Study of Sirolimus for Complex Vascular Anomalies
Complex vascular malformations can be difficult to treat with surgery and cause disfigurement, chronic pain and organ dysfunction with significant morbidity and mortality. Oncologist Denise Adams, MD, medical director of the Hemangioma and Vascular Malformation Center (HVMC), has developed an investigator-initiated phase 2 study to assess the safety and efficacy of the mTOR inhibitor sirolimus. This study, supported by an FDA Orphan Products Grant, represents the first prospective clinical trial of a new medical therapy for these conditions. Adams is an internationally recognized authority on vascular anomalies, and the HVMC is an internationally recognized referral center and a model of collaboration among the Cancer and Blood Diseases Institute, the Department of Surgery and the Division of Developmental Biology. Adams has also helped to lead development of a robust and growing interdisciplinary working group on vascular biology whose research is guiding the development of future clinical trials.
Targeted Drug Discovery and Personalized Therapies
Despite advances in cure rates with chemotherapy, many children continue to relapse with fatal cancers or suffer severe complications from current therapies. The Division of Oncology is a national leader in the development of drugs and use of personalized genomics for better therapies for pediatric cancers.
The division is home to a leading national center for research in the development of anticancer therapies targeting tumor growth factor signaling pathways in combination with synergistic inhibition of the mTOR growth regulation pathway. Projects in tumors associated with neurofibromatosis (led by Brian Weiss, MD) and in pediatric brain tumors, sarcomas, neuroblastoma and other malignancies (led by Maryam Fouladi, MD, MSc) continue with research to identify molecular markers predictive of response. Early results of this innovative clinical translational work were presented by Fouladi at the national American Society of Clinical Oncology annual meeting. Lars Wagner, MD, is extending the team’s research in this area with his leadership of a new phase 2 clinical trial of IMC-A12 and temsirolimus (CCI-779) for children and adolescents with relapsed cancers.
A new initiative this year focuses on epigenetic therapies – specifically targeting chromatin structure and pathologic gene and micro-RNA expression to kill or “mature” malignant cells. At the 2010 American Society for Hematology national meeting, Christine Phillips, MD, presented work from the division demonstrating that complete remissions could be achieved in children with highly treatment-resistant forms of acute myeloid leukemia using decitabine. This work has provided the foundation for a new research study that Phillips is developing combining a related drug, azacytidine, with a chromatin-targeting drug, vorinostat. In parallel work, Trent Hummel, MD, is leading a phase 1 study investigating vorinostat with the conventional chemotherapy drug temozolomide for the treatment of relapsed or refractory brain or spinal tumors.
Understanding the biology of cancer stem cells and using new drugs to target these pathways are a key new area of research for the division. The laboratory of Timothy Cripe, MD, PhD, is funded to find new ways to identify and develop better therapies against neuroblastoma stem cells. James Geller, MD, is leading a phase 1 clinical trial of the small molecule c-Met inhibitor ARQ-197 in children with relapsed malignancies. Signaling through c-Met, also known as the hepatocyte growth factor, is prominent in normal stem cells but not normal tissues. However, c-Met is dysregulated in many types of human malignancies, including cancers of the kidney, liver and brain. In parallel work, Fouladi is leading a phase 1 study of the AKT inhibitor MK2206 in recurrent or refractory solid tumors and leukemias, as well as a Pediatric Brain Tumor Consortium phase 1 study of the Notch inhibitor MK0751. Notch signaling is a key regulator of viability and numbers of normal and malignant stem cells, and targeting this pathway holds particular promise for brain tumor therapy. Rachid Drissi, PhD, is leading important new research efforts to understand the role of telomerase in malignant stem cells in pediatric cancers, particularly brain tumors. He also is leading correlative biology studies for a Children’s Oncology Group study, the first national phase 1 trial of a telomerase inhibitor in children with solid tumors.
The division has recently established a new Scholar Training Program in Cancer Developmental Therapeutics and obtained competitive funding through the Hyundai Hope on Wheels Foundation. We recruited our first scholar, Carrye Cost, MD, who will receive intensive mentoring in advanced clinical oncology, pharmacology and pharmacogenetics, cancer biology and new drug development. This program is integrated with other initiatives in drug discovery and pre-clinical drug development in partnership with the Division of Experimental Hematology and Cancer Biology and the University of Cincinnati’s Drug Discovery Center. Closely related efforts in tumor signature profiling are also under way in Division of Oncology laboratories for real-time mutational analysis of patient tumor samples so that patients with high-risk disease can be guided to the most appropriate experimental targeted therapies based on the specific signaling pathways active in their cancers.
National Leadership in Research Consortia
Cincinnati Children’s faculty continue to provide critical leadership in national clinical research efforts focused on pediatric cancers. John Perentesis, MD, director of the Division of Oncology, was elected to the executive committee of the Children’s Oncology Group (COG), for which he also serves as chairman of the Acute Myeloid Leukemia Relapse Committee and vice chairman of the Adolescent and Young Adult Cancer Steering Committee. In addition, he serves on the Investigational Drug Steering Committee of the National Cancer Institute’s Cancer Therapy Evaluation Program, for which he chairs the Signal Transduction Agents Task Force, and the national steering committee of the NCI-funded Pediatric Developmental Therapeutics/Phase I Consortium.
Maryam Fouladi, MD, MSc, medical director of the Neuro-Oncology Program, chairs the CNS Tumor New Agents/Relapse Committee for the Children’s Oncology Group, for which she also serves on the CNS Tumor Committee; she is a member of the national steering committee for the Collaborative Ependymoma Research Network (CERN). Brian Weiss, MD, leads a national COG pilot study of the targeted radiopharmaceutical 131I-MIBG in high-risk neuroblastoma as well as a national phase 2 study of sirolimus in neurofibromatosis type 1-related plexiform neurofibromas through the Neurofibromatosis Consortium.