DF/HCC Program Affiliation

Cancer Imaging

Research Abstract

Cancer Imaging and Experimental Therapeutics

While 40% of my time is devoted to clinical/teaching activities, I have been fortunate to be able to continue expanding the body of research based upon my previous work. My research focuses on developing strategies for delivery of bioactive therapeutic peptides into tumors. As an MRC Scholar, I studied liver tumor physiology and identified a peritumoral fibrin lattice from which angiogenic vessels arise. These fibrin neoreceptors exposed during tumor growth are a unique site for inhibiting intrahepatic tumor spread. My PhD thesis described a rapid clinical assay for measuring and distinguishing the naturally occurring fibrinolytic (D-dimer) and fibrinogenolytic fragments present in human serum. I showed that patients who develop angina at rest have active clot formation in their coronary arteries. This project was responsible for patients with unstable angina receiving immediate thrombolytic therapy to prevent progression to myocardial infarction. Modifications of this D-dimer assay are now in general clinical use as a rapid screening assay for deep vein thrombosis.

I have explored strategies for the targeted delivery of molecules into liver tumors and developed an isolated rat liver model for modulating intrahepatic perfusion to study liver blood flow, tumor kinetics and protein and drug metabolism. Along with Anders Lunderquist MD, I developed a video microscopic technique for directly visualizing microvascular perfusion in exteriorized tumor-bearing livers, and modified a mouse model of hepatic colon cancer metastases to study tumor microperfusion and to measure the biodistribution of fluorescent vectors in tumors; this has allowed us to gain essential information concerning localization of drug-carrying vectors in tumor microvasculature. We studied mechanisms with which colon cancer cells adhere, implant and grow in the liver, and demonstrated that differences in metastatic potential depend on local activation of sinusoidal cells. We identified specific phagocytic and surface receptor sites on these cells which are now used for targeting human tumors. We studied pharmacologic manipulations of intrahepatic blood perfusion and showed that reduced sinusoidal perfusion and intrahepatic shunting result from increased sinusoidal sphincter tone. This data was the first to show specific intrahepatic flow alterations produced by halothane, and is now in clinical use for diverting flow away from tumors during percutaneous tumor ablations.

In studies comparing vector delivery routes, we showed that intraarterial delivery is more efficient than IV, intraportal and direct interstitial injection. We have optimized dispersion sizes and composition to achieve maximal delivery of ethiodized oil mixtures and sterically-stabilized liposomes into tumor neovessels and interstitium. These results have been applied to lipid vector preparations when embolizing liver tumors in patients. We demonstrated that liposomes delivered into tumor cytoplasm retain aqueous fluorescent activity, preserving essential molecular activity throughout delivery. Using electron and fluorescence microscopy of exteriorized tumor-bearing livers, we identified 3 novel physiological targets: tumor-recruited macrophages, activated peritumoral endothelial cell receptors and neoendothelial permeability, and provided a physiological explanation for reduced hepatic perfusion prior to development of metastases (Roscoe Miller Award, 1999). We showed enhanced cancer cell retention of Daunomycin under hypoxic conditions, providing a scientific rationale for embolizing tumors following delivery of chemotherapeutic agents. To optimize vector delivery, we documented a changing portal and arterial blood supply with tumor growth, and described the precise growth stage and site of origin of angiogenic activity.

Currently, I am exploring methods for gene delivery and targeting angiogenic receptors. I received the RSNA Scholars Award to perform these studies, a summary of which received a Magna Cum Laude Award at the

Publications

No representative citations available.