Silvia Giordano, MD, PhD
Altered regulation of tyrosine kinase receptors is frequent in solid tumors and it is often associated with the acquisition of an aggressive phenotype. Thus, therapies targeting these receptors have been proposed as molecular approaches to treat human cancers. The main problem with these therapies is the onset of resistance, which leads to treatment failure. It is therefore important to understand the mechanisms of resistance to molecular targeted therapies, in an effort to optimize the outcome of the treatments.
The goal of delivering the right drug to the right cancer patient (precision medicine) requires a detailed understanding of how genomic alterations are linked to drug response. Hence, the clinical efficacy of target therapy depends on: i) the validation of the true biological relevance of putative targets in the context of a specific tumor type; ii) the context-specific identification of the active drug(s) and of additional molecular alterations affecting the responsiveness to treatment.
Our group aims to study the molecular mechanisms that allow tumor cells to become insensitive to molecular targeted therapies. We focused on the study of gastric cancer that is the world’s third leading cause of cancer mortality We generated a platform of more than 70 patient-derived xenografts (PDXs) that recapitulate the heterogeneity of this disease. We aim to genetically dissect the gastric tumor landscape in order to investigate mechanisms involved in sensitivity/resistance to targeted therapies against receptor tyrosine kinases. We performed the genomic analysis of the PDX tumors and we identified several alterations of tyrosine kinases such as HER2, EGFR, MET, FGFR2 and of KRAS. We exploited a MET-amplified PDX model to optimize anti-MET therapeutic strategies in gastric cancer. We report that despite the high MET amplification level (26 copies), tumors showed only partial and transient sensitivity to anti-MET therapy while dual MET/EGFR inhibition led to complete regression and prevented resistance onset. The finding that combined anti-MET/EGFR therapy even in the absence of EGFR genetic alterations induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients. We also performed pre-clinical trials on several HER2-amplified gastric xenopatiens to identify the best anti-HER2 therapeutic approach and investigate the mechanisms of resistance to treatment.
Conclusions and perspectives:
By exploiting the gastric cancer PDX platform we have generated, we aim to unravel genetic vulnerabilities in this pathology and to identify the best therapeutic strategies to target them. 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. As a whole, the results of this project will provide a scientific basis for future clinical applications and guide the rational design of molecularly-oriented clinical trials for gastric cancer.