Emerging drugs in the treatment of pancreatic cancer

Mahalingam, Devalingam; Kelly, Kevin R.; Swords, Ronan; Carew, Jennifer S.; Nawrocki, Steffan T.; Giles, Francis J.

doi:10.1517/14728210902972502

Cited by 14 publications

(14 citation statements)

References 152 publications

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“…Inhibition of MEK/ERK pathway by AZD6244 increases DPEP1 level in Panc1 cells. AZD6244 is a potent and selective MEK inhibitor that has been selected for clinical development because of its potency and favorable pharmacokinetic profile [26]. Further delineation of pathways that regulate DPEP1 expression in pancreatic cancer may provide insights into the genes and pathways associated with DPEP1 and facilitate the development of more effective therapeutic strategies for PDAC.…”

Section: Discussionmentioning

confidence: 99%

DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

et al. 2012

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T: N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = −0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24–0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27–0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.

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Section: Discussionmentioning

confidence: 99%

DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

et al. 2012

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“…Treatment failure due to local recurrence and hepatic metastases can occur within 1 to 2 years after surgery (3). Other treatment options including gemcitabine and erlotinib offer only a small survival advantage (4) and the overall 5 year survival rate for patients with pancreatic cancer across all stages remains 0.4 to 4 %, making pancreatic cancer one of the top causes of death from cancer in the Western world (5). …”

Section: Introductionmentioning

confidence: 99%

Hypoxia Triggers Hedgehog-Mediated Tumor–Stromal Interactions in Pancreatic Cancer

et al. 2013

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Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of HIF-1α by tumor hypoxia strongly activates secretion of the sonic hedgehog ligand SHH by cancer cells which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and HH signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. our findings strengthen the rationale for testing HIF inhibitors may therefore represent a novel therapeutic option for pancreatic cancer.

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“…Current treatment regimens for patients with pancreatic cancer that are not suitable for surgical resection are still not effective, due to low response rates and a 5-6 months median survival [1,2]. Over the past decades, multiple randomized trials have sought to improve the outcome of patients with advanced pancreatic cancer including treatment with platinum agents, taxanes and topoisomerase inhibitors [3]. Moreover, there has been considerable interest in combining gemcitabine (2',2'-difluoro 2'-deoxycytidine), the first-line treatment option, with ionizing radiation and a variety of other agents that exert various mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells

2010

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BackgroundPancreatic cancer is a complex genetic disorder that is characterized by rapid progression, invasiveness, resistance to treatment and high molecular heterogeneity. Various agents have been used in clinical trials showing only modest improvements with respect to gemcitabine-based chemotherapy, which continues to be the standard first-line treatment for this disease. However, owing to the overwhelming molecular alterations that have been reported in pancreatic cancer, there is increasing focus on targeting molecular pathways and networks, rather than individual genes or gene-products with a combination of novel chemotherapeutic agents.MethodsCells were transfected with small interfering RNAs (siRNAs) targeting the individual CK2 subunits. The CK2 protein expression levels were determined and the effect of its down-regulation on chemosensitization of pancreatic cancer cells was investigated.ResultsThe present study examined the impact on cell death following depletion of the individual protein kinase CK2 catalytic subunits alone or in combination with gemcitabine and the molecular mechanisms by which this effect is achieved. Depletion of the CK2α or -α' subunits in combination with gemcitabine resulted in marked apoptotic and necrotic cell death in PANC-1 cells. We show that the mechanism of cell death is associated with deregulation of distinct survival signaling pathways. Cellular depletion of CK2α leads to phosphorylation and activation of MKK4/JNK while down-regulation of CK2α' exerts major effects on the PI3K/AKT pathway.ConclusionsResults reported here show that the two catalytic subunits of CK2 contribute differently to enhance gemcitabine-induced cell death, the reduced level of CK2α' being the most effective and that simultaneous reduction in the expression of CK2 and other survival factors might be an effective therapeutic strategy for enhancing the sensitivity of human pancreatic cancer towards chemotherapeutic agents.

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Emerging drugs in the treatment of pancreatic cancer

Abstract: Molecular pathogenesis of pancreatic cancer involves several pathways and defined genetic mutations. Targeting these complex molecular pathways with a combination of novel biological and chemotherapeutic agents could potentially improve patient outcome.

Cited by 14 publications

References 152 publications

DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

Hypoxia Triggers Hedgehog-Mediated Tumor–Stromal Interactions in Pancreatic Cancer

Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells

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