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361 WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

Part of: JCTS_2023_ABSTRACT_COLLECTION

Published online by Cambridge University Press:  24 April 2023

Christopher Hubert ,
Kelly Mitchell ,
Samuel Sprowls ,
Sajina Shakya ,
Sonali Arora ,
Daniel J. Silver ,
Christopher M. Goins ,
Lisa Wallace ,
Gustavo Roversi  and
Rachel Schafer
...Show all authors
Christopher Hubert
Affiliation:
Cleveland Clinic
Kelly Mitchell
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Case Comprehensive Cancer Center, Cleveland, OH, USA
Samuel Sprowls
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Sajina Shakya
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Sonali Arora
Affiliation:
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Daniel J. Silver
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Case Comprehensive Cancer Center, Cleveland, OH, USA
Christopher M. Goins
Affiliation:
5Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Lisa Wallace
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Gustavo Roversi
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
Rachel Schafer
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
Kristen Kay
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Tyler E. Miller
Affiliation:
9Department of Pathology, Massachusetts General Hospital, Boston, MA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA
Adam Lauko
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA 7Department of Pathology, Case Western Reserve University, Cleveland, OH, USA Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA
John Bassett
Affiliation:
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Anjali Kashyap
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
J. D’Amato Kass
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Erin E. Mulkearns-Hubert
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
Sadie Johnson
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Joseph Alvarado
Affiliation:
5Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Jeremy N. Rich
Affiliation:
UPMC Hillman Cancer Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Patrick J. Paddison
Affiliation:
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Anoop P. Patel
Affiliation:
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 11Department of Neurological Surgery, University of Washington, Seattle, WA, USA
Shaun R. Stauffer
Affiliation:
5Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Christopher G. Hubert
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Case Comprehensive Cancer Center, Cleveland, OH, USA
Justin D. Lathia
Affiliation:
Departments of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Case Comprehensive Cancer Center, Cleveland, OH, USA Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
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Abstract

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OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

Type
Precision Medicine/Health
Information
Journal of Clinical and Translational Science , Volume 7 , Issue s1 , April 2023 , pp. 107
Creative Commons
Creative Common License - CCCreative Common License - BYCreative Common License - NCCreative Common License - ND
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Copyright
© The Author(s), 2023. The Association for Clinical and Translational Science