School of Biomedical Sciences cordially invites you to join the following seminar:

Speaker: Professor Ernesto Guccione, Professor of Oncological Sciences, Director of Mount Sinai Center for OncoGenomics and Innovative Therapeutics, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine
Talk Title: Precision medicine in solid tumors: new tools and (some) new ideas

Date: 13 November 2024 (Wednesday)
Time: 4:00 pm – 5:00 pm
Venue: Lecture Theatre 2, G/F, William M.W. Mong Block, 21 Sassoon Road
Host: Professor Stephanie Ma

Biography

Born and raised in Italy, I spent my first year abroad in New York as a high-school exchange student, where I got bitten by the Wunderlust bug. I got my Masters in Medical Biotechnology at the oldest University in the world, in Bologna, followed by a PhD studying the oncogenic properties of HPV, at ICGEB in Trieste. In 2004 I got a chance to work with a fantastic mentor (Bruno Amati) who pushed me to study basic mechanisms of transcription and epigenetic regulation in cancer. In 2008, I moved to Singapore to start my lab and since 2019 I am a Professor at Mount Sinai Icahn School of Medicine. I have a long-standing interest in understanding basic mechanisms of transcriptional and post-transcriptional regulation in order to identify therapeutic opportunities in oncology. In particular I focused my research on dissecting the role of oncogenic Protein Methyltransferases (PMTs), such as Protein Arginine Methyltransferases (i.e. PRMT6 and PRMT5), SET domain containing proteins (i.e. EZH2, G9a) and PRDMs (i.e. PRDM9, PRDM10 and PRDM15). To date, I have published >100 peer-reviewed papers and I am currently the PI on grants from NIH-NCI (RO1s), NIH-NICHD (RO1s) and ALSF (among others) and collaborate with Pharma companies to advance knowledge on small molecule inhibitors of PMTs. I am also an inventor of several patent applications and the scientific co-founder of two biotech startup companies (and looking forward to starting more!).

Abstract

Hepatocellular carcinoma (HCC) and Colorectal cancer (CRC) are leading causes of cancer-related deaths worldwide. A large portion of both CRC and HCC are driven by mutations in the WNT pathway (i.e. APC or β-catenin (CTNNB1) and there is currently no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we first screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multi-omic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/MAPK signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38a kinases by WNTinib allows nuclear translocation of the EZH2 transcriptional repressor to suppress WNT-targets. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index (Rialdi et al. Nature Cancer 2023). Our latest research on utilizing a similar multi-omic pipeline to discover the therapeutic relevance of oncofetal reprogramming in CRC (Mzoughi et al. Nature Genetics, in press) will also be shared at the talk.

ALL ARE WELCOME
Should you have any enquiries, please feel free to contact Miss Crystal Chan at 3917 6830.