Members of the Johns Hopkins Medical Institutions and the National Institutes of Health (NIH) have joined together to share laboratory expertise in the field of neuro-oncology.
The laboratory capabilities of this group of investigators are extensive. The multi-disciplinary nature of neuro-oncologic research has fostered collaboration between the laboratories included in this training grant. Animal models of brain tumors, peri-tumoral edema, angiogenesis, and meningeal carcinomatosis have been established. The investigators are facile at administering radiation therapy and intravenous, intraarterial, and intraventricular chemotherapy to animals by bolus injection or continuous infusion. Animal and human tumor cell lines as well as normal cell lines, such as endothelial cells and astrocytes, are available for research purposes. There are excellent care facilities, operating rooms, and radiologic facilities for experimental animals. Furthermore, the wide range of laboratories involved in this training grant have an enormous number of working assays which are available to the trainees for their projects.
Training is accomplished primarily in the laboratories of the investigators participating in this research training program. This includes laboratories in The Oncology Center and the Departments of Neurosurgery, Neurology, and Radiology at Johns Hopkins. Additional clinical and laboratory facilities of The Johns Hopkins Oncology Center and the other participating departments will also be used in the research training program. The major laboratories participating in this research training grant application, their major research focus, and the opportunities available to the fellows are listed below.
Faculty - Gary Rosner, M.D., Ph.D., Director of Biostatistics
The primary objective of this program is to provide the statistical design, analytic tools, and guidance necessary to ensure methodologically sound research. A great deal of the research interests focus on design, data collection mechanisms, and educational methods which will assist faculty and fellows in gaining analytic expertise.
There are opportunities for fellows through this office to obtain an understanding of the methods which are necessary to design, conduct, and analyze data resulting from both clinical and laboratory studies.
Cellular and Molecular Neuro-Oncology Research Laboratory
John Laterra, M.D., Ph.D., Associate Professor of Neurology, Oncology, and Neuroscience
My laboratory focuses on the cellular and molecular biology of primary brain tumor malignancy with the combined goals of determining basic mechanisms and translating these discoveries into experimental therapeutics. We are particularly interested in glioma cell growth regulation, tumor-associated angiogenesis, and blood-brain barrier function. We focus a great deal of attention on the role of soluble growth factors and their receptors in malignant progression of human gliomas. An example is the multifunction cytokine and angiogenesis factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor c-met. Studies are presently underway to determine the growth factor-dependent cell signaling pathways that are operational in human gliomas and differential gene expression analysis is being used to identify novel genes that are regulated by specific growth factors in gliomas. Ribozyme-based methods of inhibiting growth factor and growth factor receptor expression are being used to determine mechanisms and for experimental therapeutics.
We are also interested in developing novel gene delivery strategies applicable to brain and brain tumors. We recently developed endothelial-cell-based gene transfer approaches to deliver immune-activating cytokines and other secreted gene products to brain tumors for anti-tumor therapy and as tools to understanding the function of host cytokine expression within gliomas. Endothelial cell-based cytokine gene delivery is proceeding to clinical trial in patients with recurrent malignant brain tumors.
Techniques commonly used in our laboratory include: mammalian cell culture, mammalian cell transfection and cloning, in vivo models of CNS tumors, plasmid and chimeric gene development, Northern hybridization, immunoblotting, in situ hybridization, PCR, RT-PCR, immunohistochemistry, blood-brain barrier permeability assays, computer-assisted image analysis and morphometry.
Diagnostic Radiology Research
James Anderson, Ph.D., Professor of Radiology
Our major laboratory research efforts lie in the area of interventional radiology and image guided therapy. More specifically, studies concentrate on NMR imaging/spectroscopy and PET studies of tumor metabolism and transcatheter delivery of therapeutic agents for cancer. Research projects conducted during the recent past include:
- Pharmacokinetics and therapeutic efficacy of intra-arterial and intravenous chemotherapy for experimental brain tumors,
- Transcatheter vascular occlusion studies of experimental hepatic tumors,
- Blood flow to experimental renal tumors,
- MRI images of experimental brain tumors and associated edema,
- Gravimetric analysis of tumor induced cerebral edema in the rabbit,
- IIC-methionine PET studies of canine brain tumors,
- Hemodynamic studies relating to aortic outflow tract obstruction in conjunction with valuloplasty of congenital aortic valvular stenosis,
- A new technique to create an atrial septal opening to treat congenital heart disease,
- NMR spectroscopic studies of experimental liver, kidney, and muscle tumors,
- Studies of high energy phosphate metabolism (NMR) and glucose utilization, oxygen consumption and blood flow in canine brain tumors, and
- Image guided robotic assisted delivery of therapeutic agents for liver cancer.
Magnetic Resonance Spectroscopy and Imaging
Zaver M. Bhujwalla, Ph.D., Associate Professor of Radiology
The major focus in this laboratory is to understand the role of vascularization and the physiological environment in breast and prostate cancer invasion and metastasis. We use human breast and prostate cancer models and in collaboration with other laboratories study genetically modified human breast cancer lines. We measure cancer cell invasion using our newly developed MR assay to detect cell invasion dynamically over a period of time. These studies are performed with isolated perfused cells. Our in vivo studies of tumor models are performed with intra-and extravascular contrast enhanced MRI techniques and use state of the art MR Imaging and Spectroscopy techniques in combination with sophisticated 3-dimensional volume rendering software to relate 3D maps of vascular volume and permeability to 3D reconstructed immunohistochemical information. Current clinical projects include studying tumor drug pharmacokinetics and MRI characterization of breast lesions. Participating fellows can contribute and develop expertise in tumor biology, pharmacology, metabolism, molecular biology, image analysis and therapy.
Molecular Biology: Genes Involved in Human Brain Tumorigenesis
Bert Vogelstein, M.D., Professor of Oncology
Research efforts in this laboratory are focused on the genetic events underlying human tumorigenesis. Several of the genes currently studied , such as p53, APC, and hMSH2, underlie the development of multiple tumor types, including brain tumors. Ongoing studies are aimed at (I) improved detection of inactivating mutations of these genes in hereditary and sporadic cases; (ii)better understanding of the mechanisms through which these genes act to promote tumorigenesis, at the biochemical, physiologic, and clinical levels; and (iii) identifying methods to exploit these mutations through novel therapeutic approaches.
This research affords opportunities for surgical oncology fellows to learn a varient of sophisticated recombinant DNA techniques, with clear applications to basic problems in neuro-oncology.
Stuart A. Grossman, M.D., Professor of Oncology, Medicine & Neurosurgery
- During the past several years the major research efforts in the Neuro-Oncology laboratory have been designed to:
- Determine the penetration of chemotherapeutic agents into brain and brain tumor tissue following intrathecal, intra-arterial and intravenous administration. This requires sophisticated quantitative autoradiographic techniques and the analytic capabilities available in the Quantitative Image Analysis Laboratory.
- Study the neurotoxicity of antineoplastic therapies using 2-deoxyglucose autoradiography, organotypic brain cultures, and pathologic studies in animal model systems.
- Evaluate the distribution, toxicity, and efficacy of new antineoplastic agents or drug delivery systems synthesized and specifically designed for CNS malignancies.
- Conduct feasibility studies, using quantitative autoradiographic techniques, on compounds which can generate sequential in vivo data on the mitotic index of tumors using positron emission tomography.
- Develop new methods to improve the control of pain secondary to malignancies.
The Neuro-Oncology Laboratory is well equipped to approach clinical neuro-oncologic questions which are difficult to answer in patients using appropriate animal models and quantitative techniques. It is also structured to facilitate working with medical students and trainees.
Neurosurgery Brain Tumor Laboratory
Henry Brem, MD Professor of Neurosurgery, Ophthalmology, & Oncology
The neurosurgery brain tumor laboratory is devoted to transforming basic science findings to potential clinical applications. This laboratory has two major foci. First, work has been developed over the past 16 years on the role of tumor angiogenesis in controlling brain tumor growth. In the last 3 years we have:
- Isolated, purified, and sequenced a new angiogenesis factor with unique characteristics isolated from neuroblastoma cells. This work was done in collaboration with Dr. Daniel Nathans' laboratory.
- Developed a new class of antiangiogenesis agents and explored their mechanism in terms of collagenase inhibitory activity.
- Worked with Dr. Gary Goldstein's laboratory to explore the relationship between astrocytes and endothelial cells in blood brain barrier and angiogenesis process.
The laboratory's primary objective currently is to apply these findings to human brain tumors first in the laboratory and then in the clinic.
The second major focus of this laboratory has been to develop biodegradable, controlled-release polymers. These polymers are able to release any molecular weight substance over prolonged periods of time. We have demonstrated that these polymers are safe and have explored the release kinetics and effectiveness of release of chemotherapeutic agents from these polymers. As a result of these studies, a Phase I multi-institutional clinical study has been carried out demonstrating that these polymers are safe for the use in the treatment of recurrent malignant brain tumors. Currently, a Phase III prospective randomized placebo-controlled multi-institutional study is underway in the United States and Europe to determine the effectiveness of BCNU released from these polymers in patients. We are presently investigating chemotherapeutic agents, biological response modifiers, and anti-angiogenesis agents. We are also exploring the possible role of these polymers in releasing agents to control Parkinson's disease and Alzheimer's disease in animals. We are working with Dr. Donlin M. Long to develop release methods for free radical scavengers in controlling brain edema.
The development of this technology should allow a new approach to localized treatment of brain disease.
Dean Wong, M.D., Professor of Radiology
The Division of Nuclear Medicine has state-of-the-art radiotracer imaging facilities, broad experience, and a diverse background in research programs involving the application of radiotracer and techniques to oncology. Participating faculty members provide a strong basic sciences foundation and research expertise in the areas of chemistry, physics and instrumentation, radiobiology, physiology, pharmacology, microbiology, and clinical nuclear medicine. Current research of the faculty includes the design, synthesis and evaluation of radiopharmaceutical, including labeled monoclonal antibodies, potentially useful in cancer diagnosis and in monitoring cancer therapy; the application and development of state-of-the-art detection techniques such as single photon emission tomography and positron emission tomography that permit more precise localization of tumors within the body; the application of the tracer principle to study normal and abnormal cells and organs of patients with neoplasm; and finally, improving our understanding of the dynamic state of body constituents as altered by the neoplastic process. We have multiple interdisciplinary research programs ongoing with other University departments, including Oncology, Pharmacology, Neurosciences, and Radiology.
This division is currently working with members of the adult and pediatric neuro-oncology groups at Johns Hopkins to explore the use of 2-deoxyglucose, methionine, and thymidine positron emission tomographic scans in patients with brain tumors. We would welcome a close collaboration on clinical and laboratory based projects with a neurosurgical trainee funded by this training grant.
Jerry Williams, M.D., Professor of Oncology
The effect of dose rate on cell kill of human glioblastoma cell lines is being studied in an attempt to stimulate the radiation dose delivered by radioimmune therapy. High-dose rate radiation given in fractionated treatment is being compared to continuous low-dose rate radiation. The latter can be either continuous same dose or continuous variable dose. Again, the dose rates resemble those delivered by radioactive immunoglobulin therapy. It has been shown that there is increasing rate of cell kill at times greater than 20 hours, especially with dose rates of 0.25 Gy per hour or higher. Since population doubling time of these cell lines are approximately 24 hours, the cell cycle redistribution may be responsible for this increase radiosensitivity. This hypothesis has been supported by flow cytometry DNA histograms which show cells accumulating in G2 or M phases of a cell cycle. Optimization of time intervals between radiation treatments and dose rates used for glioblastoma tumors may be influenced by these findings. We are now studying different combinations of high-dose rate radiation and low dose-rate radiation to examine effects of varying time and dose rate. We are also incorporating simultaneous cisplatin with continuous low-dose rate radiation into our studies to determine whether there is a super-additive effect. (Concentrations of cisplatin were extrapolated from The Johns Hopkins Hospital clinical protocol for glioblastoma tumors).
Information obtained from glioblastoma cell line studies will be used in small animals before hopefully applying it to clinical trials (for example, simultaneous cisplatin with high-dose rate radiation and radioactive antiglioma antibodies).
Roberto Pili, M.D. Instructor in Oncology
The laboratory primary objective is to investigate the therapeutic role of angiogenesis inhibitors in combination with cytotoxic and cytostatic agents such as standard chemotherapy and differentiation-inducing compounds, respectively. In vitro studies are being conducted to elucidate the molecular mechanisms underlying common signal transduction pathways. Animal models of tumor growth (i.e. primary and metastatic prostate and colon tumors) and angiogenesis (Matrigel assay) are being utilized to test several angiogenesis inhibitors including VEGF tyrosine kinase inhibitors. In collaboration with Dr. Alessandro Olivi's lab orthotopic model of glioblastoma is also being used to test new combinations of therapeutic agents.
Our lab is also interested on intrathecal administration of cytostatic agents and angiogenesis inhibitors (i.e.matrix metalloproteinase inhibitors) as a novel therapeutic approach for neoplastic meningitis in a rabbit model (Dr. Grossman's lab).
The goal of these projects is to translate the laboratory data into clinical trials.
Participation to these research projects will allow fellows to contribute and develop expertise in tumor biology and preclinical drug testing.
Participating Laboratories at the National Institutes of Health
Clinical, translational, and basic science research opportunities at the NIH are enormous. There are literally hundreds of laboratories within the National Cancer Institute devoted to basic and applied research in cancer related topics and nearly as many research initiatives in neuroscience, many with relevance to neuro?oncology, within the National Institutes of Neurologic Disorder and Stroke. The trainee will be encourage to spend the first couple of months meeting as many principle investigators as possible and discovering, under the mentorship of his/her research advisor, which research environment and which physician/scientist offers the best potential training experience for the trainees intended career in neuro-oncology. Since research at the NIH is not grant dependent, investigators tend to be open to new initiatives and ideas thereby leading to significant opportunities for designing truly individualized research training programs.
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