Citations

Abstract Background: Esophageal adenocarcinoma (EAC) is a lethal cancer, and the incidence is increasing. Our group demonstrated that over-expression of the epidermal growth factor receptor (EGFR) correlated with reduced survival in EAC. Panitumumab (P) is a fully human IgG2 monoclonal antibody against human EGFR. Cetuximab combined with irinotecan (I) has shown activity for second-line treatment of advanced colorectal cancer (CRC). P alone is active in EGFR expressing CRC as well. Our group has empiric evidence for the activity of cetuximab + I as third-line treatment for advanced EAC. As such, a phase II study was designed to evaluate P + I as second-line therapy for advanced EAC. Trial Design: The primary endpoint is overall response (OR) as measured by RECIST (cross-sectional imaging every 2 cycles). Secondary endpoints include overall survival, safety/toxicity and correlative studies. Patients with confirmed EAC with history of one prior treatment are treated with P 9 mg/m2 on day 1 and I 125 mg/m2 on days 1 and 8 of each 21 day cycle to a maximum of 6 cycles. Inclusion criteria include confirmed EAC, measurable disease, no prior I or P, PS <2 and normal organ function. A Simon two-stage design is used with power of 80% and a type I error of 0.05. 18 patients will be tested in the first stage and will terminate the trial if 2 or fewer respond. A total of 43 patients will be studied. Blood and tissue are obtained to analyse the role of FCα-R receptors as well EGFR pathway components and kras mutations. Enrollment: The 1st patient was enrolled in May 2009. Through August 2011, 7 patients received treatment. Preliminary results: Of the 7 patients treated, all are white males, median age 62. 2 patients completed 6 cycles. 1 patient received 3 cycles, 3 received 2 cycles and 1 patient completed 1 cycle. 3 patients are still alive. However, only 1 patient is still in the trial. 4 patients received dose reductions due to grade 3 or 4 side effects, including GI disturbances (5), fatigue(1), skin rash(1), electrolyte imbalances(2) and hematologic abnormalities (5). Reasons for discontinuation included progressive disease (PD, 5 patients) and patient refusal (2). The longest survival was 338 days–1 of the 2 patients who completed 6 cycles. The second patient who completed 6 cycles is alive at 307 days. 1 patient completed 3 cycles and survived 213 days after PD. 1 patient survived 174 days followed PD after 2 cycles. 2 patients completed 2 cycles and are still alive, surviving 151 (pt refusal) and 103 days respectively. The shortest survival was 85 days who completed only 1 cycle. Conclusion: Preliminary data from this Phase II trial suggests that patients with advanced EAC might benefit from P+I regimen as 2nd line therapy. 3 additional centers will open the trial. Accrual is ongoing, and correlative studies will follow. This project used the University of Pittsburgh Cancer Institute and was supported in part by award P30CA047904 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3708. doi:1538-7445.AM2012-3708

Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β1. Increased TGF-β1, in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.