Primary tumors of the Central Nervous System (CNS) are the second leading cause of cancer mortality in people under the age of 34, and the 4th leading cause of cancer mortality in individuals under the age of 54. With the dramatic improvement in the treatment of childhood leukemia, tumors of the brain and spinal cord are quickly becoming the leading cause of cancer deaths in children in the United States. Despite dramatic advances in neurosurgery, radiation oncology, and imaging of the central nervous system, the prognosis of patients with the most common primary brain tumors (i.e. malignant gliomas), remain essentially unchanged over the last two decades with most patients surviving less then a year from the time of diagnosis. Clearly, current treatment is sub-optimal and novel therapeutic approaches are needed. The Neuro-Oncology Branch is one of the first trans-institutional initiatives at the National Institutes of Health. The Branch will develop an integrated clinical, translational and basic research program that will engage the strengths and resources of the NCI and the NINDS for the purpose of developing novel experimental therapeutics for children and adults with tumors of the brain and spinal cord. Toward this end, the translational laboratory efforts of the Neuro-Oncology Branch are focusing on the development of novel therapeutic strategies for the treatment of primary brain tumors through an understanding, exploitation, and eventual clinical translation of the principles underlying the molecular and genetic pathogenesis of these tumors. Our approach is to leverage the unique resources of the intramural NIH program, including its tremendous scientific and clinical freedom to explore high risk yet high pay off projects, to build an NIH-wide pre-clinical and clinical brain tumor experimental therapeutics center. This center will work collaboratively and synergistically with both the NIH extramural community as well as with the private sector to ensure the most efficient and rapid development of novel approaches to the treatment of these devastating tumors. Below is a brief summary of several of our current translational (clinical and laboratory-based) initiatives.Pre-Clinical/ClinicalWe have pursued our interest in defining novel mechanism of glioma growth (SERMs), invasion, and survival (see laboratory achievements below) in an effort to develop novel therapeutic agents that target these pathways. Examples of such research that has led to translational/clinical studies include:Demonstration that certain classes of selective estrogen receptor modulators can efficiently induce glioma cell apoptosis in vitro and mediate increased survival in animals harboring experimental gliomas. We have also begun to dissect the molecular pathways responsible for this surprising effect given that glioma cells do not express estrogen nor progesterone receptors. These studies have led to the preclinical and now clinical development of a new SERM named CC-8490. We have just initiated a phase I trial of this agent in patients with recurrent high-grade gliomas. Additionally, we have canvassed a number of pharmaceutical companies and have screened several potent new SERMs in early clinical development for this antiglioma activity. We are currently working with Lilly Pharmaceuticals on a promising new SERM that has potent glioma apoptotic-inducing activity.We have continued our long standing interest in the preclinical and clinical development of anti-angiogenic agents as a treatment for malignant brain tumors based on the rationale that gliomas are amongst the most angiogenic of all tumors and anti-angiogenic therapy generally requires targeting the tumor vasculature, one may negate having to transverse the blood-brain barrier. We have pursed this line of translational research by providing preclinical data/rationale for moving several novel agents into clinical phase I/II trials, and by designing and conducting these trials here at the NIH (i.e. ZD6126, CC-5013, LY317615, BCNU/Thalidomide) as well as several national trials run through one of the CTEP-sponsored brain tumor consortia (i.e. SU5416, CC-5013, pegIntron/thalidomide). Through our Glioma Molecular Diagnostic Initiative (GMDI) we have identified HDAC1 as a gene that is highly overexpressed in chemotherapy refractory gliomas and underexpressed in chemotherapy and radiation sensitive gliomas. Based on these observations, we have gone on to show that treatment of various glioma cells lines with HDAC inhibitors markedly sensitizes them to the cytotoxic effects of genotoxic stimuli. These observations have led us to respond to a CTEP RFA and be granted the rights to take a promising new HDAC inhibitor, Depsipeptide, to a national phase I/II trial in patients with recurrent high-grade gliomas. We will also be initiating a series of trials here at the NIH looking at the use of an old anti-epileptic drug, valproic acid, in combination with chemotherapy and radiation in patients with high grade gliomas based on our data demonstrating that valproic acid is a potent HDAC inhibitor at pharmacologically achievable concentrations. Please find below a partial list of clinical phase I/II trials for which H. Fine is currently the Principle investigator here at the NIH and/or nationally:- A Phase I/II Trial of SU5416, a FLK and angiogenesis inhibitor, in patients with recurrent malignant gliomas.- A Phase II Trial of Thalidomide and BCNU for Recurrent High Grade Gliomas. - A randomized phase II trial of peg-Intron with and without thalidomide in patients with recurrent high grade gliomas. - A Phase I Trial of CC-5013, a potent thalidomide analog, in patients with recurrent primary brain tumors. - A Phase II Trial of LY317615, a PKC beta inhibitor, in patients with recurrent high grade gliomas. - A Phase II trial of Talampanel, a new AMPA glutamate receptor inhibitor, for patients with recurrent high-grade gliomas. - A Phase I Trial of a novel selective estrogen receptor modulator,CC-8490, in patients with recurrent primary brain tumors. - A prospective national study to molecularly and genetically characterize human gliomas. - A Phase I/II trial of STI-571 in patients with refractory high grade gliomas. - A Phase II trial of STI-571 in patients with inoperable meningiomas.- A Phase I/II trial of the EGFR inhibitor, OSI-774, in patients with recurrent high-grade gliomas and newly diagnosed glioblastoma.- A Phase I trial of the farnesyltransferase inhibitor R117555 plus radiation in patients with newly diagnosed high grade gliomas- A Phase I Trial of ZD-6126, a potent endothelial tubulin targeting agent, in patients with recurrent primary brain tumors. - A Phase I Trial of the HDAC inhibitor, Depsipeptide, in patients with recurrent primary brain tumors. National P.I.Laboratory Research:1.Glioma Molecular Diagnostic Initiative: Although it is well recognized that human gliomas are a heterogeneous group of tumors, there are to date no pathologic classification schemas that reproducibly allow the identification of biologically similar tumors or predict for tumor-specific therapies. The lack of such a classification schema significantly limits the ability of scientists to unravel the molecular pathogenesis of different glioma subtypes and precludes clinicians from offering therapeutic options that are specific for a patient's particular tumor. We have therefore initiated a large national effort in collaboration with the Cancer Genome Anatomy Project (CGAP) and NCI's Cancer Therapy Evaluation Program (CTEP) to develop a comprehensive and novel molecular classification schema for human gliomas based on gene expression profiles using cDNA microarray technology, comparative genomic hybridization (CGH), SNP analyses, and high throughput sequencing.
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