Our Science – NOB Website
For Patients and Physicians: In addition to our scientific research, which is summarized below, please visit our patient website for information on current treatment options available to adults and children with tumors of the central nervous system, including brain tumors.
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 fourth 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), remains essentially unchanged over the last two decades with most patients surviving less than a year from the time of diagnosis. Clearly, current treatment is suboptimal 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 neural and endothelial stem cells and 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 a prognosis to patients as well as select more appropriate treatments that have a greater likelihood of being effective in any individual tumor.
There is a growing and significant interest in the neuro-oncology laboratory in neural stem cell biology. We have recently demonstrated that we can isolate neural stem cells not only from the brain of animals and humans (as many others have shown) but we can also isolate neural progenitor cells from the peripheral blood and bone marrow of adult animals and humans. These cells behave identically to those found within the brain; however, they represent a much more accessible reservoir for study and therapeutic manipulation. We have demonstrated the ability of these cells to migrate both to sites of tumor cell infiltration within the brain and to sites of neural tissue damage. We have begun to examine the genetics of these bone marrow-derived neural progenitor cells using microarray gene expression profiling through the various stages of cell differentiation into the different lineages that make up the central nervous system (i.e., glial cells, oligodendrocytes, and neurons). There are a number of ongoing studies investigating issues related to the therapeutic use of these cells for antitumor purposes, for neural damage repair, and for better understanding their biology at a molecular/genetic level.
We were interested in developing a technology that would allow us to induce tumor-selective transgene expression from our genetic vectors based on aberrant signal transduction pathways that are intrinsic to the tumorigenic process itself. We became interested in the P16/cyclinD/CDK4/RB pathways secondary to its mutation/deregulation in almost 100 percent of malignant gliomas. Thus, a prediction that until now has not been demonstrated experimentally in vivo is that E2F responsive promoters should be more active in tumor cells relative to normal cells due to an excess of free E2F and loss of pRB/E2F repressor complexes. We demonstrate that adenoviral vectors, containing transgenes driven by the E2F-1 promoter, can mediate tumor-selective gene expression in vivo, allowing for eradication of established gliomas with significantly less normal tissue toxicity than seen with standard adenoviral vectors. Our data indicate that derepression of the E2F-1 promoter occurs in cancer cells in vivo, a finding that can be exploited to design viral vectors that mediate tumor-selective gene expression. We now have demonstrated that freshly isolated human malignant gliomas have a heterogeneous mixture of tumor cells, some expressing high levels of E2F and others low. We plan on exploring the difference in the biology of these two different tumor cell populations through microdissection of the cells and gene expression profiling using cDNA microarrays (see below).
We identified a subpopulation of human and mouse hematopoietic stem cells that are actually endothelial progenitor cells (angioblasts). Human and mouse proliferation-competent, bone-marrow or peripheral circulation-derived endothelial progenitor-like cells (PBECs) were isolated, expanded, and genetically engineered ex vivo to express the beta galactosidase (beta-gal) or thymidine kinase (TK) genes using retrovirus-mediated gene transfer. Genetically-labeled PBECs were transplanted into wild-type and sublethally irradiated mice and found to migrate and incorporate into the angiogenic vasculature of growing tumors while maintaining transgene expression. Ganciclovir (GCV) treatment resulted in significant tumor necrosis in animals previously administered TK-expressing PBECs. These results demonstrate the potential of using genetically modified PBECs as angiogenesis-selective gene-targeting vectors and demonstrate the potential of this approach to mediate nontoxic and systemic antitumor responses. These experiments have also taught us a more fundamental biologic principle which is that tumor-associated neovasculature is not just derived through angiogenesis but also through the embryonic process of vasculogenesis. We are exploring a number of in vitro and in vivo experiments to better understand this process and to elucidate the cellular and molecular biology of these PBECs.
It is known that human gliomas (brain tumors) are a heterogeneous group of tumors; however, there are no pathologic classification schemas that reproducibly allow us to separate out biologically similar tumors. We have initiated a very large cDNA microarray effort in collaboration with the Human Genome Project and the Cancer Genome Anatomy Project (CGAP) to develop a comprehensive and novel molecular classification schema for human gliomas based on a gene expression profile using cDNA microarray technology. We have constructed our own cDNA microarray "chips" which will be enhanced for new and selective genes thought to be important in glioma biology. This project will include hundreds of tumor specimens and offer an unprecedented opportunity for gene discovery, dissecting signal transduction pathways, and learning this exciting new technology.
We have a growing interest in better understanding the cellular, molecular, and genetic basis for drug- and radiation-induced neurotoxicity. We have established several proficient in vitro models of the blood brain barrier that appear to mimic the functional as well as the cellular and molecular phenotype of the in vivo barrier. This, along with our significant experience with neural stem cells and our animal models incorporating both chemotherapy and radiation therapy to the central nervous system, put us in a prime position to begin to unravel the pathophysiologic mechanisms behind drug- or radiation-induced demyelination, neuronal loss, and endothelial cell destruction.
Additionally, we also have projects in neurostem biology as it relates to glioma tumorigenesis and in random peptide and single chain antibody phage screening for identifying novel binding motifs to tumor cells and tumor-associated endothelium.
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, we hope, will then 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 program for tumors of the brain and spinal cord.
This page was last updated on 11/7/2012.