Alex's Lemonade Stand Foundation for Childhood Cancer

Lay Summary: Children with metastatic osteosarcoma have an especially poor prognosis. Treatments for osteosarcoma have not changed in decades which highlights the need for new and novel therapies. Little is known about why tumors form metastases in some patients and remain localized in other patients. Cells from the tumor break free and circulate in the bloodstream of patients with osteosarcoma. These cells can be detected as circulating tumor cells (CTCs) and are thought to contribute to metastasis formation.

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. Although many high-risk neuroblastoma patients respond to conventional radiation and chemotherapy, only half survive and many continue to suffer from significant toxicities. Novel therapeutics are desperately needed for this disease, especially target specific therapies that will reduce off-target toxicity. Here, we plan to develop an effective strategy for NB by targeting a novel oncoprotein, EP300, which we identified as a dependency in NB.

Most childhood cancers contain tumor cells that are diverse in nature. In an individual patient's tumor, some cells divide to produce two more dividing tumor cells (symmetric proliferation), resulting in faster tumor growth, while other tumor cells divide and produce one daughter that will divide and one daughter that will not (asymmetric proliferation), resulting in slower tumor growth. We have found that a protein called Eya1 is usually present at high levels in a common brain tumor of children called medulloblastoma, and that Eya1 pushes cells to divide symmetrically.

Collaborator

Michelle Monje, MD/PhD, Stanford University

Project Summary

Children and young adults with inherited mutations in the GATA2 gene have an increased risk of developing blood cancers. These cancers arise from abnormal blood stem cells. The mutant stem cell clone multiplies and expands, acquiring additional mutations that promote leukemia formation. The process is poorly understood, especially in the context of predisposition syndromes to myeloid cancers.