CANCER MOLECULAR BIOLOGY

Principal Investigators

Staff

Research topic

Our group aims to identify and validate novel targets and therapeutic strategies in gastric cancer.

Background

Gastric cancer (GC) is the world’s third leading cause of cancer mortality. In spite of significant therapeutic advances, the overall clinical outcome for patients with advanced GC is poor, with median survival of less than 1 year. In spite of whole genome molecular profiling which shed light on the genetic landscape of this tumor, at present few targeted therapies are licenced to treat GC.

Achievements

We generated a platform of around 300 patient-derived xenografts (PDXs) that recapitulate the heterogeneity of this disease; at present, this is the widest gastric cancer PDX platform in an academic institution in the world. We also set up a collection of gastric cancer primary cell lines and organoids. Taking advantage of this platform we have achieved several goals: i) we have identified the MET oncogene as a target in gastric cancer patients in which this gene is amplified; ii) we reported the clinical activity of EGFR monoclonal antibodies (mAb) in patients bearing a high level (>8 copies) of EGFR gene amplification, and showed that in patient-derived xenografts, the combination of an EGFR mAb and a tyrosine kinase inhibitor is significantly more effective and long lasting than mAb monotherapy; iii) In preclinical randomized trials we have shown that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade (association of Trastuzumab/Pertuzumab or of Trastuzumab and Lapatinib) is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results thus suggest that a selected subpopulation of HER2-“hyper”-amplifed GC patients could strongly benefit from this strategy; iv) we have demonstrated that PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended; v) we have generated mouse models of gastric cancer bearing microsatellite instability to reveal the evolution of this subtype of tumor; vi) we have identified and characterized gastric cancer “persister cells”, responsible for tumor relapse.

Conclusions and perspectives

Since gastric cancer is a very common disease worldwide, the identification of novel ‘druggable’ and validated targets would be extremely important from a clinical point of view, even if their prevalence is very low. Our results lay the foundations for a focused design of clinical trials aimed at the effective treatment of a fraction of GC patients with drugs targeting molecular alterations identified as oncogenic drivers.  

Publications

At this link, you can find all the scientific publications of the Principal Investigator.