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Curing The Incurable:

The Crazy 8 Initiative Projects

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

8 Projects
28 Institutions
$35 Million in grant funding
One Goal: Cures for all children with cancer

Alex’s Lemonade Stand Foundation (ALSF) 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. To accelerate childhood cancer research, ALSF has developed the Crazy 8 Initiative, with $35 million committed so far to solve the most intractable problems in childhood cancers. The goal is to fund game-changing collaborative projects that connect researchers across the globe. We have already awarded grants to eights projects that are taking on the deadliest of 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

Founding Partner

Northwestern Mutual

Newborn Screening for Early Childhood Cancer Predisposition Syndromes

Funded 2025

Collaborators:

  • Team Leader: Sharon Plon, MD/PhD, FACMG, Baylor College of Medicine
  • Donald W. (Will) Parsons, MD/PhD, Baylor College of Medicine
  • Lisa Diller, MD, Dana-Farber Cancer Institute
  • Philip Lupo, PhD, Emory University
  • Richard Parad, MD, Brigham and Women's Hospital
  • Stacey Pereira, PhD, Baylor College of Medicine
  • Sarah Scollon, MS, CGC, Baylor College of Medicine

The Goal: To make newborn screening for cancer risk genes a reality.  

Every newborn in the United States gets a “heel-stick” blood test to check for certain rare diseases, but cancer risk isn’t included.

Led by co-principal investigators Dr. Sharon Plon and Dr. Lisa Diller, this Crazy 8 team will study the implementation and promise of a genetic test using this newborn blood samples, to screen for several cancer predisposition syndromes. The team has identified nine genes that could signal a high risk for early-onset cancers, including the RB1 gene which can cause retinoblastoma, a type of eye cancer. If identified early, babies with a faulty RB1 gene could receive eye exams and treatment before the cancer progresses preserving their eyesight and their lives. 

The team’s goal is to develop an affordable, AI-supported genetic test to screen newborn blood samples. They will also create educational materials for parents and test them in Boston and Houston to see how parents and pediatricians respond to this new screening. If successful, the research will help push for nationwide adoption of newborn cancer risk screening.

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Towards LNP Vaccine Immune-Interception for Childhood Cancer Predisposition Syndromes

Funded 2025

Collaborators:

  • Team Leader: Uri Tabori, MD, The Hospital for Sick Children
  • David Malkin, MD, FRCP(C), The Hospital for Sick Children
  • Drew Weissman, MD/PhD, University of Pennsylvania
  • Gad Getz, PhD, Broad Institute
  • Derin Keskin, PhD, Dana-Farber Cancer Institute
  • Steve Lipkin, MD/PhD, Weill Cornell Medical College
  • Trevor Pugh, PhD, University Health Network
  • Cynthia Hawkins, MD/PhD, The Hospital for Sick Children

The Goal: To develop a cancer vaccine for predisposition syndromes. 

The two most aggressive childhood cancer predisposition syndromes — Li-Fraumeni syndrome and replication repair deficiency — are associated with an almost 100% lifetime risk of cancer that can occur in almost any organ of the body. Cancers driven by these syndromes are often resistant to standard treatments like chemotherapy and radiation. While many of these cancers could be detected early, clinicians and researchers still struggle to find effective, curative treatments for kids with cancers driven by predisposition.

Led by Dr. Uri Tabori and Dr. David Malkin, this project team will study the potential for a cancer vaccine that could provide an early-stage intervention in kids with certain cancer predisposition syndromes. The vaccine would use mRNA technology and harness the immune system to destroy early cancer cells before they spread within the body. The success of this project could lead to the development of additional cancer vaccines. 

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Understanding and Inhibiting Mechanisms of Metastatic Spread in Osteosarcoma

Funded 2022

Alejandro Sweet-Cordero, MD

Collaborators:

  • Team Leader: Alejandro Sweet-Cordero, MD, University of California San Francisco
  • Poul Sorensen, MD/PhD, BC Cancer, Provincial Health Services Authority
  • Anna Obenauf, PhD, Research Institute of Molecular Pathology, Vienna BioCenter in Vienna, Austria
  • Sam Aparicio, PhD, BC Cancer, Provincial Health Services Authority
  • Katie Janeway MD, Dana-Farber Cancer Institute

The Goal: To understand how osteosarcoma cells survive in the body once they have spread from the initial tumor. 

Like most cancer tumors, osteosarcoma tumors are not homogenous; but are instead heterogenous and made up of a variety of different cells. No two osteosarcoma tumors are the same and within one tumor, it is likely each cell is different from the others.

This presents a challenge in treatment; making osteosarcoma resistant to therapy and prone to metastasis. Dr. Alejandro Sweet-Cordero and his team theorize that just a few cells within an osteosarcoma tumor have these special resistance and spread capabilities. To cure osteosarcoma, understanding these cells is critical.

Using a new technology called a “molecular time machine,” will enable the team to identify the cells that cause metastases and isolate these from the primary tumor to enable early intervention. The results will be used to study the molecular heterogeneity of osteosarcoma that will ultimately inform new drug development and clinical trials that are critically needed for children battling osteosarcoma.

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Targeting the Biological Underpinnings of Pulmonary Metastasis in Osteosarcoma

Funded 2022

Rani George, MD PhD

The Collaborators:

  • Team Leader: Rani George, MD PhD, Dana-Farber Cancer Institute
  • Ruben Dries, PhD, Computational Biomedicine, Boston University
  • Nathanael Gray, PhD, Chemical Biology, Stanford University
  • Berkley Gryder, PhD, Genetics and Genome Sciences, Case Western Reserve University
  • Ryan Roberts, MD/PhD, Nationwide Children’s, The Ohio State University
  • Peter Scacheri, PhD, Genetics and Genome Sciences, Case Western Reserve University
  • Cheng-Zhong Zhang, PhD, Dept. of Data Sciences, Dana-Farber Cancer Institute

The Goal: To create genetic wiring diagrams that be used to re-wire cancer genes, making them more susceptible to targeted treatments.

Treatment for osteosarcoma is difficult and has not improved in almost four decades. When osteosarcoma metastasizes, it most often moves to the lungs, creating a deadly situation for children facing the disease.

Therapies to prevent or treat metastatic osteosarcoma could be a game-changer for kids facing the disease.

The challenge, according to Dr. Rani George, is three-fold: the common genetic changes in osteosarcoma are known but not understood; the steps that drive the development of metastatic lesions are not known; and lastly, the few identified drivers of metastatic osteosarcoma are not druggable, with available therapies.

The team will work to understand gene behavior in osteosarcoma and build reference genomes specific to each tumor. Using these references and a new technique pioneered by members of the Crazy 8 team, a map of connections will be made to determine how each genetic switch becomes wired to drive the development of osteosarcoma tumors. Then the team will use the same technology to rewire those cancer gene connections making them more susceptible to targeted treatments, with the hope of ultimately leading to cancer cell death and a cure.

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Drugging MYCN

Funded 2020

Yael Mossé

Collaborators :

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

Funded 2020

Heinrich Kovar, PhD

Collaborators:

  • 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

Funded 2020

Leonard Zon, MD

The Collaborators:

  • Team Leaders: Leonard Zon, MD, Boston Children’s Hospital and 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

Funded 2020

Charles Mullighan, MBBS (Hons)

Collaborators:

  • 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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