Department of Oncology, University of Turin, ITALY

Gastric cancer in the age of targeted agents: identification and validation of novel

therapeutic strategies

Host: G. Del Sal

Gastric cancer (GC) was the world’s third leading cause of cancer mortality in 2018. In spite of significant therapeutic advances, the overall clinical outcome for patients with advanced GC is poor, with median survival 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.

The postulate of precision oncology is to exploit treatments targeting the molecular characteristics of a specific tumour. At present, only around 5-10% of cancer patients can benefit from targeted therapies. Delivering the right drug to the right cancer patient requires a detailed understanding of how genomic alterations are coupled to drug response. Thus, to improve the value of a target therapy it is mandatory to: (i) molecularly annotate tumors, (ii) properly select patients that could benefit from that therapy, (iii) validate the real biological relevance of the identified targets in a specific tumor type and (iv) identify molecular alterations that could affect the responsiveness to treatment. Targeted therapies licenced to treat GC are restricted to Trastuzumab (and its derivative Trastuzumab deruxtecan), Ramucirumab and the ICIs nivolumab and pembrolizumab. Most of the clinical trials performed during the last years in GC patients to identify new targets and to test new drugs failed. The reason for this failure, in many cases, can be ascribed to the lack of proper patient selection and/or to the inadequacy of robust preclinical data. These considerations imply that, before going to clinic, we need a better knowledge of the genomic environment associated to each oncogenic driver and necessitate predictive biomarkers to better select patients.

At present, the best strategy to fulfil all the above-mentioned prerequisites is the use of a large series of human cancer specimens directly transplanted into mice (Patient-derived xenografts, PDXs), in order to generate a study population that could be concomitantly profiled for biomarker assessment and randomized for prospective treatment with targeted agents. This approach combines the flexibility of preclinical analysis with the informative value of population-based studies. We aimed at identifying and validating novel targeted therapeutic strategies in GC, taking advantage of a multi-level platform of GC models, comprising more than 250 PDXs, primary cell lines and organoids. Exploiting this proprietary and unique resource, we: (1) provided a scientific basis for the rational selection of GC patients for anti-HER2 therapies through the identification of positive and negative predictors of response; (2) investigated mechanisms of acquired resistance to Trastuzumab; (3) re- evaluated EGFR as a therapeutic target in a subgroup of GC patients; (4) fighted drug-resistance through targeting persister cancer cells; (5) investigated genetic dependencies guiding response to PARP1 inhibitors; (6) dissected intratumor mismatch repair (MMR) heterogeneity.

As a whole, the results of our work have provided a scientific basis for future clinical applications and for guiding the rational design of molecularly oriented clinical trials for gastric cancer.


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