ß receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1-2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1-2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.
View details for PubMedID 25762644
Pancreatic Cancer-Associated Diabetes Is an "Exosomopathy"
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
Authors: Korc M;
Publication Date: 2015 Feb 2

Abstract

Diabetes may be a consequence of pancreatic cancer, preceding cancer diagnosis. The underlying mechanism is the release of exosomes delivering adrenomedullin to ß cells, inducing endoplasmic reticulum stress and perturbations in the unfolded protein response, leading to ß-cell dysfunction and death. This knowledge could lead to improved diagnostic strategies for pancreatic cancer. Clin Cancer Res; 21(7); 1508-10. ©2015 AACR. See related article by Javeed et al. p. 1722.
View details for PubMedID 25645860
Longitudinal Bioluminescence Imaging of Primary Versus Abdominal Metastatic Tumor Growth in Orthotopic Pancreatic Tumor Models in NSG Mice.
Journal: Pancreas
Authors: Shannon HE; Fishel ML; Xie J; Gu D; McCarthy BP; Riley AA; Sinn AL; Silver JM; Peterman K; Kelley MR; Hanenberg H; Korc M; Pollok KE; Territo PR;
Publication Date: 2015 Jan

Abstract

The purpose of the present study was to develop and validate noninvasive bioluminescence imaging methods for differentially monitoring primary and abdominal metastatic tumor growth in mouse orthotopic models of pancreatic cancer.
View details for PubMedID 25406955
Critical role of NF-?B in pancreatic cancer.
Journal: Oncotarget
Authors: Prabhu L; Mundade R; Korc M; Loehrer PJ; Lu T;
Publication Date: 2014 Nov 30

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor ?B (NF-?B) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-?B pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-?B involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-?B regulators which could be used to design novel therapeutic strategies for PDAC.
View details for PubMedID 25473891
Highly specific plasmonic biosensors for ultrasensitive microRNA detection in plasma from pancreatic cancer patients.
Journal: Nano letters
Authors: Joshi GK; Deitz-McElyea S; Johnson M; Mali S; Korc M; Sardar R;
Publication Date: 2014 Nov 7

Abstract

MicroRNAs (miRs) are small noncoding RNAs that regulate mRNA stability and/or translation. Because of their release into the circulation and their remarkable stability, miR levels in plasma and other biological fluids can serve as diagnostic and prognostic disease biomarkers. However, quantifying miRs in the circulation is challenging due to issues with sensitivity and specificity. This Letter describes for the first time the design and characterization of a regenerative, solid-state localized surface plasmon resonance (LSPR) sensor based on highly sensitive nanostructures (gold nanoprisms) that obviates the need for labels or amplification of the miRs. Our direct hybridization approach has enabled the detection of subfemtomolar concentration of miR-X (X = 21 and 10b) in human plasma in pancreatic cancer patients. Our LSPR-based measurements showed that the miR levels measured directly in patient plasma were at least 2-fold higher than following RNA extraction and quantification by reverse transcriptase-polymerase chain reaction. Through LSPR-based measurements we have shown nearly 4-fold higher concentrations of miR-10b than miR-21 in plasma of pancreatic cancer patients. We propose that our highly sensitive and selective detection approach for assaying miRs in plasma can be applied to many cancer types and disease states and should allow a rational approach for testing the utility of miRs as markers for early disease diagnosis and prognosis, which could allow for the design of effective individualized therapeutic approaches.
View details for PubMedID 25379951
A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile.
Journal: The American journal of gastroenterology
Authors: Cote GA; Gore AJ; McElyea SD; Heathers LE; Xu H; Sherman S; Korc M;
Publication Date: 2014 Oct 28

Abstract

Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls.
View details for PubMedID 25350767
Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance.
Journal: Biomaterials
Authors: Ki CS; Lin TY; Korc M; Lin CC;
Publication Date: 2014 Aug 28

Abstract

The development of pancreatic ductal adenocarcinoma (PDAC) is heavily influenced by local stromal tissues, or desmoplasia. Biomimetic hydrogels capable of mimicking tumor niches are particularly useful for discovering the role of independent matrix cues on cancer cell development. Here, we report a photo-curable and bio-orthogonal thiol-ene (i.e., cross-linked by mutually reactive norbornene and thiol groups via photoinitiation) hydrogel platform for studying the growth, morphogenesis, drug resistance, and cancer stem cell marker expression in PDAC cells cultured in 3D. The hydrogels were prepared from multi-arm poly(ethylene glycol)-norbornene cross-linked with protease-sensitive peptide to permit cell-mediated matrix remodeling. Collagen 1 fibrils were incorporated into the covalent network while cytokines (e.g., EGF and TGF-ß1) were supplemented in the culture media for controlling cell fate. We found that the presence of collagen 1 enhanced cell proliferation and Yes-associated protein (YAP) translocation to cell nuclei. Cytokines and collagen 1 synergistically up-regulated MT1-MMP expression and induced cell spreading, suggestive of epithelial-mesenchymal transition (EMT) in the encapsulated cells. Furthermore, PDAC cells cultured in 3D developed chemo-resistance even in the absence of collagen 1 and cytokines. This phenotype is likely a consequence of the enrichment of pancreatic cancer stem cells that expressed high levels of CD24, sonic hedgehog (SHH), and vascular endothelial growth factor (VEGF).
View details for PubMedID 25176061
Improving the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration using microRNAs.
Journal: Gastroenterology
Authors: Sina M; Coté GA; Korc M;
Publication Date: 2014 Aug 22
p38 MAPK in pancreatic cancer: finding a protective needle in the haystack.
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
Authors: Korc M;
Publication Date: 2014 Aug 18

Abstract

Activated p38 MAPK alpha (pp38a) is a good prognostic marker in pancreatic ductal adenocarcinoma that could be used to personalize therapy. pp38a suppresses JNK-mediated proliferation, both in vitro and in vivo. These findings support the testing of combination therapies that include JNK targeting and/or suppressing negative regulators of pp38a.
View details for PubMedID 25135483
Pancreatic cancer stroma: friend or foe?
Journal: Cancer cell
Authors: Gore J; Korc M;
Publication Date: 2014 Jun 16

Abstract

Pancreatic cancer desmoplasia is thought to confer biological aggressiveness. In this issue of Cancer Cell, Özdemir and colleagues and Rhim and colleagues demonstrate that targeting the stroma results in undifferentiated, aggressive pancreatic cancer that responds to checkpoint blockade or antiangiogenic therapy, uncovering a protective role by stroma in this cancer.
View details for PubMedID 24937454
Nestin delineates pancreatic cancer stem cells in metastatic foci of NOD/Shi-scid IL2R?(null) (NOG) mice.
Journal: The American journal of pathology
Authors: Matsuda Y; Yoshimura H; Ueda J; Naito Z; Korc M; Ishiwata T;
Publication Date: 2014 Jan 9

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with a high incidence of hepatic metastases, as well as occasional pulmonary metastases. To delineate the potential role of cancer stem cells (CSCs) in PDAC metastasis, human PDAC cells were injected into the spleen of mice. The characteristics and expression of markers associated with CSC and epithelial-mesenchymal transition (EMT) of metastatic cells that developed in the liver and lung were then compared with parental cells. The metastatic cells were polygonal, and larger than parental cells. Metastatic cells also exhibited decreased proliferation and increased adhesion to extracellular matrices, as well as enhanced migration and invasion in vitro and increased metastatic capacity in vivo. The CSC markers ALDH1A1, ABCG2, and nestin were expressed at high levels in metastatic cells and exhibited changes consistent with EMT (eg, decreased E-cadherin expression). Moreover, metastatic cells readily formed spheres in culture and exhibited an increased side population by flow analysis. Nestin and ABCG2 were also expressed at high levels in metastatic lesions from PDAC patients, and silencing nestin with shRNA in PDAC cells derived from lung metastases resulted in a marked decrease in the capacity of the cells to form spheres and to yield pulmonary or hepatic metastases. Thus, the metastatic potential of human PDAC cells correlates with CSCs and with EMT characteristics and is dependent on nestin expression.
View details for PubMedID 24412093
DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
Journal: PloS one
Authors: Liu F; Gore AJ; Wilson JL; Korc M;
Publication Date: 2014 Jan 7

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1) is a key negative regulator of mitogen activated protein kinases (MAPKs). Yet, DUSP1 is overexpressed in pancreatic cancer cells (PCCs) in PDAC where it paradoxically enhances colony formation in soft agar and promotes in vivo tumorigenicity. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human PCCs, we show that gemcitabine activates c-JUN N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK), key kinases in two major stress-activated signaling pathways. Gemcitabine-induced JNK and p38 MAPK activation mediates increased apoptosis, but also transcriptionally upregulates DUSP1, as evidenced by increased DUSP1 mRNA levels and RNA polymerase II loading at DUSP1 gene body. Conversely, shRNA-mediated inhibition of DUSP1 enhances JNK and p38 MAPK activation and gemcitabine chemosensitivity. Using doxycycline-inducible knockdown of DUSP1 in established orthotopic pancreatic tumors, we found that combining gemcitabine with DUSP1 inhibition improves animal survival, attenuates angiogenesis, and enhances apoptotic cell death, as compared with gemcitabine alone. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the advantage of enhancing gemcitabine chemosensitivity while suppressing angiogenesis.
View details for PubMedID 24409315
Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.
Journal: Molecular cancer therapeutics
Authors: Slee RB; Grimes BR; Bansal R; Gore J; Blackburn C; Brown L; Gasaway R; Jeong J; Victorino J; March KL; Colombo R; Herbert BS; Korc M;
Publication Date: 2013 Nov 26

Abstract

Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.
View details for PubMedID 24282275
Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop.
Journal: Pancreas
Authors: Andersen DK; Andren-Sandberg Å; Duell EJ; Goggins M; Korc M; Petersen GM; Smith JP; Whitcomb DC;
Publication Date: 2013 Nov

Abstract

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI) on "Pancreatitis-Diabetes-Pancreatic Cancer" focused on the risk factors of chronic pancreatitis (CP) and diabetes mellitus (DM) on the development of pancreatic ductal adenocarcinoma (PDAC). Sessions were held on (a) an overview of the problem of PDAC; (b) CP as a risk factor of PDAC; (c) DM as a risk factor of PDAC; (d) pancreatogenic, or type 3c, DM; (e) genomic associations of CP, DM, and PDAC; (f) surveillance of high-risk populations and early detection of PDAC; and (g) effects of DM treatment on PDAC. Recent data and current understandings of the mechanisms of CP- and DM-associated factors on PDAC development were discussed, and a detailed review of the possible risks of DM treatment on the development of PDAC was provided by representatives from academia, industry, and the Food and Drug Administration. The current status of possible biomarkers of PDAC and surveillance strategies for high-risk populations were discussed, and the gaps in knowledge and opportunities for further research were elucidated. A broad spectrum of expertise of the speakers and the discussants provided an unusually productive workshop, the highlights of which are summarized in the accompanying article.
View details for PubMedID 24152948
microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-ß actions.
Journal: Oncogene
Authors: Ouyang H; Gore J; Deitz S; Korc M;
Publication Date: 2013 Oct 7

Abstract

Increased microRNA-10b (miR-10b) expression in the cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a marker of disease aggressiveness. In the present study, we determined that plasma miR-10b levels are significantly increased in PDAC patients by comparison with normal controls. By gene profiling, we identified potential targets downregulated by miR-10b, including Tat-interacting protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b or siRNA-mediated silencing of TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. EGF-induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal-regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing. The actions of EGF in the presence of miR-10b were blocked by EGFR kinase inhibition with erlotinib and by dual inhibition of PI3K (phosphatidylinositol 3'-kinase) and MEK. Moreover, miR-10b, EGF and transforming growth factor-beta (TGF-ß) combined to markedly increase cell invasion, and this effect was blocked by the combination of erlotinib and SB505124, a type I TGF-ß receptor inhibitor. miR-10b also enhanced the stimulatory effects of EGF and TGF-ß on cell migration and epithelial-mesenchymal transition (EMT) and decreased the expression of RAP2A, EPHB2, KLF4 and NF1. Moreover, miR-10b overexpression accelerated pancreatic cancer cell (PCC) proliferation and tumor growth in an orthotopic model. Thus, plasma miR-10b levels may serve as a diagnostic marker in PDAC, whereas intra-tumoral miR-10b promotes PCC proliferation and invasion by suppressing TIP30, which enhances EGFR signaling, facilitates EGF-TGF-ß cross-talk and enhances the expression of EMT-promoting genes, whereas decreasing the expression of several metastasis-suppressing genes. Therefore, therapeutic targeting of miR-10b in PDAC may interrupt growth-promoting deleterious EGF-TGF-ß interactions and antagonize the metastatic process at various levels.
View details for PubMedID 24096486
Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases.
Journal: Oncogene
Authors: Ueda J; Matsuda Y; Yamahatsu K; Uchida E; Naito Z; Korc M; Ishiwata T;
Publication Date: 2013 Sep 30

Abstract

Epithelial splicing regulatory protein 1 (ESRP1) binds the FGFR-2 auxiliary cis-element ISE/ISS-3, located in the intron between exon IIIb and IIIc, and primarily promotes FGFR-2 IIIb expression. Here we assessed the role of ESRP1 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis was performed using anti-ESRP1, FGFR-2 IIIb and FGFR-2 IIIc antibodies in 123 PDAC cases. ESRP1 expression vector and small interference RNA (siRNA) targeting ESRP1 were transfected into human PDAC cells, and cell growth, migration and invasion were analyzed. In vivo heterotopic and orthotopic implantations using ESRP1 overexpression clones were performed and effects on pancreatic tumor volumes and hepatic and pulmonary metastases determined. ESRP1 immunoreactivity was strong in the nuclei of cancer cells in well-to-moderately differentiated PDACs but weak in poorly differentiated cancers. Well-to-moderately differentiated cancers also exhibited high FGFR-2 IIIb and low FGFR-2 IIIc expression, whereas this ratio was reversed in the poorly differentiated cancers. Increased ESRP1 expression was associated with longer survival in comparison with low ESRP1 expression, and PANC-1 cells engineered to express ESRP1 exhibited increased FGFR-2 IIIb expression and decreased migration and invasion in vitro, whereas ESRP1 siRNA-transfected KLM-1 cells exhibited increased FGFR-2 IIIc expression and increased cell growth, migration and invasion. In vivo, ESRP1-overexpressing clones formed significantly fewer liver metastases as compared with control clones. ESRP1 regulates the expression pattern of FGFR-2 isoforms, attenuates cell growth, migration, invasion and metastasis, and is a favorable prognostic factor in PDAC. Therefore, devising mechanisms to upregulate ESRP1 may exert a beneficial therapeutic effect in PDAC.
View details for PubMedID 24077287
Molecular imaging in pancreatic cancer--a roadmap for therapeutic decisions.
Journal: Cancer letters
Authors: Kramer-Marek G; Gore J; Korc M;
Publication Date: 2013 Aug 11

Abstract

Pancreatic ductaladeno carcinoma (PDAC) is a deadly cancer characterized by multiple molecular alterations, the presence of an intense stroma, poor perfusion, and resistance to therapy. In addition to standard imaging techniques, experimental imaging strategies, such as those utilizing molecular probes, nanoparticle-based agents, and tagged antibodies are actively being explored experimentally. It is hoped that advances in these technologies will allow for detecting PDAC at an early stage, and could serve to validate experimental therapies, rapidly identify non-responders, and assist in the design of novel therapeutic strategies tailored to the patient's molecular profile.
View details for PubMedID 23941833
Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells.
Journal: Molecular cancer therapeutics
Authors: Liu F; Korc M;
Publication Date: 2012 Aug 6

Abstract

Aberrant activation of Cyclin D-Cdk4/6 signaling pathway is commonly found in pancreatic ductal adenocarcinoma (PDAC). Here, we show that PD-0332991, a highly specific inhibitor for Cdk4 and Cdk6, exerted growth inhibitory effects on three human PDAC cell lines. Microarray analysis revealed that PD-0332991 downregulated cell-cycle-related genes, but upregulated genes implicated in extracellular matrix (ECM) remodeling and pancreatic cancer cell invasion and metastasis. Moreover, PD-0332991 enhanced invasion in TGF-ß-responsive PDAC cell lines that harbor a wild-type SMAD4 gene (COLO-357, PANC-1), but not in TGF-ß-resistant AsPC-1 cells that harbor a mutated SMAD4. PD-0332991 also induced epithelial-mesenchymal transition (EMT) in COLO-357 and PANC-1, but not in AsPC-1 cells. Inhibition of CDK4/6 using shRNA mimicked the effects of PD-0332991 on EMT induction. Furthermore, PD-0332991 increased Smad transcriptional activity in luciferase readout assays and activated TGF-ß signaling. SB-505124, an inhibitor of the type-I TGF-ß receptor (TßRI) kinase, completely blocked EMT induction by PD-0332991. When combined with PD-0332991, SB-505124 inhibited the growth of COLO-357 and PANC-1 cells. Taken together, these data suggest that anti-Cdk4/6 therapy could induce EMT and enhance pancreatic cancer cell invasion by activating Smad-dependent TGF-ß signaling, and that combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in PDAC.
View details for PubMedID 22869556