Neuroblastoma and rhabdomyosarcomas are childhood cancers in need of improved therapy. For continual growth cancer cells must maintain the ends of chromosomes (called telomeres) which erode if not maintained by telomere maintenance mechanisms (TMM). The most common TMM uses an enzyme in cells called telomerase which is capable of adding DNA to the ends of chromosomes. Some cancers use a non-telomerase mechanism known as alternate lengthening of telomeres (ALT). We have shown that TMM assays can divide neuroblastoma patients into 3 groups with distinctly different survival; patients with ALT+ tumors have the lowest survival.

This project will continue to work with the national Children's...

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Neuroblastoma and rhabdomyosarcomas are childhood cancers in need of improved therapy. For continual growth cancer cells must maintain the ends of chromosomes (called telomeres) which erode if not maintained by telomere maintenance mechanisms (TMM). The most common TMM uses an enzyme in cells called telomerase which is capable of adding DNA to the ends of chromosomes. Some cancers use a non-telomerase mechanism known as alternate lengthening of telomeres (ALT). We have shown that TMM assays can divide neuroblastoma patients into 3 groups with distinctly different survival; patients with ALT+ tumors have the lowest survival.

This project will continue to work with the national Children's Oncology Group to generate data supporting revision of clinical risk stratification (important for determining intensity of therapy) by incorporating TMM into current clinical practice. We will also determine if ALT+ rhabdomyosarcomas have the same poor clinical outcome seen in neuroblastoma. We have shown that the enzyme ATM kinase is a driver of ALT, that causes chemotherapy resistance, and that ALT+ cancers are addicted to ATM. Cancer cells must inactivate p53 in order to survive having high ATM, and many ALT+ cancers have mutant p53, which is a "Achilles heel" for ALT cancers. We will demonstrate that a clinical-stage investigational drug called APR-246, that can reactivate p53, is selectively and highly active in ALT+ neuroblastoma and rhabdomyosarcoma when combined with chemotherapy.

Our proposed studies will enable classifying neuroblastomas based on TMM, thus helping to categorize children with neuroblastoma into risk groups that are used to determine the intensity of therapy. As ALT+ neuroblastomas have low survival, and we anticipate showing the same for ALT+ rhabdomyosarcomas, our demonstration that APR-246 is active against ALT+ cancers will support development of clinical trials testing APR-246 in children with neuroblastoma and rhabdomyosarcoma.

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