Initiated in 2018 in collaboration with Elena Garralda, Head of VHIO’s Early Clinical Drug Development Group, our IMMUNOMICs project has entered its next phase. This year, we have started to analyze data from our multimodal liquid biopsy approach on longitudinal tumor and plasma circulating cell-free DNA (cfDNA) samples of >300 patients with metastatic, refractory tumors (PanCancer cohort) treated with immunotherapy in phase I clinical trials. This project will generate new insights into the utility of different liquid biopsy assays in characterizing the baseline and early dynamic ctDNA profiles in patients treated with immunotherapy. We will also correlate data with response to therapy and clinical outcome.

In collaboration with other VHIO groups, we previously described RNF43 mutations as predictive biomarkers of response to anti-BRAF/EGFR combinatory therapy in patients with microsatellite stable BRAF-V600E metastatic colorectal cancer (Élez et al. 2022). Our findings have now been validated by real-world data in patients in the USA (Quintanilha et al. 2023). We have participated in an international study to further assess the predictive role of RNF43 mutations. (Moretto et al. 2023). In collaboration with Elena Élez, Head of VHIO’s Colorectal Cancer Group, we continue to work on RNF43 and other factors that we have identified in BRAF-mutated CRC.

In 2023, we have applied our in-house liquid biopsy discovery platform in different clinical settings. In collaboration with Nicholas McGranahan’s lab at the University College London Cancer Institute (UCL, UK), we have developed a new liquid biopsy approach: ACT-Discover – Aneuploidy in Circulating Tumor DNA. This technique is 30% more sensitive than current methods in detecting ctDNA in plasma. We have shown that this platform can characterize the evolutionary history of pancreatic cancer (Hubner et al. 2023). We have also used ACT-Discover to study >150 samples from rare, therapeutically orphan, metastatic neuroendocrine tumors (mNETs).

We have also continued to work on the impact of hypoxia on clinical and genomic features. We have shown that, as with other therapies, hypoxia can shape cancer genomes by promoting specific selective pressures. Additionally, we have reviewed the efficacy of inhibitors of the hypoxia-inducible factor-2 alpha (HIF2α) in tumors harboring mutations in the hypoxia pathway (Toledo et al. 2023).

By pushing the boundaries of scientific discovery and translational research, our group endeavors to make meaningful progress toward a future where every patient receives optimal tailored care.