The Childhood Cancer Blog

Childhood Cancer Research In Progress: The Crazy 8 Initiative

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By: Trish Adkins

Earlier in 2021, Alex’s Lemonade Stand Foundation (ALSF) 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.

In September, the four project teams gathered at the Crazy 8 Summit, a two-day virtual event in which the scientists shared, collaborated and challenged each other. In just a few months of work, these four interdisciplinary teams have already made significant progress, setting the stage for discoveries that are already changing the way the research community understands pediatric cancer. 

“The incredible progress each team has made, across nations and across scientific disciplines, in the year of a global pandemic is nothing short of extraordinary. Discoveries are already being made that are changing the way we think about where these cancers come from and how we can devise new treatments that will lead to cures. This is high-risk-high reward research at its absolute best. It was also so inspiring to see how many new and young investigators are active in all four teams. The future of pediatric cancer research is bright and ALSF deserves lot of credit for this,” said Beth Lawlor, MD, PhD from Seattle Children’s Hospital and moderator of the Crazy 8 Summit meeting in September.

Childhood cancer is the leading cause of death by disease in children under the age of 19 in the United States. Children who survive childhood cancer are twice as likely to suffer from chronic health conditions as a result of treatment versus children without a history of cancer. Despite these facts, childhood cancer research is consistently underfunded.

 These four Crazy 8 Initiative projects are aiming to not just level the playing field — but to give children what they need: cures and safer treatments:

1. Personal Motivations

One grant recipient, Dr. Heinrich Kovar from St. Anna Children’s Cancer Research Institute in Vienna, Austria, has a personal motivation for his study of bone sarcomas. When Dr. Kovar was starting out in research and studying Ewing sarcoma, his younger brother was diagnosed with the disease. Doctors tried to give his brother hope by reminding him that researchers were working to find safer treatments and cures. 

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 pediatric 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.

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 safer treatments and cures for the children most at risk of dying from bone sarcoma.

2. Collaborations for Cures 

A key component of the Crazy 8 Initiative is its approach in bringing cross-disciplinary scientists to work collaboratively in order to accelerate the pace of discovery. For example, connecting neurologists and biologists with pediatric oncologists to work hand-in-hand in growing scientific discovery, while aiming to provide detailed roadmaps for hard-to-treat childhood cancers. 

Dr. Yael Mosse from Children’s Hospital of Philadelphia will be working to find a drug match for MYCN, a currently “undruggable” driver of pediatric cancers including some types of high-risk neuroblastoma, 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. 

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.

3. Cutting Edge Tools for Cures 

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.

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, the degradation of the mutant transcription factor causes the cancer cell to die. 

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. 

4. Safer Treatments and Cures for All Children 
 
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, from Boston Children’s Hospital.

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

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,” said Dr. Zon.

Donate to The Crazy 8 Initiative

Building on its history as a leading funder in pediatric cancer research, ALSF established the Crazy 8 Initiative to harness collaborative spirit across global institutions to go after the most pressing pediatric cancer research roadblocks. ALSF focused the program to address the eight most challenging aspects of pediatric oncology: embryonal brain cancers; high-grade gliomas; fusion-positive sarcomas; fusion-negative sarcomas; leukemias; neuroblastoma; big data; and catalyzing clinical trials. 

While work on the first awarded Crazy 8 Initiative grants is underway, a second Crazy 8 Initiative request for applications will be issued later this year, bringing the total commitment to $25 million. To learn more visit the Crazy 8 page