Novel approaches to target pancreatic cancer.
Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, D-06120 Halle (Saale), Germany. Current cancer drug targets
(Impact Factor: 3.52).
Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.
Available from: ncbi.nlm.nih.gov
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ABSTRACT: In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States. Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo. Moreover, phase III trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit. Several meta-analyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status. Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine. Strikingly, a phase III trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and objective response rates. This regimen also resulted in greater, albeit manageable toxicity.
Available from: William Greenhalf
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ABSTRACT: Late diagnosis of pancreatic ductal adenocarcinoma (pancreatic cancer) and the limited response to current treatments results in an exceptionally poor prognosis. Advances in our understanding of the molecular events underpinning pancreatic cancer development and metastasis offer the hope of tangible benefits for patients. In-depth mutational analyses have shed light on the genetic abnormalities in pancreatic cancer, providing potential treatment targets. New biological studies in patients and in mouse models have advanced our knowledge of the timing of metastasis of pancreatic cancer, highlighting new directions for the way in which patients are treated. Furthermore, our increasing understanding of the molecular events in tumorigenesis is leading to the identification of biomarkers that enable us to predict response to treatment. A major drawback, however, is the general lack of an adequate systematic approach to advancing the use of biomarkers in cancer drug development, highlighted in a Cancer Biomarkers Collaborative consensus report. In this Review, we summarize the latest insights into the biology of pancreatic cancer, and their repercussions for treatment. We provide an overview of current treatments and, finally, we discuss novel therapeutic approaches, including the role of biomarkers in therapy for pancreatic cancer.
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ABSTRACT: Prognosis of pancreatic cancer is extremely poor, suggesting critical needs for additional drugs to improve disease outcome. Here, we examined efficacy and associated mechanism of a novel agent bitter melon juice (BMJ) against pancreatic carcinoma cells both in culture and nude mice.BMJ anticancer efficacy was analyzed in human pancreatic carcinoma BxPC-3, MiaPaCa-2, AsPC-1 and Capan-2 cells by MTT, cell death ELISA and annexin/PI assays. BMJ effect on apoptosis regulators was assessed by immunoblotting. In vivo BMJ efficacy was evaluated against MiaPaCa-2 tumors in nude mice, and xenograft analyzed for biomarkers by immunohistochemistry (IHC). Results showed that BMJ (2-5% v/v) decreases cell viability in all four pancreatic carcinoma cell lines by inducing strong apoptotic death. At molecular level, BMJ caused caspases activation, altered expression of Bcl2 family members, and cytochrome-c release into the cytosol. Additionally, BMJ decreased survivin and XIAP but increased p21, CHOP and phosphorylated MAPKs (ERK1/2 and p38) levels. Importantly, BMJ activated AMP-activated protein kinase (AMPK); a biomarker for cellular energy status, and an AMPK inhibitor (Compound C) reversed BMJ-induced caspase 3 activation suggesting activated-AMPK involvement in BMJ-induced apoptosis. In vivo, oral administration of lyophilized BMJ (5 mg in 100 µl water/day/mouse) for 6 weeks inhibited MiaPaCa-2 tumor xenograft growth by 60% (p<0.01) without noticeable toxicity in nude mice. IHC analyses of MiaPaCa-2 xenografts showed that BMJ also inhibits proliferation, induces apoptosis and activates AMPK in vivo. Overall, BMJ exerts strong anti-cancer efficacy against human pancreatic carcinoma cells, both in vitro and in vivo, suggesting its clinical usefulness.
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