apricoxib and Pancreatic-Neoplasms

COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/erlotinib in preclinical models of pancreatic cancer.. Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined.. COX-2 inhibition reduced the IC(50) of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression.. Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Synergism; Epithelial-Mesenchymal Transition; ErbB Receptors; Erlotinib Hydrochloride; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neovascularization, Pathologic; Pancreatic Neoplasms; Pyrroles; Quinazolines; Sulfonamides

The high mortality rate of pancreatic cancer places this uncommon malignancy quite high as a cause of cancer related deaths. Compared to other solid tumors, there is a lag in the development of new effective drugs and the actual clinical benefit remains poor over the last decade or so. The lack of therapeutic options necessitates the invention of the important molecules playing role in pancreatic carcinogenesis and the development of specific targeted therapies. Treatment advances have to be proven first in the bench before applying them at the bedside, thus why translational research is so needed. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, preclinical evidence was presented regarding the efficacy of C4 compound against focal adhesion kinase (FAK) (Abstract #214), the role of the cyclooxygenase-2 (COX-2) inhibitor apricoxib in enhancing the efficacy of gemcitabine and erlotinib (Abstract #227) and the role of curcumin and ABT-888 (a poly-ADP ribose polymerase (PARP) inhibitor) as potent radiosensitizers (Abstracts #222 and #203). Interestingly, the invention of a novel monoclonal antibody (ensituximab) against the mucin epitope NPC-1C in pancreatic and colon cancer cell lines exhibited notable antibody-dependent cellular cytotoxicity (Abstract #235). Finally, enhanced selective targeting of pancreatic tumors was achieved by combining antibody-drug conjugates (ADC) with radioimmunotherapy (Abstract #206).

Topics: Animals; Antibodies, Monoclonal; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2 Inhibitors; Epitopes; Focal Adhesion Protein-Tyrosine Kinases; Humans; Mucins; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Pyrroles; Radiation-Sensitizing Agents; Sulfonamides; Translational Research, Biomedical; Xenograft Model Antitumor Assays