Toxic compounds targeted to lung tumor blood vessels
Abstracts
Initial Award Abstract |
|
Scientists have long thought that body organs and their blood vessels might have molecular differences resembling an "area code" system. Our group found a new way of looking for compounds that can home to individual normal organs or tumors through the blood stream and discovered a system of "addresses" in the blood vessels. Every organ we have examined has turned out to put a signature on its blood vessels that our compounds can use as a homing signal Thus, we can design molecular drones that use the address system to home to the intended target organ and can reconnoiter the organ for signs of disease such as cancer. The compounds can also be designed in such a way that they deliver a drug into the target organ. We have already developed precision drugs that can target overt cancers. A tumor cannot get larger than 1/250 inches in diameter, without attracting blood vessels to nurture it. These new blood vessels are different from normal blood vessels, and we can make use of these differences in targeting anti-cancer drugs into cancers (so far we have only worked with cancers grown in mice). We would now like to study the possibility of extending the targeting to lung cancer.
Lung cancer is the most common malignant tumor in the world. In the United States, it is the leading cause of cancer death in men and women. Surgery, chemotherapy, and radiotherapy are commonly used for lung cancer but, overall, only 13% of the patients who develop this disease survive 5 years. New and improved treatments are clearly needed. We hope to develop methods of delivering precision drugs into lung cancer.
We propose to utilize compounds that have the ability to home into the blood vessels that feed the lung cancer and allow its growth. This way, we are able to guide toxic drugs to the tumor while sparing normal tissue. We have demonstrated that this approach is possible with the anticancer drug doxorubicin by treating mice with breast cancer. Doxorubicin is only used to relieve symptoms in patients with disseminated lung cancer. Therefore, we will attempt to use our compounds to guide an experimental drug-dolastatin 10-to lung cancer blood vessels. Dolastatin l0 is an exceptionally potent natural compound extracted from a shell-less marine mollusk (sea hare) found in the Indian Ocean. To our knowledge, it is the most active anticancer substance currently known. Thus, dolastatin 10 is clearly a promising drug but it is also very toxic to bone marrow, which limits its use in patients. We hope that, by guiding dolastatin 10 directly to the blood vessels that nourish the lung cancer, we may make it into an improved and perhaps curative, form of targeted anticancer treatment. |
Final Report |
|
Scientists have long thought that body organs and their blood vessels might have molecular differences resembling an "area code" system. Our group found a new way of looking for probes that can home to individual normal organs or tumors through the blood stream and discovered a system of "addresses" in the blood vessels. Every organ we have examined has turned out to put a signature on its blood vessels that our probes can use as a homing signal. Thus, we can design molecular drones that use the address system to home to the intended target organ and can reconnoiter the organ for signs of disease such as cancer. The probes can also be designed in such a way that they deliver a drug into the target organ. We have already developed precision drugs that can target overt cancers. A tumor cannot grow larger than 1/250 inches in diameter, without attracting blood vessels to nurture it. All tumors, including lung cancers, depend on this new blood supply. The new blood vessels in tumors are different from normal blood vessels, and we have made use of those differences to develop probes that home into the tumor blood vessels, but ignore normal blood vessels.
We utilize our homing probes to guide toxic drugs to the tumor while sparing normal tissue. We have demonstrated that this approach is possible with the anticancer drug doxorubicin by treating mice with breast cancer (so far we have only worked with cancers grown in mice). Doxorubicin is, at best, palliative in patients with disseminated lung cancer. Our aim, therefore, was to try to use our probes to guide a more potent drug to lung cancer blood vessels. We were also hoping that the compound would be easier to make than our targeted doxorubicin compounds. We also hope that one of the new compounds will prove to be an improved (perhaps curative) form of targeted anticancer therapy.
We have been very successful in the first part of the project. It resulted in the design of targeted anti-cancer compounds based on a new principle, and that are, indeed, easier to make than our earlier targeted drugs. The principle is to use a peptide (a short piece of protein) that upon entering a cell, causes the cell to die. We designed this peptide so that it could only enter a cell when it is connected with the homing probe (also a peptide, but quite different from the "killer" peptide). As a result, the new compound kills only cells targeted by the homing peptide--tumor vasculature. Our initial experiments in treating tumor mice have been promising, and we have described the principle and the treatment results in a paper that appeared in Nature Medicine 5: 1032 (1999). We will next optimize the killer peptide component to reduce its non-selective toxicity (which is considerable) and then test the new compounds for their efficacy in lung cancer models. |
Publications
| Anti-cancer activity of target pro-apoptotic peptides |
| Periodical: Nature Medicine |
Index Medicus: |
| Authors: Ellerby HM, Arap W, Ellerby LM, et al |
ART |
| Yr: 1999 |
Vol: 5 |
Nbr: |
Abs: |
Pg: 1032-1038 |
| Anti-cancer activity of target pro-apoptotic peptides |
| Periodical: Nature Medicine |
Index Medicus: |
| Authors: Ellerby HM, Arap W, Ellerby LM, et al |
ART |
| Yr: 1999 |
Vol: 5 |
Nbr: |
Abs: |
Pg: 1032-1038 |
