Charles Mullighan, MD, MBBS, of the St. Jude Department of Pathology, will lead a St. Jude team focused on targeting aberrant transcription factors that drive acute leukemias and medulloblastoma, the two leading causes of childhood cancer death.
St. Jude Children’s Research Hospital scientists will play key roles in research funded with grants announced today by Alex’s Lemonade Stand Foundation (ALSF). The grants are part of the foundation’s Crazy 8 Initiative to fund four multidisciplinary projects to remove obstacles to increasing cure rates for childhood cancer.
The projects were awarded grants totaling more than $18.5 million, including $9.9 million for research that St. Jude investigators will either lead or serve as a co-investigator.
Childhood cancer is the leading cause of death by disease in children. The Crazy 8 Initiative hopes to change the trajectory of pediatric oncology by tackling the most obstinate issues in pediatric cancer research, said Liz Scott, Co-Executive Director of Alex’s Lemonade Stand Foundation.
Transcription factors
Charles Mullighan, M.D., MBBS, of the St. Jude Department of Pathology, will lead a St. Jude team focused on targeting aberrant transcription factors that drive acute leukemias and medulloblastoma, the two leading causes of childhood cancer death. The researchers include M. Madan Babu, PhD, FRSC, of Structural Biology; Marcus Fischer, PhD, and Zoran Rankovic, PhD, of Chemical Biology and Therapeutics; Jeffery Klco, MD, PhD, of Pathology; Paul Northcott, PhD, of Developmental Neurobiology; and Martine Roussel, PhD, of Tumor Cell Biology.
Transcription factors are proteins that regulate gene expression. Mutations altering the expression or function of transcription factors are hallmarks of childhood leukemia and medulloblastoma, and are exceedingly difficult to inhibit with traditional drugs. Researchers will use a new technology called molecular glues to degrade transcription factors. Investigators will develop and deploy a library of molecular glues to identify agents that kill acute leukemia or medulloblastoma cells.
“The grant will help us expand a library of molecular glues that will be used to find therapeutic targets in these tumors,” Mullighan said. “This is a new area of drug development that holds great promise. If successful, we expect this approach will be able to be applied to many other tumor types. We are grateful to the Foundation and donors for their critical support.”
Co-investigator Martine Roussel, PhD, of the St. Jude department of Tumor Cell Biology, will play a key role in research to remove obstacles to increasing cure rates for childhood cancer.
Targeted degradation
Roussel is also co-investigator on a Crazy 8 Initiative project led by Yael P. Mossé, MD, of Children’s Hospital of Philadelphia. The team includes researchers from the U.S. and Germany who are focused on creating a drug to target the transcription factor MYCN, which drives medulloblastoma and other aggressive pediatric solid tumors such as neuroblastoma.
Researchers will employ cutting-edge technology called targeted degradation to design a drug that tricks cancer cells to dissolve MYCN, leading to cancer cell death.
“Transcription factors have been thought to be ‘undruggable’ but new technologies now offer novel approaches to target them,” Roussel said. “The success of these projects could not be possible without the close collaboration of structural biologists, chemical biologists and molecular biologists, clinicians and basic scientists – which is possible because of the vision of the ALSF members."
The other projects are led by Leonard Zon, MD, of Boston Children’s Hospital, and Heinrich Kovar, PhD, of St. Anna Children’s Cancer Research Institute, Vienna, Austria. The first will use new genetic fingerprinting technology to study leukemia and other blood cancers during development. The second will examine the developmental origins of malignant bone tumors, such as Ewing sarcoma and ostosarcoma.
About Alex’s Lemonade Stand Foundation
Alex’s Lemonade Stand Foundation (ALSF) emerged from the front yard lemonade stand of 4-year-old Alexandra “Alex” Scott, who was fighting cancer and wanted to raise money to find cures for all children with cancer. Her spirit and determination inspired others to support her cause, and when she passed away at the age of 8, she had raised $1 million. Since then, the Foundation bearing her name has evolved into a national fundraising movement. Today, ALSF is one of the leading funding of pediatric cancer research in the U.S. and Canada raising more than $200 million so far, funding over 1,000 research projects and providing programs to families affected by childhood cancer. For more information, visit https://www.alexslemonade.org/.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food — because all a family should worry about is helping their child live. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.