Gastric cancer is the world third leading cause of cancer mortality. In spite of the significant therapeutic advances, the overall clinical outcome for patients with advanced gastric cancer is poor, with 5-20% 5-year survival. The only targeted therapy approved so far are trastuzumab, and Ramucirumab which have given unsatisfactory results. Around 50% of gastric tumors bear genetic alterations affecting tyrosine kinase pathways (mainly EGFR, HER3, FGFR2 and MET pathways, besides HER2) but their clinical validation as tumor drivers is missing. The need for new therapeutic options and the possible presence of ‘druggable’ targets prompted us to investigate potential targeted therapies for this disease.
Our project aims at identifying and validating targeted therapeutic strategies in gastric cancer, through the generation of a platform of gastric tumor patient-derived xenografts (PDXs), animal models in which tumor surgical specimens are directly transferred into mice. Upon engraftment, the tumor is split and re-implanted in a cohort of mice, allowing the simultaneous testing of different drugs on the same tumor. Thanks to the establishment of a network of 15 Italian centers for samples collection, we generated around 80 gastric PDXs and successfully derived cell lines and organoids from engrafted tumors. Among the tumors collected so far, we found HER2, EGFR, FGFR2, MET and KRAS amplifications. This gastric PDX platform will be exploited for: 1) Validation of candidate oncogenes as relevant targets and identification of efficient therapeutic strategies 2) Identification of novel molecular targets; 3) identification of genetic predictors of response/resistance.
In the PDX platform we identified one tumor bearing a high level of MET gene amplification (26 gene copies). We thus performed a preclinical study on a cohort of patient-derived xenografts generated from the MET-amplified gastroesophageal tumor. Despite the high amplification level, MET inhibitors induced only a partial response, while the combined anti-MET/EGFR treatment led to complete tumor regression. Most important, the combo treatment also prevented resistance onset. This data represent the proof of concept that a combined anti-MET/EGFR therapy can be more effective than anti-MET treatment alone in MET-amplified gastroesophageal tumors, in the absence of EGFR genetic lesions.
Citation Format: Silvia Menegon, Maria Apicella, Cristina Migliore, Tania Capeloa, Marilisa Cargnelutti, Maurizio Degiuli, Anna Sapino, Paola Cassoni, Michele De Simone, Paolo M. Comoglio, Silvia Marsoni, Simona Corso, Silvia Giordano. Gastric cancer in the age of targeted agents: identification and validation of novel therapeutic strategies through the generation of a patient-derived xenografts platform. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 622.