New Approaches to Neuroblastoma Therapy

Forty-five percent of children with neuroblastoma have high-risk disease, which nearly always has spread throughout the body when first diagnosed. From 1991 to 1996, the Children's Cancer Group (CCG, now part of the Children's Oncology Group or COG) conducted a five-year study of more than 500 children that showed a three-fold improvement in disease-free survival for high-risk patients and established a new treatment standard.

The therapy that resulted in this improved survival consisted of high-dose chemotherapy, irradiation, transplantation of the patient's own bone marrow cleansed of tumor cells, and treatment with a vitamin A - like drug, 13-cis-retinoic acid.

These therapies, tested and proved in the CCG trial, were based upon laboratory and clinical studies conducted by New Approaches to Neuroblastoma Therapy (NANT) consortium investigators. Even with this improvement, only approximately 40% of children with high-risk neuroblastoma survive for five years after diagnosis without tumor recurrence.

To further improve treatment of high-risk neuroblastoma, we are focusing on developing new therapies that are effective against neuroblastoma cells resistant to chemotherapy, irradiation, and retinoic acid.

To accelerate finding new and better treatments for neuroblastoma, we submitted a multi-investigator Program Project Grant (PPG) proposal entitled "Biology and Therapy of High-Risk Neuroblastoma" to the National Cancer Institute (NCI) with Dr. Robert C. Seeger at Childrens Hospital Los Angeles as the Principal Investigator. The proposal received an outstanding score from reviewers, and the NCI awarded funding for 5 years (2000-2005) to support laboratory and clinical trials research. In 2005, following the initial award, we again received an outstanding score for our work in Neuroblastoma

research and was awarded funding for an additional 5 years (2006-2010) (see NEWS section for details).

The award of the PPG allowed us to form the NANT Consortium, which is comprised of a wide geographic group of institutions throughout North America, committed to working together on clinical trials of novel approaches to treating high-risk neuroblastoma. The NANT consortium is led by pediatric oncologist Dr. Katherine K. Matthay (UCSF) and the NANT Operations Center operates under the direction of Dr. Judith Villablanca (CHLA), NANT Medical Director, and Dr. Araz Marachelian (CHLA), NANT Assistant Medical Director. Through their leadership, and in conjunction with the efforts of Dr. Seeger and other PPG Project Leaders, the NANT Consortium has grown from 8 participating sites to 15 sites within the last 10 years.

The NANT Consortium continues to discover new targeted therapies for high-risk neuroblastoma through collaborative laboratory efforts performed at various NANT institutions. With the vision in mind, we are working towards developing new therapies that are effective against neuroblastoma cells resistant to chemotherapy, irradiation, and retinoic acid. These new findings result in the conduct of early clinical trials (phase I and II) that determine the potential for such novel approaches to improve the outcome of patients with high-risk neuroblastoma.

These therapies may also be important for other cancers of children and adults. Promising new therapies pioneered by the NANT consortium are proposed to the Children's Oncology Group for testing in large-scale trials that are necessary for proving the value of any new therapy in treating neuroblastoma.