Summer 2006

UCSF Researchers Attack Neuroblastoma

Neuroblastoma is an especially deadly childhood cancer, killing more than half of those afflicted. Under the direction of UCSF pediatric oncologist Kate Matthay, M.D., however, UCSF has become a national leader in treating neuroblastoma and saving kids who might have been lost to the cancer a decade ago.

"We are involved in research and clinical trials that look for neuroblastoma's vulnerabilities along a number of different pathways," Matthay says. "We hope that by hitting neuroblastoma at multiple levels, we can more effectively treat the cancer."

Neuroblastoma is the most common solid tumor in children under 1 year old, but it is still relatively rare: Each year, there are about 650 children in the United States diagnosed with the tumor. The cause of neuroblastoma is unknown, but researchers think it results from developmental processes gone awry. Although a relative rarity, neuroblastoma is the third most common childhood cancer, after leukemia and brain tumor.

Neuroblastomas usually begin in the adrenal gland or in nerve tissue in the neck, chest or pelvis. Although they may be present at birth, they are often not detected until their expansion causes pain or they metastasize to lymph nodes, the central nervous system, bone or bone marrow.

Matthay is a leader in national efforts to combat neuroblastoma, and was the leader of a national team that established what is now the accepted therapy for the disease. In a multiyear, multi-center study, the research group found that the best therapy for neuroblastoma consists of high-dose chemotherapy, irradiation and then transplantation of the patient's own bone marrow after it has been cleansed of tumor cells. These procedures are followed by treatment with 13-cis-retinoic acid, which causes remaining cancerous or precancerous cells to differentiate into less harmful cell types.

The multiphasic treatment of neuroblastoma has been highly effective, lowering the mortality rate from 90 percent 15 years ago to 60 percent now. But that significant increase in survival among children with neuroblastoma should not be considered adequate, Matthay says. And in a quest to further lower mortality, Matthay and her colleagues are engaged in a number of new clinical trials.

One of the most promising trials involves attaching highly radioactive compounds to a substance that preferentially seeks out neuroblastoma. A molecule called metaiodobenzylguanidine (MIBG) is known to concentrate in certain tissues. Clinicians have long been using a radioactive tag attached to MIBG to image the location of neuroblastoma and other tumors. Researchers at UCSF and the University of Michigan were the first to attach a highly radioactive molecule (iodine 131) to MIBG, so that the molecule could be used as a therapy, rather than just in diagnostic imaging.

Matthay and her colleagues continue to conduct trials of MIBG with kids who are nonresponsive to other neuroblastoma therapies. (An article on MIBG treatment at UCSF was recently published in the Journal of Clinical Oncology.*) The therapy is arduous -- kids must be kept in lead-lined rooms for five days while being given high doses of nonradioactive iodine to keep radioactive iodine from collecting in the thyroid.

The UCSF research group is also involved in a number of experimental therapies such as high-dose chemotherapy with stem cell support, new chemotherapeutic agents with stem cell support, and newly discovered molecular switches that can inhibit the growth of neuroblastoma.

New research at UCSF is also seeking to unravel the genetic missteps that cause neuroblastoma and make it so pernicious. William Weiss, M.D., Ph.D., is looking for genes that collaborate with established oncogenes to cause neuroblastoma in a mouse model. For instance, the proto-oncogene MYCN has increased expression in one-third of kids with neuroblastoma. Weiss is using genetic arrays to find other genes that have correlative changes in expression in neuroblastoma, indicating a possible multigene basis for the disease.

"Looking at microarray patterns, you can pretty much predict who will do well and who will do poorly" with existing therapies, Matthay says. "What this tells us is that there are many new potential targets for new therapies, once we understand what these predictive genes are doing."


Matthay KK, Tan JC, Villablanca JG, Yanik GA, Veatch J, Franc B, Twomey E, Horn B, Reynolds CP, Groshen S, Seeger RC, Maris JM: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol. 2006 Jan 20;24(3):500-506.

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