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Updates from the Largest, Most Ambitious Privately Funded Childhood Cancer Research Grant

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Above, Crazy 8 Grant teams gathered in Philadelphia in April to share progress on their projects, collaborate, and make valuable connections. Teams traveled from all over the world. 

Above, Crazy 8 Grant teams gathered in Philadelphia in April to share progress on their projects, collaborate, and make valuable connections. Teams traveled from all over the world. 

By: Trish Adkins

In 2020, ALSF launched its largest, most ambitious grant category ever — the Crazy 8 Initiative. More than just a funding source, the Crazy 8 brings together multi-disciplinary teams from all around the world to study, collaborate, and ultimately make breakthroughs in the search to cure the deadliest childhood cancers. They meet monthly virtually, travel to one another’s labs, and gather in Philadelphia to problem-solve and share progress and technology. 

Together, these scientists are making a difference, one incredible discovery at a time. 

Several years into their work, the six Crazy 8 teams have made landmark progress in their projects and they aren’t stopping there.

1.    Dr. Heinrich Kovar, a researcher at St. Anna Children’s Cancer Research Institute in Vienna, Austria,  leads the team looking for the cell of origin for a type of pediatric bone cancer, Ewing sarcoma. His team has had exciting success using Zebrafish models to find the types of cells that are susceptible to mutating and becoming cancer. The team is working to establish an atlas that charts human cell development as it relates to bone sarcoma development, to help better understand when normal cells become sarcoma. 

This research is personal for Dr. Kovar, who lost his brother to Ewing sarcoma thirty years ago. “If I would have a brother who would now get sick from this disease, I would still, even 30 years later, have to tell him, look I’ve tried hard, but I have not yet managed to find a cure,” said Dr. Kovar. “I have to do something about it. Hopefully, before I retire, there will be successes that will help patients.” 

2.    MYCN, a driver of pediatric cancers like neuroblastoma and medulloblastoma, has long been considered undruggable, but the Crazy 8 team led by Dr. Yael Mossé from Children’s Hospital of Philadelphia is determined to find a drug that will destroy MYCN. The team developed hybrid molecules that can specifically attach to MYCN and trick the cancer cells' own internal machinery to dissolve MYCN, which will lead to cancer cell death. Team member Martin Eilers, PhD, at the University of Würzburg in Germany is involved in testing potential molecules that could become treatments someday. “It’s a very intense, day-to-day collaboration,” said Eilers.

The Crazy 8 work has also led to another huge investment in MYCN research: a $25 million grant funded by Cancer Research UK, Institut National Du Cancer and KiKa (Children Cancer Free Foundation) through Cancer Grand Challenges, a UK-based initiative, to expand their research. 

3.    Dr. Alejandro Sweet-Cordero leads an international team that is also studying osteosarcoma, but with a different approach. Osteosarcoma is extremely heterogenous — meaning that within a tumor no two cells are alike. This makes treatment difficult, because some cells may respond to therapy and others may not.

By using new technology developed by team member Dr. Ana Obenauf from the Research Institute of Molecular Pathology in Vienna, Austria, the team will identify and isolate osteosarcoma cells with increased resistance to therapy or increased ability to form metastasis, enabling early intervention that will change the fight against osteosarcoma. His team includes researchers from four different institutions with specialties in molecular pathology and oncology.

“The Crazy 8 grants brought people together, motivating all of us to be part of a bigger effort,” said Dr. Sweet-Cordero.

4.    Glue sounds like an unlikely tool for a pediatric oncology researcher. But for Dr. Charles Mullighan from St. Jude Children’s Research Hospital and his Crazy 8 project team, molecular glue offers the promise for effective treatments and cures for children with brain tumors and leukemia. The glue is designed to bind to specific part of a tumor cell and then direct that cell to break the tumor down — effectively killing only cancer cells in the body. The potential is enormous — it could be a treatment that is effective and safer. 

Working together across expertise and disciplines, Dr. Mullighan’s team has designed a collection of several thousands of molecular glues that have the potential to degrade cancer cells. Those glues were screened across a panel of leukemia and medulloblastoma cell lines, resulting in the identification of several potential glues that could stop tumors in experimental models. 

Now, the team is looking to optimize the design of the glues to make them as effective as possible with an aim to establish more lab studies and someday, clinical trials for children. “My motivation to do this work is driven by our patients, many of whom do not have effective treatment options, or experience side effects from toxic, non-targeted treatments,” said Dr. Mullighan. 

A few of these glues have been patented and also have the potential to be commercially licensed, expanding access for other researchers and children waiting for cures. 

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5.    For kids with osteosarcoma, one of the most common types of bone cancer, treatments haven’t changed much in decades. Treatments can be effective, but if the disease spreads, the chance of remission lessens significantly. Dr. Rani George, from Dana-Farber Cancer Institute, leads the Crazy 8 team working to understand gene behavior in osteosarcoma to better understand the steps that happen to change osteosarcoma from a localized bone tumor to a deadly lung tumor. On her multi-disciplinary team is Ruben Dries, PhD, from Boston University, who is utilizing a technology called spatial biology to study the organization and structure of single cells of cancer. 

“I am a young dad. It’s heartbreaking to know the stories of kids who have so much potential, but then don’t get the opportunity,” said Dries. 

Spatial biology allows investigators to take a picture of a small piece of tumor, and then another picture and another, until there are thousands of pictures of the tumor, each zooming in closer and closer first to the single cell level and then to the components of the single cell level, showing the bits of RNA and DNA and proteins that make the individual cell work. Using this technology, Dr. George’s team is working towards not only understanding the dynamics behind lung metastases development, but also identifying potential treatments for kids with osteosarcoma. 

6.    Co-led by Dr. Ross Levine from Memorial Sloan Kettering Cancer Center and Dr. Leonard Zon, from Boston Children’s Hospital, their Crazy 8 team is using cellular barcoding to trace leukemia back to its roots — to find the moment a normal blood cell turns into a cancerous blood cell and then develop targeted, less toxic therapies. While there have been significant advances in the treatment of childhood leukemia, two fundamental problems remain: the treatments that work produce long-term side effects and remission rates are low after relapse. Sadly, not all children are cured. 

“As a clinician, it’s really devastating to give somebody a diagnosis of leukemia,” said Dr. Zon. The team has already made significant discoveries which have led to high-impact publications in Cell and Nature, further expanding the body of knowledge and continuing to push pediatric leukemia research forward. The team has also developed and distributed a novel genetic model of leukemia that enables researchers to use barcoding in lab experiments efficiently and cost-effectively. The model has been distributed to more than 15 investigators and also deposited in the Jackson Labs repository, ensuring even more access to this breakthrough model. 

As the project continues, they’ve turned their focus to recruiting infants with leukemia to the study, sequencing their cancer, and validating those results with lab models. The end goal isn’t just a better understanding of leukemia origins, it’s better treatments and cures. “The patients are the motivation. We need to do better,” said Dr. Zon.

Want to get to know the researchers behind the Crazy 8? Check out their new profile pages on our website.