NYU Cancer Institute research related to brain tumors is taking place both in the laboratory and in the clinic, with translational efforts forging collaborations between basic science researchers and clinicians.
Dr. Sarah Milla’s research interests include using advanced imaging techniques in the diagnosis of pediatric brain tumors. Specifically, she and her colleagues are using MRI techniques such as diffusion-weighted-imaging, diffusion tensor imaging, and non-Gaussian diffusion imaging techniques, particularly diffusional kurtosis imaging.
Research in Dr. Hae-Ri Song’s laboratory focuses on the biology of central nervous system (CNS) tumors. Studies on CNS tumorigenesis suggest that many of the genetic changes and pathways in tumor cells are similar to those utilized by normal neural cells during development. The group's primary interest is to understand how genes that are important in normal glial development are "hijacked" to cause glioma, the most common CNS tumor. One gene, named Nuclear Factor I (NFI), was recently identified as a glial fate determinant in the developing CNS. Dr. Song and her colleagues have shown that NFI is highly expressed in astroglial tumors, and that genetic manipulation of NFI impacts glioma growth in animal models. Their current research efforts are geared toward understanding the molecular mechanism(s) of NFI in glioma development. By elucidating this role, they hope to generate insights into the biology of glioma that will ultimately lead to the development of novel therapies. (Neuro Oncol.2010;12(2):122-32.)
Dr. Howard Weiner has explored signaling pathways underlying the development of medulloblastoma, the most common brain tumor in children. Understanding of the sonic hedgehog pathway in this tumor has led to the development of strategies to target this pathway as a therapeutic approach. Now Dr. Weiner and Dr. Delia Talos are focusing on the biology of tuberous sclerosis complex (TSC), which strikes 1 in 6,000 children. TSC can result in tumors in the brain (particularly giant cell astrocytomas) and other organs (skin, heart, kidneys, and lungs) and malformations in the brain. Two-thirds of children with TSC experience problems such as refractory epilepsy and autism. Dr. Weiner and his team are studying cellular abnormalities in tissue samples from patients with TSC who had surgery, working with radiologists to improve approaches to imaging the disease, and refining the role of neurosurgery for giant cell astrocytomas. Studies have shown that the mTOR pathway is upregulated in TSC, so clinical trials are evaluating the effectiveness of drugs that target this pathway (such as rapamycin and everolimus) in patients with TSC.
Dr. Dimitris Placantonakis’ laboratory is exploring the role of stem cells in the pathogenesis of glioblastoma, a deadly brain tumor. The lab is particularly interested in the function of the Notch pathway, a signaling system involved in glioblastoma stem cell self-renewal, in the context of hypoxia and angiogenesis. Using gliobblastoma stem cells obtained from surgical specimens, genetically modifying them in the laboratory, and injecting them into the mouse brain, they hope to perform fate mapping of such stem cells in vivo. The Placantonakis lab is collaborating with Dr. Wenbiao Gan’s lab to use two-photon confocal microscopy to perform such fate mapping. The lab is also investigating novel approaches to targeting glioblastoma stem cells for therapy. Currently, the team is testing a viral vector that may be able to specifically infect only stem cells within such tumors. The ultimate goal of the laboratory is to further our understanding of glioblastoma stem cell biology and to design novel treatments for the disease.
Dr. Matthias A. Karajannis, Dr. Jeffrey Allen, and other investigators focus on developing novel, molecular targeted therapies in pediatric CNS tumors through translational research and clinical trials. Their projects focus on neurofibromatosis type 1 and 2 (NF2)-related tumors, high-grade and low-grade astrocytomas, receptor tyrosine kinase/MAPK signaling pathways, ubiquitin- proteasome pathways, and survival/apoptosis pathways. Projects include:
- determining if lapatinib can be used to treat NF2-related tumors by assessing the molecular effects of this drug
- evaluating sorafenib in children with recurrent low-grade astrocytoma by targeting mutated BRAF
- elucidating the mechanism through which the FERM domain protein Merlin, encoded by the tumor suppressor NF2, mediates contact inhibition and suppresses tumorigenesis
- studying Sprouty protein expression in subgroups of pediatric low-grade astrocytomas that have different mechanisms of RAS/RAF/MEK/ERK pathway activation
Dr. Ashwatha Narayana is conducting research to learn how to optimize the use of anti-angiogenic therapy to treat patients with glioma. He and his fellow investigators were among the first to show that two-thirds of patients with recurrent gliomas respond to treatment with bevacizumab, ultimately leading to approval of this drug by the U.S. Food and Administration for patients with this tumor type. The researchers have also shown the feasibility of using this drug as initial therapy in newly diagnosed glioma patients, showing that it improved outcome by increasing overall survival and quality of life. However, many patients develop small tumors elsewhere in the brain after a few months of bevacizumab therapy. Dr. Narayana and his team are now assessing the addition of lithium to treatment with bevacizumab, temozolomide, and radiation therapy in patients with newly diagnosed gliomas to see if this treatment regimen reduces the likelihood of such "pop-up" tumors in the brain. Finally, Dr. Narayana is also assessing how to combine imaging modalities -- such as magnetic resonance spectroscopy and perfusion imaging -- to improve the visualization of the extent of brain tumor growth, which would enhance surgical precision and radiation therapy planning. The researchers are also trying to incorporate functional imaging in the treatment of gliomas to spare critical parts of the brain responsible for memory, speech, and vision, to preserve patients' quality of life.
Dr. Sharon Gardner leads clinical trials of new approaches to treating brain tumors in children. One such study, initiated by NUCI investigators and available only at this institution, is assessing a vaccine therapy based on four tumor antigens mixed with an immune booster called montanide. Researchers are assessing the vaccine to see if it can induce an immune response against cancer cells in select patients under age 21 with recurrent or refractory brain tumors. Dr. Gardner and her colleagues are also designing a similar study evaluating another vaccine based on a different set of tumor antigens in adult patients. In another project, they are assessing the use of autologous stem cell transplantation (ASCT) with high-dose chemotherapy to avoid the need for radiation therapy in young children with brain tumors, and in older children and young adults with recurrent brain tumors after radiation therapy who also receive retinoic acid.