Preclinical Research in Treatment of Pancreatic Cancer
Abstract
Pancreatic adenocarcinoma is an aggressive type of malignancy and remains a treatment-refractory cancer. Because of the few treatment options, understanding of the molecular mechanisms is necessary, for new drugs be developed against molecular targets. Two of the novel, promising regimens against molecular targets, NVP-BEZ235 and MSK-777, were examined in three preclinical studies performed in human pancreatic cell lines and mouse models and presented in the 2013 ASCO Annual Meeting. Two of the studies evaluated the role of NVP-BEZ235, an oral phosphatidylinositol-3-kinase (PI3K) inhibitor, in pancreatic cancer treatment, alone and in combination with nab-paclitaxel (Abstract #e15007) or gemcitabine (Abstract #e15070). The third study presents the effectiveness of the novel cell division cycle 7 (Cdc7) kinase inhibitor, MSK-777 (Abstract #e15059). All studies demonstrated promising results and further investigation is ongoing.
Image: PI3K-AKT-mTOR signalling pathway.
Downloads
References
Schneider G, Schmid RM. Genetic alterations in pancreatic carcinoma. Mol Cancer. 2003; 2: 15.
Altwegg R, Ychou M, Guillaumon V, Thezenas S, Senesse P, Flori N, et al. Second-line therapy for gemcitabine-pretreated advanced or metastatic pancreatic cancer. World J Gastroenterol. 2012; 18: 1357-64.
Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403-2413.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gall¬inger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960-1966.
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817-1825.
Von Hoff DD, Ervin TJ, Arena FP, Chiorean EG, Infante JR, Moore MJ, et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol 30: 2012 (suppl 34; abstr LBA148).
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801-1806.
Agbunag C, Bar-Sagi D. Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells. Cancer Res 2004; 64: 5659–5663.
Cao P, Maira SM, García-Echeverría C, Hedley DW. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer. 2009; 100: 1267-76.
Venkannagari S, Fiskus W, Peth K, Atadja P, Hidalgo M, Maitra A, Bhalla KN. Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer. Oncotarget. 2012; 3: 1416-27.
Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68: 8022-30.
Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851–1863
Sawa M, Masai H. Drug design with Cdc7 kinase: a potential novel cancer therapy target. Drug Des Devel Ther. 2009; 2: 255-64.
Davis J, Zhang R, Frattini MG. Synergy between conventional chemotherapy and Cdc7 inhibition as a novel approach for cancer therapy. Molecular Cancer Therapeutics 2011: 10 (suppl 1; abstr75).
Jackson PK. Stopping replication, at the beginning. Nat Chem Biol. 2008; 4: 331-2.
Loaiza-Bonilla A, Kittaneh M, Guardiola Amado VD, Kovacs K, Merchan JR. Preclinical study of cytotoxicity and predictive markers of response to dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 with or without paclitaxel or nab-paclitaxel as a new therapeutic strategy in pancreatic cancer cell lines. J Clin Oncol 31, 2013 (suppl; abstr #e15007).
Maute L, Wicht J, Zoernig M, Niederhagen M, Bergmann L. Effect of the combination of the dual mTOR/PI3K inhibitor NVP-BEZ235 with gemcitabine on growth inhibition in pancreatic cancer cells in vitro and in vivo. J Clin Oncol 31, 2013 (suppl; abstr #e15070).
Frattini MG, Regales L, Santos R, Carrillo D. Cdc7 inhibition as a novel approach for pancreas cancer therapy. J Clin Oncol 31, 2013 (suppl; abstr #e15059).
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002; 52: 23-47.
Awasthi N, Yen PL, Schwarz MA, Schwarz RE. The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. J Cell Biochem. 2012; 113: 784-91.
Montagnoli A, Moll J, Colotta F. Targeting cell division cycle 7 kinase: a new approach for cancer therapy. Clin Cancer Res. 2010; 16: 4503-8.
Copyright (c) 2014 Evangelia Skoura, Konstantinos N Syrigos, Muhammad Wasif Saif
This work is licensed under a Creative Commons Attribution 4.0 International License.
As a member of Publisher International Linking Association, PILA, iMedPub Group’s JOP follows the Creative Commons Attribution License and Scholars Open Access publishing policies. Journal of the Pancreas is the Council Contributor Member of Council of Science Editors (CSE) and following the CSE slogan Education, Ethics, and Evidence for Editors.