PROGNOSTIC RADIOLOGY AND THE PATHOPHYSIOLOGY OF TUMORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this research is to gain a comprehensive understanding of tumor physiology as related to tumor growth, development and response to therapy. A number of nonNMR approaches such as optical techniques are under development, However, we continue to pursue our MRI efforts related to measurement of oxygen tension and enzyme activation. Specifically, we will develop, demonstrate, and evaluate a novel approach to assessing tumor oxygenation with a view to rapid translation to the clinic. We believe it will be most pertinent to high dose hypofractionated radiotherapy in diseases such as prostate cancer. DOCENT (Dynamic Oxygen Challenge Evaluated by NMR T1 and T2*) exploits BOLD (blood oxygen level dependent) and TOLD (tissue oxygen level dependent) contrast to non-invasively detect changes in tumor oxygenation using proton MRI. We propose to develop DOCENT as a robust prognostic test to reveal tumor hypoxia. While the investigations proposed here are entirely pre-clinical, we believe they will demonstrate a strong rationale for rapid implementation in patients. Aim 1 will rigorously demonstrate the ability of DOCENT to categorize tumors as hypoxic (resistant or responsive) or oxic by comparison with 19F MR oximetry. Aim 2 will examine whether DOCENT does indeed predict response to hypofractionated radiation in subcutaneously growing prostate tumors. Aim 3 will extend studies to orthotopic prostate tumors. Aim 4 will seek to overcome therapeutic resistance of hypoxic tumors by including a radiation boost. This project responds to conclusions of a recent NCI-sponsored workshop to assess the current status of hypoxia imaging. There was consensus that a robust practical method is needed to identify patients with hypoxic tumors. Requisite criteria relate to invasiveness, radiation exposure, resolution, safety, and time to potential clinical implementation. A BOLD approach was considered to be particularly practical and the addition of the TOLD assessment can make it even more useful. Targeting the vasculature of tumors promises a new effective therapy for prostate cancer. We propose a new approach targeting the blood vessels in the tumor. Specifically, a novel antibody 3G4, which targets phosphatidylserine (PS) expressed on tumor vasculature was developed by Thorpe et al. and is being developed by Peregrine Pharmaceuticals for clinical trials. Normally, PS exclusively resides on the cytosolic leaflet of the plasma membrane. However, in tumors PS becomes externalized and provides a viable target. The agent not only targets various tumors, but also induces vascular damage and tumor regression with minimal accompanying toxicity. In developing a new therapy, critical issues include scheduling, optimal combination with other interventions to achieve synergy and early assessment of efficacy. Magnetic resonance imaging allows us to follow the induction and development of tumor vascular damage providing new insight into spatial and temporal activity and facilitating effective combination with the hypoxic cell selective cytotoxin tirapazamine. Importantly, this therapy may be effective at any stage of tumor development, and could be most effective for advanced disease. Success will confirm the potential of this new therapeutic approach to prostate cancer in man and lay the foundation for future clinical trials.