Southwestern In Vivo Cellular and Molecular Imaging Program

Project 3
Novel and Integrated Approach to Clinical Assessment of Brain Tumor Development and Response to Therapy

Investigators and Areas of Expertise:

Karen L. Fink, M.D. Ph.D., an Assistant Professor of Neurology is Director of the Neuro-Oncology Service. She has an active clinical practice and serves as a referral practice for patients with primary brain tumors in the North Texas region. She participates in the North American Brain Tumor Consortium (NABTC) and provides multiple investigational therapies to patients with newly diagnosed and recurrent malignant brain tumors. James Fleckenstein, M.D. is Professor of Radiology, and has experience with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) imaging of primary central nervous system malignancies. Zerrin Yetkin, M.D. is a neuroradiologist with extensive experience in fMRI. Dana Mathews, M.D. Ph.D. is an Associate Professor of Radiology, and has expertise in the area of nuclear medicine imaging of brain tumors. Orhan K. Öz, M.D., Ph.D., is an Assistant Professor of Radiology with expertise in the application of nuclear imaging techniques of tumors.

Hypothesis and Specific Aims:

Background and Significance:

Despite more than thirty years of research developing interventional strategies for treating patients with malignant brain tumors, survival of patients treated with conventional radiation and cytotoxic chemotherapy remains disappointingly short. New therapeutic strategies are undergoing clinical trials, including anti-angiogenesis and cytokine down-regulators, which might be expected to be cytostatic rather than cytotoxic. With the development of these non-cytotoxic therapies, there is a need for imaging techniques that are more sensitive to tissue changes than the typical contrast MRI scan. Traditional contrast-enhanced MRI demonstrates changes in the size of the enhancing portion of the tumor, but does not provide information about metabolism or the proliferative activity within the tumor. With the new cytostatic approaches to brain tumor therapy, it is important to more directly assess changes in tumor blood flow, metabolism, and proliferation. A variety of imaging techniques have been developed over the last five years that are applicable to the clinical care of patients with brain tumors. This project will explore the applicability of these imaging techniques for patients undergoing treatment with new non-cytotoxic agents.

New imaging techniques measure parameters that go beyond water proton signal density. These techniques include MR spectroscopy (MRS), which can qualitatively and semi-quantitatively characterize tumor metabolites; MR sequences such as blood oxygen level dependent (BOLD) to assess oxygenation, flow sensitive alternating inversion recovery (FAIR) for cerebral blood flow; and positron emission tomography (PET) imaging of tumor metabolism or proliferation. This project will use these new imaging techniques to assess patients with brain tumors, who are undergoing treatment with agents that are expected to be cytostatic to assess which imaging techniques are best able to predict the outcome of treatment with these agents, when used in conjunction with traditional MRI.

All of these techniques can be used to evaluate an important determinant of tumor growth, angiogenesis. For over 20 years, it has been recognized that malignant gliomas are well-vascularized tumors. Endothelial proliferation is so frequently found within and adjacent to high grade gliomas that it is one of the pathologic criteria for grading these tumors. The obvious conclusion is that high grade gliomas must stimulate the proliferation of endothelial cells and generate new blood vessels to support their growth. Direct evidence of the angiogenic potential of gliomas was supplied by Brem, who demonstrated that human gliomas transplanted into rabbit cornea elicit intense neovascularization, and by Folkman et al who demonstrated that glioblastoma cells are the most potent of all stimulators of angiogenesis in a chorioallantoic membrane assay. Some of the molecular mechanisms underlying brain tumor mediated angiogenesis include over-expression of basic fibroblastic growth factor (bFGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and the epidermal growth factor receptor. These have all been found to be highly over-expressed in astrocytomas. New agents have been developed to circumvent this vascular recruitment by malignant gliomas, and a few of these are being tested in humans.

SU5416 is one such putative angiogenesis inhibitor. It is a small molecule that specifically and selectively binds to, and inhibits, the vascular endothelial growth factor (VEGF) tyrosine kinase receptor, Flk-1. SU5416 inhibits Flk-1 autophosphorylation, and thus, VEGF-induced endothelial proliferation. SU5416 inhibits a variety of human xenographic tumors such as melanoma, lung, prostate, fibrosarcomas and gliomas in immunodeficient animals. SU5416 is being evaluated in patients with recurrent malignant gliomas as part of a North American Brain Tumor Consortium (NABTC) trial that will include patients from UTSWMC. Thalidomide is a commercially available agent that inhibits the angiogenic activity of bFGF, and is active in patients with recurrent gliomas. Patients receiving treatment with either of these anti-angiogenic therapies will be asked to participate in this multi-modality imaging protocol. This will allow the assessment of regression or stasis in blood flow and changes in tumor metabolism or proliferation that might be expected following treatment with angiogenesis inhibitors. As additional cytostatic agents are incorporated into clinical trials, patients will also be offered the opportunity to participate in this multi-modality imaging project.

For Further Information Contact: RALPH  P. MASON, Ph.D.
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