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Curing The Incurable:

The Crazy 8 Initiative Projects

Crazy 8 Group of Researchers

Crazy 8 Group of Researchers

Curing The Incurable:

The Crazy 8 Initiative Projects

Curing the Incurable: The Crazy 8 projects that are trying to find cures for all children

4 Projects
15 Institutions
$18.5 Million in grant funding
One Goal: Cures for all children with cancer

Alex’s Lemonade Stand Foundation founder Alex Scott believed that if we all work together, we would find cures for childhood cancer. 

As researchers continue to move closer to cures for all children, there are still types of childhood cancer that continue to be incurable. In the spirit of Alex’s legacy, Alex’s Lemonade Stand Foundation has committed $18.5 million to four game-changing, collaborative projects at 15 institutions in the United States and Europe. Funded through the Crazy 8 Initiative, these projects are taking on the most deadly childhood cancers with one singular focus: curing the incurable. Below, meet the Crazy 8 researchers who are leading the way to cures.

“This is a high-risk project. You cannot just neglect these problems—and say okay, we’ve tried for such a long time and we can’t do anything about it. That’s not helping the kids. You have to take the risk.” – Dr. Heinrich Kovar, Crazy 8 Awardee

Drugging MYCN

Yael Mossé

Collaborators :

  • Team Leader: Yael Mossé, MD, Children's Hospital of Philadelphia
  • John Maris, MD, and Ophir Shalem, PhD, Children’s Hospital of Philadelphia
  • William Weiss, MD, PhD; Natalia Jura, PhD; Kliment Verba, PhD, University of California San Francisco
  • Martine F. Roussel, PhD, St. Jude Children’s Research Hospital
  • Martin Eilers, PhD, and Elmar Wolf, PhD, University of Würzburg
  • Seychelle Vos, PhD, MIT
  • Gwenn Hansen, PhD, Nurix Therapeutics

The Goal: Targeted drugs for MYCN, a currently “undruggable” driver of pediatric cancer.

In her clinic, Yael Mossé, sees firsthand the toll that neuroblastoma and the treatments used to treat the disease take on the lives of children. In her lab, Dr. Mossé sees the hope that targeted treatment could bring to children. Many of the children in Dr. Mossé’s care have high-risk neuroblastoma driven by a protein called MYCN. MYCN can also drive other pediatric cancers, including some types of medulloblastoma, rhabdoid tumors and retinoblastoma. Having too much of this protein fuels tumor growth, but in its absence, the cancer won’t grow.

So far, no one has figured out how to drug MYCN because it comes from a family of transcription factors that are essential for normal cell processes. “To date, virtually all of the strategies targeting MYCN haven’t really led to any responses in kids because all have been indirect,” said Dr. Mossé.

Dr. Mossé brought together a team of complementary researchers, each with unique expertise to attack MYCN with innovative new technologies. The team will work to develop new drugs with the support of Nurix Therapeutics, a pharmaceutical company whose mission is to drug undruggable proteins, and will be overseen by a Scientific Advisory Board led by Chi Dang, MD, PhD, of the Ludwig Institute of Cancer Research, and composed of the top MYCN and drug development experts.

“We are now poised to deliver on the Holy Grail of pediatric cancer and that is to develop a drug that will allow for MYCN to degrade in a cancer cell and directly impact patients with MYCN-driven childhood cancers,” said Dr. Mossé.

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Tracking Ewing Sarcoma Origin by Developmental and Trans-Species Genomics

Yael Mossé


  • Team Leader: Heinrich Kovar, PhD, St. Anna Children’s Cancer Research Institute, Vienna, Austria
  • Florian Halbritter, PhD, and Martin Distel, PhD, St. Anna Children’s Cancer Research Institute
  • Igor Adameyko, PhD, and Matthias Farlik, PhD, Medical University of Vienna
  • Cornelia Kasper, PhD, University of Natural Resources and Life Sciences, Vienna, Austria

The Goal: Discover the origins of bone sarcomas and develop tumor models that can be used to test targeted drugs to treat this deadly pediatric cancer.

Dr. Heinrich Kovar began his research career studying Ewing sarcoma. He was led to this field of study by his love of science. Then, in a twist of fate, his younger brother was diagnosed with Ewing sarcoma. Doctors told his brother that researchers were working to find better treatments. But, for Dr. Kovar’s brother, those treatments did not come in time. His brother died, and Dr. Kovar was left with a mission: find cures for Ewing sarcoma.

While there have been some improvements in disease understanding and treatments over the past 30 years, little is known about why frontline treatment works well for some children and other children are left facing a poor prognosis.

“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.

Dr. Kovar and his team are driven to change that. With the Crazy 8 Award, his team will study the origins of Ewing sarcoma — developing an understanding of the moment a cell becomes Ewing sarcoma. Then, they will use this knowledge to develop pre-clinical models that can be used to test therapeutics, eventually leading to safe treatments and cures for the children most at risk of dying from Ewing sarcoma.

“I have to do something about it,” said Dr. Kovar. “Before I retire, I hope to have success that will help patients with Ewing sarcoma.”

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Barcoding Pediatric Leukemia for Therapeutic Purposes

Yael Mossé

The Collaborators:

  • Team Leader: Leonard Zon, MD, Boston Children’s Hospital
  • Ross Levine, MD, Memorial Sloan Kettering Cancer Center
  • Scott A. Armstrong, MD/PhD, and Serine Avagyan, MD/PhD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center
  • Fernando Camargo, PhD, and Vijay G. Sankaran, MD/PhD, Boston Children's Hospital
  • Juerg Schwaller, MD, Uniersity Children's Hospital and Department of Biomedicine, University of Basel, Switzerland
  • Jay Shendure, MD/PhD, University of Washington
  • Peter Campbell, MD/PhD, Wellcome Sanger Institute

The Goal: To barcode pediatric leukemia, trace its development and match targeted therapies to children with uncured cancers.

While there have been significant advances in the treatment of childhood leukemia, two fundamental problems remain: the treatments that work are toxic and sadly, not all children are cured. “As a clinician, it’s really devastating to give somebody a diagnosis of leukemia. There are lots of people in the room who are scared of that particular word,” said Dr. Leonard Zon.

Dr. Zon’s Crazy 8 team co-led by Dr. Ross Levine aims to turn the tide by tracing leukemia back to its roots — to its cell of origin and find targeted therapies that can cure children who are currently incurable.

The team hypothesizes that pediatric leukemias develop from the blood stem cells that arise during fetal life. These stem cells exist beyond these very early stages of development and into early adolescence. Using an understanding of normal blood cells, the team will use cellular barcoding techniques to map and track these leukemia cells.

Cellular barcodes work like the barcodes you see at the grocery store; but instead of being a barcode that is created with lines and tells you the item and the price, these barcodes are created by DNA. The cellular barcodes will allow the team to follow blood cells as they develop, to see where in the developmental process leukemia arises. Importantly, this barcoding technology can eventually be extended to learn more about the development of all childhood cancers, making an even larger impact.

“The patients are the motivation. We need to do better. Going into the laboratory is the opportunity to develop a set of findings and translate those findings,” said Dr. Zon.

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Small Molecule Degraders for Targeting Transcription Factor Drivers of Childhood Cancers

Yael Mossé


  • Team Leader: Charles Mullighan, MBBS (Hons), MSc, MD, St. Jude Children’s Research Hospital
  • Zoran Rankovic, PhD; M.Madan Babu, PhD, FRSC; Marcus Fischer, PhD; Jeffery M. Klco, MD/PhD; Paul A. Northcott, PhD; Martine F. Roussel, PhD, St Jude Children’s Research Hospital

The Goal: To expand and utilize a library of molecular glues to treat several of the deadliest forms of childhood cancer.

Glue sounds like an unlikely tool for a pediatric oncology researcher. But for Dr. Charles Mullighan and his Crazy 8 project team, molecular glue offers the promise for effective treatments and cures for children with brain tumors and leukemia.

“Small molecule protein degraders, often referred to as molecular glues, offer the tantalizing prospect of targeting currently undruggable oncoproteins.” said Dr. Rankovic, the chemistry lead of this multidisciplinary team.

Molecular glues are a recent concept in drug discovery, and their application to childhood cancer hasn’t yet been fully explored. The molecular glue is designed to bind to a specific transcription factor that drives tumor growth, and then directs the cancer cell to break it down. Since transcription factors are master regulators of cell growth and commonly mutated in leukemia and brain tumors, by degrading mutant transcription factors, the cancer cell dies.

The result: a targeted therapeutic that can attack cancer with potentially fewer side effects to the patient. For medulloblastoma and leukemias, which combined make up the deadliest types of childhood cancers, molecular glues hold the promise for more effective and safer treatments and cures.

“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. His team will work to expand a library of these glues that can be used to treat specific targets that are known to drive childhood cancer. To make this library happen, a diverse team of experts is needed.

“Collaboration is absolutely essential,” said Dr. Mullighan. “We need expertise in chemistry, structural biology, genetics, tumor biology and therapy. And our team has all these elements.”

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