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 new strategies for selective tumor targeting through gene transfer using novel genetic vectors, through the identification of tumor selective processes such as angiogenesis, and through the identification of tumor specific markers. Additionally, the Branch is undertaking a large national study to create a molecular classification of gliomas so that physicians will more accurately be able to give prognoses to patients as well as select more appropriate treatments that have a greater likelihood of being effective in any individual tumor. In the area of tumor targeting, the Branch has developed a technology that has allowed us to create viral vectors that are inducible by a family of transcriptional factors known as E2F. Secondary to mutations in the P16, Cyclin D, CDK4/CDK6, RB axis it is known that almost all gliomas are deregulated for RB function and hence have high E2F activity. Through the construction of E2F responsive viral vectors we have been able to demonstrate tumor selective transgene expression in gliomas with transcriptional inactivation in normal brain tissue. These initial experiments were performed using adenoviral vectors however, we are currently in the process of constructing lentiviral vectors that are E2F responsive secondary to our belief that these smaller viruses will be more easily amenable to enhanced convection delivery secondary to their smaller size and their better safety profile. We are additionally in the process of identifying unique proteins expressed on infiltrating glioma cells and on endothelium, associated with the angiogenic response of tumors, for the purpose of identifying novel peptides and single chain antibody molecules through random phage display. It is our ultimate intention to tag these peptides and single chain antibody molecules with radioisotopes for diagnostic purposes and to conjugate these molecules with immunotoxins for the purpose of developing selective cytotoxic targeting proteins. Through our extensive collaboration with Dr. Edward Oldfield in the Neurological Surgery Branch of NINDS we are working out parameters of enhanced convection delivery to ensure the homogeneous distribution of large macro-molecules throughout the brain using this novel delivery technology. We are also extending our long-standing interest in angiogenesis inhibition as a novel therapeutic strategy for the treatment of malignant gliomas through our identification and characterization of circulating endothelial progenitor cells within normal adult and pediatric patients. Not only have we been able to isolate these cells and grow them in vitro but we have also been able to genetically transduce these cells with viral vectors. We have now demonstrated that these progenitor cells grown ex vivo have the ability, when injected back into the systemic circulation of tumor bearing animals, to migrate selectively to sites of tumor-associated angiogenesis and to incorporate into the growing capillary loops associated with the tumor. This allows us a unique opportunity to selectively deliver through cellular means, genes of choice to tumor-associated angiogenesis through the genetic transduction of the endothelial progenitor cells. We have subsequently shown that delivery of a conditionally cytotoxic gene such as the herpes thymidine-kinase gene can be delivered to tumor neovasculature with the subsequent destruction of the tumor vascular bed upon administration to the animal of the pro-drug, ganciclovir. It is our attention to bring this novel strategy to the clinic within a very short period of time. Our final major translational laboratory effort, is a collaborative effort between the Neuro-Oncology Branch, Robert Strausberg and the Cancer Genome Anatomy Project, and Dr. Ed Liu in the Advanced Technology Center for the development of a glioma specific cDNA microarray chip. We are in the process of currently constructing such a chip. The purpose of this study is to ultimately develop a molecular classification scheme of malignant gliomas. Current classification schemes for malignant gliomas are sub-optimal and do not clearly predict prognosis or likelihood of response to therapy. It is our hope that through the identification of signature gene expression profiles, we will be able to group pediatric and adult gliomas into tumors that are biologically more related. Not only will this allow us greater ability to offer accurate prognoses for any given patient but also to begin to address the issue of individualized therapies for each specific patient. This will be a large undertaking done in conjunction with the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute and through a collaborative effort between the Neuro-Oncology Branch and the CTEP sponsored CNS Consortia made up of at least 16 different brain tumor centers across the country. Finally, we are building an administrative and clinical infrastructure to begin to see and treat pediatric and adult patients with primary tumors of the central nervous systems at the Clinical Center at the NIH. This patient population has not historically been seen in an organized fashion at the NIH and thus we are spending a great deal of time and effort building such an infrastructure. We are developing close relationships with outside Institutions and with the collaborative cancer groups, specifically the CNS Tumor Consortium, and have opened up a referral base for patients with CNS neoplasms and their physicians to obtain information and advice about potential therapeutic options. Through this flow of patients, we will have ready access to the relatively large numbers of patients that will be necessary to complete the early clinical trials of the novel therapeutic agents as they come out of the laboratory. It is our intention to conduct early pilot and feasibility trials within the clinical centers and then to export the most promising of these therapeutic approaches to the NCI sponsored CNS Consortia for more extensive Phase I/II trials. The most promising of these therapies then will hopefully go on to large-scale national randomized trials. It is through this process that we hope to develop a unique NCI sponsored, nationally coordinated therapeutics development programs for tumors of the brain and spinal cord.
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