Project Funding Details

Antibody-drug conjugates (ADCs) represent a paradigm shift in how we treat patients with cancer. The anti-HER2 ADC trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive metastatic gastric cancer (mGC) after failure of trastuzumab thanks to clinically meaningful benefit in terms of response and survival. Other ADCs targeting specific antigens such as Claudin18.2 (CLDN18.2) yielded promising results and phase 3 trials are ongoing. Other targets for different ADCs are also promising. To extend long-term efficacy of ADCs, and according to our preliminary clinical and experimental data, understanding the biological and mechanistic bases of resistance to ADCs can be significantly informative to design novel more effective therapeutic strategies. 1) Tissue-based identification and validation of the mechanisms of resistance to T-DXd and anti-CLDN18.2 ADCs; 2) Detection of actionable resistance mechanisms in tumor-matched liquid biopsies; 3) Generation of matched pre- and post-ADC therapy PDX and primary cell lines to unveil resistance mechanisms and test novel combos to overcome resistance; 4) Amendment of the ongoing TRINITY trial to generate an umbrella study for anti-CLDN18.2 ADCs and other ADCs and using TRINITY as a translational platform. - To elucidate primary and acquired resistance mechanisms to T-DXd and anti-CLDN18.2 ADCs in GC through RNA-seq, IHC profiling, digital spatial profiling, and whole exome sequencing (AMNESIA-ADC observational study); - To investigate actionable resistance mechanisms in tumor-matched extracellular vesicles and CTCs for real-time monitoring and therapeutic decision-making (AMNESIA-ADC observational study); - To functionally evaluate in properly generated suitable experimental GC models identified targets and test novel combination strategies to overcome ADCs-driven resistance; - To validate the previously identified tissue and blood biomarkers using the TRINITY adjuvant randomized of T-DXx versus chemotherapy, and to transform TRINITY into an umbrella proof-of-concept trial testing anti-CLDN18.2 ADCs or other ADCs. The study aims to identify genomic and transcriptional signatures associated with ADC resistance, validate targets in preclinical models, and translate findings into clinically relevant strategies. Amendment of the TRINITY trial into a platform umbrella trial will accelerate the evaluation of novel ADC-based therapies in GC, potentially transforming the treatment landscape. This multidisciplinary approach addresses critical gaps in understanding ADC resistance mechanisms in GC, an issue that has never been addressed before, with implications for precision translational medicine and therapeutic development. By identifying actionable targets and developing novel combination strategies, this project aims to improve patient outcomes and advance the treatment paradigm in GC.