A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy

Bodoky, G.; Timcheva, Constanta; Spigel, David R.; Stella, Phillip J.; Ciuleanu, Tudor-Eliade; Pover, G.; Tebbutt, Niall C.

doi:10.1007/s10637-011-9687-4

Cited by 206 publications

(122 citation statements)

References 33 publications

(32 reference statements)

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“…However, two phase II studies of MEK inhibitors have failed to demonstrate any significant survival advantage for patients with pancreatic cancer (38,39). Furthermore, although MEK inhibition conferred a significant survival advantage in the present orthotopic pancreatic cancer xenograft model, the effect was somewhat limited (median survival of 82 days vs. 101 days for vehicle vs. PD325901, respectively).…”

Section: Discussionmentioning

confidence: 57%

“…One plausible explanation for these limitations may be that oncogenic pathway(s) other than RAS-MEK-ERK may also contribute to progression of early invasive cancers to aggressive malignant cancers, such as locally disseminated or distant metastatic cancers. Indeed, the two previous phase II studies of MEK inhibitors enrolled patients with metastatic or refractory pancreatic cancers (38,39). Furthermore, PANC-1 cells, from which we developed our orthotopic models, were derived from locally disseminated pancreatic cancers (40).…”

Section: Discussionmentioning

confidence: 99%

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Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

et al. 2016

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The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

et al. 2016

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“…AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. Previous studies have shown that the inhibition of MEK1/2 can induce apoptosis by inhibiting ERK-mediated B-cell lymphoma 2 phosphorylation and stabilization (16,17). Currently available MEK1/2 inhibitors have shown moderate single-agent activity in various tumors (18).…”

Section: Discussionmentioning

confidence: 99%

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

Li¹,

Chen²,

Jiang³

et al. 2015

Oncology Letters

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Abstract. With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) in patients with advanced non-small cell lung cancer (NSCLC), acquired resistance has become a major clinical problem. A combination of different signaling pathway inhibitors is a promising strategy to overcome this. In the present study, the mitogen-activated protein kinase kinase 1/2 inhibitor, AZD6244, was used in combination with gefitinib to investigate the efficacy of this treatment in NSCLC cell lines, particularly in gefitinib-resistant cells. The EGFR-TKI-sensitive PC-9 (mutant EGFR/wild-type K-Ras) and EGFR-TKI-resistant A549 (wild-type EGFR/mutant K-Ras) human NSCLC cell lines were treated with AZD6244 alone, gefitinib alone or the combination of the two drugs, and the effects were evaluated using cell proliferation assays, with alterations in signaling pathways analyzed by western blotting. It was found that the growth inhibitory effect of combination treatment with gefitinib and AZD6244 was greater than that of gefitinib alone in the EGFR-TKI-resistant A549 cells. Treatment of A549 cells with gefitinib alone reduced the expression level of the activated form of Akt, and the combination of the two drugs showed stronger inhibition of phosphorylated-Akt and phosphorylated-extracellular signal-regulated kinases. The data showed that the combination of AZD6244 and gefitinib exhibited dose-dependent synergism in gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of AZD6244 to enhance the efficacy of gefitinib in patients with EGFR-TKI-resistant NSCLC.

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“…Selumetinib, a mitogen-activated protein kinase inhibitor, demonstrated similar efficacy as capecitabine in a phase II study (84), and was further tested in combination with erlotinib in the second line setting (85). There were no responders but median OS was about 7.5 months with 51% disease control rate.…”

Section: Kras and Associated Targetsmentioning

confidence: 99%

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Vijayvergia

Cohen

2016

J. Gastrointest. Oncol.

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In 2015, pancreatic cancer was the 10th most commonly diagnosed cancer and the fourth leading cause of cancer death in the United States. The incidence of pancreatic cancer has been slowly rising over the past 10 years. It is estimated that about 53,000 new cases were diagnosed and 42,000 people died from pancreatic cancer in 2015 (1). The small difference between the incidence and death rate of pancreatic cancer reflect the early distant spread and inadequacy of current therapies. The 5-year survival rates for localized and advanced pancreatic cancer are 27% and less than 5%, respectively, lower than all other common cancers (2). The majority of patients are diag nosed at an advanced stage and are not eligible for surgical resection (2). These patients are often symptomatic and quickly deteriorate in the absence of effective therapy and many are unable to receive second and third line therapies for the same reason. Hence, finding the optimal first line regimen may be the key to improving outcomes. Increases in our knowledge of hu man and cancer genomics provide opportunities to un derstand the impact of genetic alterations on pancreatic cancer outcomes and develop predictive biomarkers for newer targeted therapies (3,4). Unfortunately, the amount of tissue obtained by fine needle aspiration of the primary pancreatic tumor is usually insufficient to perform adequate molecular analysis. As we move into the era of personalized medicine, obtaining core biopsy samples from metastatic sites, like liver, may help eliminate this problem. What do we know about pancreatic cancer genetically?Pancreatic cancer is a disease of significant genetic variability. Recent whole exome and genome sequencing have identified a wide range of genetic alterations including mutations and copy number variations that characterize pancreatic cancer (4,5). Some of these are recurrent and are clearly needed to identify subsets of patients likely to benefit from these therapies. Advances in our understanding of the molecular drivers of pancreatic cancer offer the hope of personalized therapy that may benefit our patients. In this review, we summarize the current knowledge about the biology of pancreatic cancer and its implication for treatment. We discuss recent advances in targeted therapies and the role of potential biomarkers in predicting response to established therapies. We also review novel therapeutic approaches that may be able to fulfill the promise of personalized therapy for pancreatic cancer.

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A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy

Cited by 206 publications

References 33 publications

Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

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