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Proteomic Mapping of Human Lung Tumor Endothelium

Institution: Proteomics Research Institute for Systems Medicine
Investigator(s): Jan Schnitzer, M.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20XT-0161 Award: $487,182
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Lung cancer is the leading cause of cancer deaths with over 200,000 new cases in the United States alone. Most lung cancer therapies are highly invasive (surgery), globally toxic (chemotherapy), and/or destructive (radiation). Lung cancer is most commonly treated with a combination of radiation and chemotherapeutic drugs. This intensive treatment has severe side effects which limit the length of treatments as well as how much drug can be given. For many patients, this intensive treatment is effective, at least at first. However, if any of the cancer cells survive this initial onslaught, they can mutate and become drug-resistant. Once the cancer reappears, it is very difficult to treat. In fact, less that 15% of patients survive for more than five years after diagnosis of lung cancer. Clearly, we need more effective treatments.

One way to overcome many of the problems associated with the treatment of lung cancer is to target drugs specifically to the tumor itself. This can increase the amount of drug that gets to the tumor because it is not spread throughout the entire body and can kill tumor cells more effectively, thus reducing the chance of cancer cells becoming drug-resistant. Targeted delivery can also reduce side effects by concentrating drug in the tumor, which limits exposure elsewhere and reduces systemic side effects. Most therapies are injected into the blood and must penetrate into the tumors to be effective. Though these therapies work very well in the lab, they usually fail when used in human patients. Tumor access is largely prevented by a thin lining of cells on the inner surface of blood vessels called the endothelium that act as a barrier between blood and tissue.

Instead of searching for more targets on tumor cells, we have shifted focus to find targets that are expressed on the endothelium. We have shown that the endothelium is specially adapted to support the tissue around it. Each type of tissue appears to express a unique set of proteins that are not found elsewhere. In the rat, healthy lung is distinct from other organs and from lung tumors. Thus, proteins that are induced in tumors can act as biomarkers to diagnose disease.

Some of these tumor-induced biomarkers will stick out into the blood where they can directly bind targeted agents that been intravenously injected. We have discovered that when radioactive agents are targeted against proteins that are only found in tumor blood vessels, they bind to the tumor blood vessels and can effectively destroy solid tumors within days of treatment without damaging the surrounding healthy tissue. Thus, identifying and validating these key proteins is the first step in developing safer, more effective therapies.

We have spent years optimizing all the techniques needed and overcoming major hurdles using rat models of disease. However, in order to address human disease, we must study human tissue. We hypothesize that blood vessels in human lung tumors will express distinct proteins that are not found in blood vessels in normal human lung. Here, we will use our novel techniques to identify the proteins at the surface of blood vessels from both normal lung and lung tumors. We will then compare lung and lung tumor blood vessels to discover those few proteins that are only found in tumor tissue. We will validate candidate biomarkers and targets using antibodies to assess protein expression in multiple types of lung tumors and human tissue. We expect to generate a detailed map of protein expression in lung tumors and identify novel, tumor-induced biomarkers could provide new ways to diagnose and classify lung tumors. Additionally, these biomarkers may be useful therapeutic targets. Finally, because these targets are likely to be accessible to the blood, they can mediate in vivo tumor targeting. Ultimately, antibodies against tumor-induced, accessible biomarkers could be used to target imaging and therapeutic agents specifically to tumors. This could create safer and more effective ways to diagnose, image, and treat lung cancer. Thus, this work clearly impacts TRDRPs Lung Cancer priority issue and could have tremendous impact for patients with lung cancer.