Northwestern Events Calendar


SQE Lecture Series: “Precision Medicine in Solid Tumors” with Ernesto Guccione, PhD

When: Tuesday, December 6, 2022
10:00 AM - 11:00 AM CT

Where: Simpson Querrey Biomedical Research Center, Simpson Querrey Auditorium, 303 E. Superior Street, Chicago, IL 60611 map it

Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students

Contact: Beverly A Kirk   (312) 503-5217

Group: Simpson Querrey Institute for Epigenetics Lecture Series

Category: Lectures & Meetings


The Simpson Querrey Institute for Epigenetics presents:

Ernesto Guccione, PhD

Professor, Oncological and Pharmacological Sciences
Icahn School of Medicine at Mount Sinai, NYC

"Precision Medicine in Solid Tumors"

Our lab has a long-standing interest in understanding basic mechanisms of transcriptional and post-transcriptional regulation in order to identify therapeutic opportunities in oncology, with a particular focus on protein methyltransferases.

I will describe our general strategy and give one specific example of how we identified a small molecule able to reactivate EZH2 by promoting its nuclear translocation. In particular we focused on b-catenin (CTNNB1)-mutated HCCs, which represent 30% of the disease, and that are characterized by the inactivation of EZH2 via its sequestration in the cytoplasm. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffo­lds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic 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 key anti-targets by WNTinib relative to other FDA-approved multi-KIs is necessary to avoid compensatory feedback signaling - providing a durable and selective transcriptional repression of mutant b-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. 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. 

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