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First Clinical Trial of DFMO for Neuroblastoma Completed; Drug Targets a Cancer Stem Cell Pathway and Shows Early Promise

Researchers at Spectrum Health Helen DeVos Children's Hospital in Grand Rapids, Michigan have completed the first clinical trial of a new treatment for children suffering from neuroblastoma. In a clinical trial led by Giselle Sholler, M.D., Pediatric Oncologist at Helen DeVos Children's Hospital and the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC), DFMO (difluoromethylornithine), an investigational agent, showed minimal side effects with long-term survival of three patients. This is the first clinical study of an oral dosing form of DFMO in any pediatric population. DFMO has previously been shown to inhibit ornithine decarboxylase (ODC), an independent indicator of poor prognosis in neuroblastoma. "This DFMO trial is an important advancement in neuroblastoma research," explained Dr. Sholler. "We believe that by using DFMO to target an important cancer stem cell pathway to 'turn cells off,' we may prevent children from relapsing. Cancer cells have pathways that drive the cancer to grow and DFMO targets a specific pathway to turn these cells off." Dr. Sholler recently published her laboratory studies describing how this drug works in neuroblastoma in preventing tumor formation in lab models and also published the full results of the phase one trial. The work was published online on May 27, 2015 in the open-access journal PLOS ONE. The article is titled “A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma.” Will Lacey, a patient in the phase 1 clinical trial, was free from side effects and needed no additional treatment following the trial. This is a new way of life for a 10-year old whose neuroblastoma had kept him in and out of hospitals and on various treatments for most of his life. Patrick Lacey, Will's father explained, "His quality-of-life has been amazing! He was never in the hospital and he was indistinguishable from his peers. Will has had an incredible two and a half years and has not required any further tumor directed therapy since." Key findings of the trial include: DFMO is well tolerated with minimal side effects in children with relapsed neuroblastoma; children with specific genetic changes are predicted to have better response to DFMO; and there were three patients enrolled in the trial who are now long-term survivors. Dr. Sholler's laboratory investigated the effectiveness of combining DFMO with the drug etoposide. She incorporated early work performed by Dr. Andre Bachmann, Professor of Pediatrics and Human Development at Michigan State University College of Human Medicine. Dr. Bachmann's work identified the relationship of this drug (DFMO) targeting the ODC gene in neuroblastoma. Dr. Sholler then designed and led a clinical trial to test the combination of drugs in children being treated for the disease at sites participating in the NMTRC. Dr. Sholler and the NMTRC are now testing this concept in a Phase II clinical trial to prevent relapse.

"Since 2001, I have focused my research career on translating DFMO from bench to clinic, and a dream has come true," said Dr. Bachmann. "DFMO is now available to neuroblastoma patients thanks to Dr. Sholler and the wonderful NMTRC team."
Dr. Sholler received her M.D. from New York Medical College, in Valhalla, New York. She was a resident in pediatrics and, subsequently, a fellow in pediatric hematology/oncology at Brown University, before coming to international prominence for her work with relapsed neuroblastoma at the University of Vermont.

She then transferred her clinical program to Helen DeVos Children's Hospital in Grand Rapids. She is now Haworth Endowed Director of the Innovative Therapeutics Clinic focused on early phase clinical trials for pediatric cancers and Department of Pediatrics. Here she sees patients as part of the NMTRC, which she chairs.

Dr. Sholler's lab research at Helen DeVos Children's Hospital where she runs the NMTRC Research Laboratory is focused on identifying new therapies for children with neuroblastoma.

Image shows Dr. Sholler with neuroblastoma patient.

[Press release] [PLOS ONE article]