Emerging pathways and future targets for the molecular therapy of pancreatic cancer.

Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.
Expert Opinion on Therapeutic Targets (Impact Factor: 4.9). 08/2011; 15(10):1183-96. DOI: 10.1517/14728222.2011.607438
Source: PubMed

ABSTRACT INTRODUCTION: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. AREAS COVERED: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. EXPERT OPINION: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-κB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK, which controls canonical NF-κB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that KRAS+ upregulates GSK-3α leading to its interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3α is required for promoting critical non-canonical NF-κB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with the loss of expression of oncogenic genes such as c-myc and TERT. These data identify GSK-3α as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-κB signaling pathways.
    Cancer Discovery 04/2013; · 15.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related death in the world. The etiology of pancreatic cancer is heterogeneous with a wide range of alterations that have already been reported at the level of the genome, transcriptome, and proteome. The past decade has witnessed a large number of experimental studies using high-throughput technology platforms to identify genes whose expression at the transcript or protein levels is altered in pancreatic cancer. Based on expression studies, a number of molecules have also been proposed as potential biomarkers for diagnosis and prognosis of this deadly cancer. Currently, there are no repositories which provide an integrative view of multiple Omics data sets from published research on pancreatic cancer. Here, we describe the development of a web-based resource, Pancreatic Cancer Database (, as a unified platform for pancreatic cancer research. PCD contains manually curated information pertaining to quantitative alterations in miRNA, mRNA, and proteins obtained from small-scale as well as high-throughput studies of pancreatic cancer tissues and cell lines. We believe that PCD will serve as an integrative platform for scientific community involved in pancreatic cancer research.
    Cancer biology & therapy 05/2014; 15(8). · 3.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Pancreatic cancer is one of the most lethal cancer types known with no successful clinical therapy available and a 5-year survival rate of < 5%. Demographic calculations predict pancreatic cancer to be the second-leading cause of cancer-related deaths by 2030. Hence, the identification of novel drug targets and the subsequent development of novel therapeutic strategies are of utmost importance. Areas covered: In this review, the authors describe the role of the transcription factor pancreatic and duodenal homeobox 1 (Pdx1) in pancreatic organ development and pancreatic cancer. Published data suggest that Pdx1 possesses oncogenic traits fostering cell proliferation, inhibition of apoptosis and increased cell invasion. Resulting from these findings, the authors discuss the potential use of Pdx1 as an anticancer drug target. Expert opinion: In summary, Pdx1 should be considered as an interesting potential molecular target in future therapeutic approaches. Although no specific therapies exploiting Pdx1 are available at the moment and more preclinical data has to be accumulated, several putative applications in the areas of cancer diagnostics and therapy are conceivable.
    Expert opinion on therapeutic targets. 07/2014;