Childhood Cancer

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Small Molecule Degraders for Targeting Transcription Factor Drivers of Childhood Cancers

St. Jude Children’s Research Hospital
Charles G. Mullighan, MBBS(Hons), MSc, MD, FRACP, FRCPA
Grant Type: 
Crazy 8 Awards
Year Awarded: 
Type of Childhood Cancer: 
Brain Tumors, Medulloblastoma, Leukemia
Project Description: 

Project Team
M. Madan Babu, PhD FRSC, St. Jude Children's Research Hospital
Marcus Fischer, PhD, St. Jude Children's Research Hospital
Jeffery M. Klco, MD/PhD, St. Jude Children's Research Hospital
Paul A. Northcott, PhD, St. Jude Children's Research Hospital
Zoran Rankovic, PhD, St. Jude Children's Research Hospital
Martine F. Roussel, PhD, St. Jude Children's Research Hospital

Acute leukemia and medulloblastoma are leading causes of cancer-related death in children. Most current treatments are non-specific, not directed against cancer-causing pathways, are incompletely effective, and are associated with substantial side effects. The majority of leukemias and medulloblastomas develop due to genetic changes in genes that encode transcription factors (TFs) that drive abnormal cell development and proliferation. Mutant TFs have been difficult to inhibit with conventional drug development approaches. Recently, a new concept, "molecular glues" has emerged, in which small molecules may be developed that bind to widely expressed proteins called ubiquitin ligases. These ligases are responsible for binding to and degrading cell proteins. Molecular glues can be developed that bind to ubiquitin ligases and direct their activity specifically to an abnormal protein of interest, such as a mutated transcription factor in cancer. The original molecular glue is thalidomide, which causes the ubiquitin ligase Cereblon to degrade proteins such as Ikaros and is effective in myeloma. Many of the mutated and abnormally expressed transcription factors in acute leukemia and medulloblastoma harbor regions known or predicted to interact with Cereblon and are thus targets for molecular glue-based degradation. Our research team has demonstrated expertise in developing small molecule-based mediators of targeted protein degradation in childhood cancer and has developed a unique library of Cereblon-interacting molecular glues that may be exploited to degrade key transcription factor targets in childhood cancer. The molecular glue approach is a disruptive technology that provides an exciting new opportunity to directly target previously undruggable targets in childhood cancer.

2023 Update

Molecular glues provide an new opportunity to directly degrade abnormal proteins that drive the development of high-risk childhood tumors, such as acute leukemia and medulloblastoma. In this project, we have assembled a team of scientists with complementary expertise to develop MG to tackle these diseases: Drs Mullighan and Klco (leukemia), Northcott and Roussel (medulloblastoma), Rankovic (chemistry), Fischer (structural biology) and Babu (systems biology). We have developed a collection of several thousand rationally-designed MGs that interact with Cereblon, a protein that mediates degradation of protein targets in the cell. These have been used to screen a panel of leukemia and medulloblastoma cell lines. Several are selectively active in subsets of lines, and are being pursued to identify the targets of action, and to further optimize for testing in tumor models. We have determined the structural basis of interaction of selected MGs with CRBN. This provides insights into the mechanism by which MGs alter the protein surface of Cereblon and determines interaction with new targets. In addition, we have developed reagents to enable direct testing of the MG library against key transcription factor targets of interest. We are also performing systems biology analyses of our in-house database of several thousand cases of acute leukemia and medulloblastoma and public databases to prioritize additional transcription factor targets that are likely drivers of disease and potentially amenable to MGmediated degradation. We have generated several MG that have been shown to have potent antileukemic activity in vivo and for which provisional patents have been filed.

Project Goal
This project will develop molecular glue small molecule degraders of transcription factor vulnerabilities in childhood cancer. The project will exploit a new library of molecular glues developed at St. Jude to identify and target transcription factor vulnerabilities in leukemia and medulloblastoma. Our research team comprises leaders in genetics and experimental modeling of childhood acute leukemia, medulloblastoma, targeted protein degradation, ubiquitin biology and computational analysis.  Aim 1 will screen the molecular glue library in cell line, xenograft (human tumor in mouse) and engineered mouse models of key acute leukemia and medulloblastoma subtypes to identify agents that cause cell death. Downstream protein characterization studies will be performed to identify the “Achilles heel” vulnerabilities mediating cell death. Aim 2 will use the library to identify glues that mediate interaction and degradation of key mutated/deregulated transcription factor targets in acute leukemia (e.g. mutated Ikaros, MECOM and ZNF384) and medulloblastoma (e.g. GFI1, GFI1B, PRDM6). This aim will incorporate computational analysis of our large pediatric cancer datasets to identify additional transcription factor vulnerabilities and ubiquitin ligase mediators for molecular glue development and testing. Aim 3 will expand the molecular glue library to over 5000 compounds. Active molecular glues will be developed to optimize drug-like properties, with the goal of showing activity in preclinical (mouse) leukemia/medulloblastoma models, and translating to clinical trials. This proposal has great potential to target hitherto undruggable targets in pediatric cancer.

Co-funded by: 
The Swifty Foundation
Layla’s Legacy Foundation