Our researchers are investigating safer, less toxic and more effective methods of treatment for children with brain and spinal cord tumors.
We are members of the NIH-sponsored Pediatric Brain Tumor Consortium (PBTC) and Children's Oncology Group (COG) Early Phase-Clinical Trial Network, as well as the Department of Defense (DOD) Neurofibromatosis Clinical Trials Consortium. Our participation in the PBTC, COG and DOD consortia enables us to offer all of the available cutting-edge government-sponsored national clinical trials for children with difficult-to-treat brain and spinal cord tumors. Jason Fangusaro, MD, serves as the national co-chair for PBTC and is the leader of the Aflac Developmental Therapeutics Program. He currently leads numerous national clinical trials through COG and PBTC. His main focus of research within pediatric brain tumors are low-grade gliomas and central nervous system germ cell tumors.
Within the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, our researchers are also studying aberrant signaling pathways and novel medicines, technologies, and therapeutic combinations with the goal of improving survival and the quality of life and long-term outcomes of our patients. These studies have directly led to additional innovative clinical trials offered locally at Children’s and collaborating institutions.
Their research includes:
STAT3-targeted therapies: The lab of Tobey J. MacDonald, MD, focuses on understanding the role of the cancer stem cell survival factor, STAT3, in childhood brain tumors. His lab is developing and optimizing drug combinations to target STAT3 in tumor cells and the immune system. In collaboration with Waldemar Priebe, PhD, at MD Anderson Cancer Center, they successfully tested the efficacy of the drug WP-1066 (Moleculin Inc.), a STAT3-selective inhibitor, in models of pediatric brain cancer. Dr. MacDonald is preparing to lead the "first-in-child" investigation of WP1066 in a Phase I clinical trial at Children’s for children with relapsed malignant brain tumors. CURE Childhood Cancer Foundation supported these investigations.
Infant high-risk embryonal brain tumors and childhood medulloblastoma: Claire Mazewski, MD, and Anna J. Janss, MD, PhD, have each led the two most recent COG national clinical trials for these aggressive tumors (COG studies ACNS0334 and ACNS0331, respectively). Dr. Mazewski has a longstanding interest in the treatment of infants with malignant brain tumors. The goal of these studies is to use high-dose chemotherapy and stem cell transplant in place of radiation. The focus of Dr. Janss’ research is in the treatment of childhood brain cancers, particularly medulloblastoma, in a way that maximizes chances for survival but preserves quality of life and minimizes the acute and long-term toxic side effects.
Immunotherapy: Dolly Aguilera, MD, leads several clinical trials, initiated by the Aflac Cancer and Blood Disorders Center, of immunotherapy for pediatric brain tumors. Her clinical trials with interferon-modulating drugs (polyICLC and pegylated-interferon) have shown some early evidence of efficacy for children with progressive low-grade glial tumors. The therapy appears to have very little, if any, toxicity. She hopes to confirm this activity and low toxicity in an upcoming (2020) national trial of polyICLC for children with NF1 and progressive low-grade gliomas that have not responded to standard therapies. In addition, she is collaborating with investigators at Augusta University in a Phase II trial of the immunotherapy Indoximod for children with relapsed aggressive malignant brain tumors.
Experimental therapeutics for WIP1-associated brain tumors: The lab of Robert "Craig" Castellino, MD, studies the role of the Ser/Thr protein phosphatase PPM1D (aka WIP1) in high-grade pediatric brain tumors. PPM1D amplification or overexpression occurs in medulloblastoma (MB). Dr. Castellino has shown high PPM1D expression in Grp3/4 MB and PPM1D amplification in a subset of Sonic Hedgehog (SHH) MB. High PPM1D expression enhances the growth of TP53 wild-type MB, in part due to increased expression of the major p53 regulator HDM2. He also recently demonstrated important cross-talk between PPM1D and SHH signaling that promotes MB and that may be targetable using small molecule inhibitors of SHH and PPM1D.
Molecular mechanisms of medulloblastoma progression and treatment resistance: The laboratory of Anna Marie Kenney, PhD, is investigating molecular mechanisms driving therapeutic resistance in medulloblastoma (MB). Using mouse models for MB, her group has identified proteins and signaling pathways that contribute to resistance and may drive tumor recurrence. Their goal is to carry out pre-clinical studies in mouse models to determine whether manipulating these pathways may be a way to increase the effectiveness of current radiation and chemotherapies, or may enable dose de-escalation to improve survivors’ quality of life. A related interest in her lab is exploring the microenvironment in MB, including the immune component, to determine how these cells may contribute to or impair MB growth in manners that may be specific to the genetics of the tumors. Such findings could have future implications for prioritizing patients for immune-targeting or -enhancing therapies.
Outcomes in children with brain tumors: Lisa Ingerski, PhD, is leading critical investigations into the neurobehavioral and quality of life (QOL) outcomes of children with brain tumors. More specifically, in collaboration with Dr. MacDonald and investigators at Augusta University, Dr. Ingerski is evaluating QOL outcomes in children with brain tumors treated with precision medicine-based and immunotherapeutics. Drs. Ingerski, Mazewski and Janss are also investigating long-term outcomes of survivors of childhood brain tumors. Together with Dr. MacDonald and investigators at Georgia State University, the group is examining the influence of genetic predispositions on long-term survivor cognitive outcomes. Dr. Janss also conducts clinical work in the Neuro-oncology Long-Term Brain Tumor Survivor Clinic and facilitates evaluation of the medical, cognitive and neurological late effect of brain tumor treatments. Drs. Janss and Mazewski are studying the impact of genetics, diet and the gut biome on the severity of late effects of brain tumor therapy, hoping to find ways to reduce them and increase the quality of life in survivors. They are also interested in the ongoing care of adult survivors of childhood brain tumors and work with colleagues to create guidelines and pathways to support and monitor individuals as they transition from pediatric to adult neuro-oncology care.
Nanotechnology: In collaboration with researchers at the Georgia Institute of Technology, we are exploring new bioengineering strategies to improve the delivery of therapies across the blood-brain barrier (BBB) and to target the brain tumor. These investigations include the use of focused ultrasound to disrupt the BBB and nanoparticle drug carriers that hone to brain tumors. As part of our precision medicine program for brain tumors, we are also employing uniquely designed microfluidic "chips" to investigate the properties of circulating cancer cells captured from the blood of brain tumor patients and to screen in real time the efficacy of new drugs and drug combinations directly on the tumors obtained from patients.