Katherine K. Matthay, M.D.
	Targeted Therapy for high-risk neuroblastoma
	Email: matthayk@peds.ucsf.edu Website: Division
Selected Publications Complete Publications

Neuroblastoma is a highly malignant tumor of children that arises in the peripheral sympathetic nervous system, and spreads widely to bones and bone marrow. The survival of children with metastatic neuroblastoma is less than 40%, despite intensive chemotherapy, radiation and bone marrow transplant. Our research is focused on the development or more specific targeted agents that will be cancer specific either through targeting surface receptors, or genetic and metabolic pathways specific to the neuroblastoma cell.

We have developed a very extensive program exploiting the noradrenalin transporter (NAT) expressed on the surface of 90% of neuroblastomas, as a tumor-specific target. Metaiodobenzylguanidine (MIBG) is a chemical similar in structure to noradrenalin and specifically taken up via this NAT by attaching a radioactive iodine-131 molecule. We have shown that 131I-MIBG can achieve responses of 40% in children with relapsed neuroblastoma, and that the main side effect of myelosuppression can be abrogated with hematopoietic stem cell support. In an effort to impact children prior to disease relapse and development of resistance, we have also shown the efficacy and safety of combining the MIBG therapy with myeloablative chemotherapy, and are now beginning a national cooperative study in newly diagnosed patients. We are also exploring in pre-clinical and clinical studies the ability to enhance efficacy with radiosensitizers, such as irinotecan, and with other drugs targeting proliferative genetic pathways related to the key role of MYCN gene amplification and overexpression in this tumor.

Other targeted therapies are being tested through the phase I 13 institution consortium, New approaches to Neuroblastoma Therapy that I direct, which is funded by the NCI. This consortium is testing multiple different targeted therapies, focused particularly on the role of immune and NK regulatory cells on neuroblastoma, ceramide pathways, bone metastasis and invasion and angiogensis, Trk inhibitors, among others.

Selected Publications

Messina JA, Cheng S-C, Franc BL, Charron M, Shulkin B, To B, Maris JM, Yanik G, Hawkins RA, Matthay KK. Evaluation of semi-quantitative scoring system for Metaiodobenzylguanidine (mIBG) scans in patients with relapsed neuroblastoma. Pediatr Blood & Cancer 2006; 47:863-4; ePub ahead of print.

Osenga KL, Hank JA, Albertini MR, Gan J, Sternberg AG, Seeger RC, Matthay KK, Reynolds CP, Twist C, Krailo M, Adamson PC, Eickhoff J, Reisfeld RA, Gillies SD,Sondel PM. A Phase I Clinical Trial of the Hu14.18-IL2 (EMD 273063) as a Treatment for Children with Refractory or Recurrent Neuroblastoma and Melanoma: A Study of the Children's Oncology Group. Clinical Cancer Res 2006; 12:1750-59.

Chesler L, Goldenberg D, Schlieve C, Kim G, McMillan A, Kenney A, Matthay KK, Rowitch D, Weiss WA. Inhibition of PI3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Research 2006; 66:8139-8146.

Asgharzadeh S, Pique-Regi R, Wang H, Yang Y, Shimada H, Matthay K, Buckley J, Sposto R, Ortega A, Seeger RC. Gene expression profiling of metastatic neuroblastomas without MYCN amplification identifies molecular signatures associated with distinct outcomes. JNCI 2006;98:1193-1203.

Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, Veatch J, Goldsby R, Brophy P, Kersun LS, Hawkins RA, Maris JM. Effect of Disease Sites, Age, and Prior therapy on Response to 131I-metaiodobenzylguanidine Therapy in Relapsed and Refractory Neuroblastoma: A Phase II Study. J Clin Oncol, 2007; 25:1054-1060.

Meyer GE, Chesler L, Liu D, Gable K, Maddux BA, Youngren JF, Goldfine ID, Weiss WA, Matthay KK, Rosenthal SM. Nordihydroguaiaretic acid inhibits insulin-like growth factor signaling, growth, and survival in human neuroblastoma cells. In press J Cell Biochem, 2007.

Information last updated April 2007