Lung cancer is the leading cause of cancer deaths with over 200,000 new cases in the United States alone. Over 80% of these cases can be contributed to tobacco smoke. Lung cancer is 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 targeted agents are designed to interact directly with the tumor cells. Though these work very well in the lab, they usually fail when used in human patients. This is probably because targeted drugs that are injected into the blood cannot reach the tumor cells because movement from the blood into the tissue is prevented by a thin lining of cells on the inner surface of blood vessels called the endothelium.
Instead of searching for more targets on tumor cells, we have shifted focus to find targets that are expressed on the endothelium. The endothelium is specially adapted to support the tissue around it. Different tissues have different needs. To fulfill those distinct needs, each type of tissue appears to express a unique set of proteins that are not found elsewhere. Healthy lung is distinct from other organs and from lung tumors. When these proteins stick out into the blood, they can directly bind targeted agents that been intravenously injected. We have shown that when antibodies are targeted against proteins found in the blood vessels of normal lung tissue, they bind only to blood vessels in the lung. Surprisingly, if these agents bind within special domains of the endothelium called caveolae, they are rapidly pumped out of the blood, across the endothelium, and concentrated in the tissue. 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.
Here, we propose using targeted antibodies to see if we can image and treat lung tumors. Instead of the tumor being treated as a “black box” that develops deep inside the body, we will use intravital microscopy to image tumor development in real time. We will image the development of tumors over time and closely follow what happens to antibodies once they reach the tumors. Where do they go? Are they broken down? How long do they stay in the tissue? From there, we will determine the safety and effectiveness of targeted radioactive antibodies against tumors. We can see if and when blood flow stops in the tumor and if, when and how the tumor cells die. We will then test several different types of radiation to see which is the most effective at destroying tumor cells without hurting healthy tissue. If we can successfully target tumors and destroy them without harming normal tissues, then a clinical trial for lung tumor therapy will be warranted as the next phase of this project.
Targeting antibodies against the endothelium and caveolae is a novel pathway to rapidly pump drugs out of the blood and into tissue. Because human tumors have the same specific proteins that we see in other organisms, it is highly likely that these same pathways can be targeted in humans and used to create more effective treatments. |