Abstract 10: Evaluation of metronomic chemotherapy regimens in preclinical orthotopically implanted colon cancer models, and in patient-derived xenografts

Abstract

Recent advances for the treatment of late stage colon cancer include a metronomic capecitabine plus bevacizumab maintenance regimen as reported for the CAIRO3 phase 3 clinical trial (Simkens et al, Lancet: 2015; 385: 1843-52) . We previously reported a phase 2 trial evaluating metronomic cyclophosphamide (CTX) plus UFT (a 5-fluorouracil prodrug) and celecoxib in gastrointestinal cancer patients (Allegrini et al, Angiogenesis: 2012; 15, 275-286). We also reported the preclinical evaluation of metronomic oral topotecan in mouse models of colon cancer (Hackl et al, Gut: 2013; 62, 259-71). Here we report our studies using orthotopic (intracecal) implantation of human HT29/luc/hCG colon cancer cells in SCID mice. Disease progression was noninvasively assessed using the transfected human chorionic gonadotropin (hCG), whose levels in the mouse urine correlate with tumor burden - and this was coupled with luciferase (luc) bioimaging of the mice. These implanted tumor models were used together with patient derived xenografts (PDX), to evaluate metronomic regimens of etoposide (80mg/kg/day, p.o.), gemcitabine (given i.p.; at either 120mg/kg every 3 days, or at the much lower 1mg/kg/day), or CTX given as a monotherapy (20mg/kg/day given via the drinking water) or combined with neutralizing antibodies against VEGF or EGFR. Our results indicate; 1) effective anti-tumor activity of daily etoposide, and of 2) daily gemcitabine (as well as when the gemcitabine was given every 3 days), and that 3) orthotopic HT29/luc/hCG colon tumors are weakly responsive to CTX or CTX plus targeted agents compared to the same tumors implanted subcutaneously or intraperitoneally. The effectiveness of metronomic etoposide was confirmed in a colon PDX model in NSG mice (n=5 mice/group; p<.05) - obtained from Jackson labs. Notably ovarian cancer and breast cancer PDX models did not respond to etoposide therapy (n=5/group), indicating the response may be tumor specific. Collectively, these results highlight the importance of advanced disease models to confirm sometime overly optimistic experimental therapeutic results from subcutaneously or intraperitoneally implanted tumor models. They also demonstrate the promising anti-tumor activity of metronomic etoposide and gemcitabine regimens for colon cancer, and they lead us to advocate the concerted use of both implanted xenografts and PDX for the testing of new therapeutic strategies for the treatment of colon cancer. Citation Format: Jose Lopez, Paloma Valenzuela, Valerie Gallegos, Karla Parra, Valeria Rolih, Diana Gonzalez Garcia, Joel Martinez, Urban Emmenegger, Guido Bocci, Robert S. Kerbel, Giulio Francia. Evaluation of metronomic chemotherapy regimens in preclinical orthotopically implanted colon cancer models, and in patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 10.