#IDIBELLfellows: Anne-Sophie Chong / Luca Ruvo

Tracing the Molecular Route to Progression in Defective miRNA Biogenesis Benign vs Malignant Thyroid Lesions
Anne-Sophie Chong – Hereditary Cancer

I will be talking about the genomic landscape of benign and malignant thyroid lesions with DICER1 and DGCR8 mutations (technique: WES); the miRNA profiles of benign and malignant thyroid lesions with DICER1 and DGCR8 mutations (technique: Nanostring miRNA assay); the transcriptomics profiles of benign and malignant thyroid lesions with DICER1 and DGCR8 mutations (technique: Nanostring spatial transcriptomic GeoMx WTA); the methylomic profiles of benign and malignant thyroid lesions with DICER1 and DGCR8 mutations (technique: 450K/850K Illumina methylation array); the proteomic profiles of benign and malignant thyroid lesions with DICER1 and DGCR8 mutations (technique: Nanostring spatial transcriptomic DSP IPA)

Systems-Based Characterization of Cancer Drug Metabolites for Precision Medicine
Luca Ruvo – Medicinal Chemistry & Drug Design

Whereas precision medicine aims at personalized therapies, its current reach is limited—with less than 4% of the human proteome currently targeted by existing drugs. Drug metabolites are one rather unexplored route to extending these therapeutic possibilities in the case of precision oncology because they can reach significant in-plasma concentrations.
To address this gap, we compiled a library of 25 metabolites, stemming from FDA- and EMA-approved cancer drugs, with a particular focus on those surpassing 10% in-plasma human concentration and exhibiting differential off-target profiles than the parent drug. The selection was guided by computational approaches, including similarity-based methods, machine and deep learning, to identify candidates with unique therapeutic potential. We have chemically synthesized 18 drug-metabolite pairs, which are currently undergoing biological validation by targeted isolated protein screening and real-time cell imaging using the Incucyte® platform.
Among our key findings, several predicted off-target interactions have been experimentally validated, suggesting significant therapeutic relevance. For instance, the rucaparib metabolite M324 was confirmed to inhibit PLK2, thus contributing to killing prostate cancer cells and showed neuroprotective effects against Parkinson’s disease in in vitro models. This was the first successful case study of the group confirming our hypothesis1.
This presentation will cover new findings on cancer drug metabolites, including the major metabolite of darolutamide, keto-darolutamide, that proved increased potency compared to the parent compound in various prostate cancer cell lines, which aligns with its unique ADORA3 inhibition activity. We have also validated unique off-targets of the sunitinib metabolite SU-12662 and the metabolite of ponatinib.
Accordingly, these findings illustrate the power of comprehensive metabolite profiling that has opened up previously unappreciated therapeutic options and point to ways in which metabolite insights can extend the reach of precision medicine to improve patient outcomes.