A $2.5 million grant from the National Cancer Institute’s (NCI) Tumor Microenvironment Network will enable cancer researchers from City of Hope and Children’s Hospital Los Angeles to investigate drug resistance in neuroblastoma, the most common cancer in infants.

Neuroblastoma usually develops in the nervous system of children ages 5 or younger, and physicians diagnose about 650 new cases a year in the U.S.

Hua Yu (Walter Urie Photography)

It can be treated using various methods, including chemotherapy drugs. But drug-resistant cancer cells can develop in the bone marrow, contributing to cancer progression and significantly lowering the rate of patients’ long-term disease-free survival.

Researchers believe that bone marrow provides a unique microenvironment that protects cancer cells from the effects of chemotherapy, and that malignant tumor cells develop specific signaling pathways in the bone marrow that help neuroblastoma cells survive and replicate into drug-resistant offspring.

The NCI grant will establish an Environment-Mediated Drug Resistance (EMDR) center at Children’s Hospital Los Angeles — one of 11 NCI Tumor Microenvironment Network Centers in the U.S. — to help researchers better understand this process and identify possible targets for new therapies.

“Our research demonstrated that the interactions between cancer cells and normal cells in the tumor microenvironment are essential for the growth and spread of neuroblastoma cancers,” said Children’s Hospital Los Angeles’ Yves DeClerck, M.D., professor of pediatrics, biochemistry and molecular biology at the Keck School of Medicine of the University of Southern California.

Richard Jove (Walter Urie Photography)

DeClerck is principal investigator on the program project grant. Hua Yu, Ph.D., Tim Nesvig Lymphoma Research Fellow and co-leader of the Cancer Immunotherapeutics Program in City of Hope’s comprehensive cancer center, is principal investigator for one of the two projects under the grant. Richard Jove, Ph.D., Morgan and Helen Chu Director’s Chair at Beckman Research Institute of City of Hope, is co-principal investigator on that project.

Yu and Jove will focus on a pathway central to their work: Signal transducer and activator of transcription 3, or STAT3.

“We found that one such pathway of interaction, called STAT3, is persistently activated in both tumor cells and in the tumor microenvironment, and we believe that targeting STAT3 signaling in bone marrow stromal cells will inhibit EMDR for neuroblastoma,” Yu said.

The researchers hope to identify new ways to disrupt this pathway so neuroblastoma can be more effectively treated.

Through the second project, which is led by DeClerck, they are collaborating with colleagues Robert Seeger, M.D., and Shahab Asgharzadeh, M.D., from The Saban Research Institute at Children’s Hospital Los Angeles. This project focuses on understanding the role of the interaction between macrophages and other bone marrow-derived cells in the progression of neuroblastoma.

With new data, investigators aim to develop specific, targeted therapies that can be tested in pediatric clinical trials. Inhibiting drug resistance will improve survival not only for children with neuroblastoma, but also for children and adults with other types of cancer, Seeger said.

The investigators at both institutions credit a 2009 seed grant from ThinkCure, the official charity of the Los Angeles Dodgers, in helping researchers collaborate for the initial stages of their research, which led to securing the NCI grant at a time when many funding sources are disappearing.

“This is an excellent example of the benefits of such collaboration between world-class research institutions, and the dedication of ThinkCure supporters who help push forward scientific research,” said City of Hope’s Stephen J. Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation and chair of the Department of Hematology & Hematopoietic Cell Transplantation.