Effect of PDGF inhibition on angiogenesis in lung cancer
Initial Award Abstract
Smoking accounts for most cases of lung cancer. An estimated 170,000 new cases of lung cancer are diagnosed each year. The need for novel treatments for lung cancer is shown by the continuing high mortality, with nearly 60% of patients dying within one year of initial diagnosis. One novel approach to treating lung cancer is the use of drugs that stop the growth of new blood vessels. Like normal organs, tumors depend on their blood supply for survival. New blood vessels must form for tumors to grow. The formation of blood vessels (angiogenesis) in tumors is regulated by substances such as vascular endothelial growth factor (VEGF) and platelet derived growth factor-B (PDGF-B) that are released within tumors. VEGF is essential for growth and survival of endothelial cells that line blood vessels, and PDGF-B is essential for the survival of pericytes, which surround endothelial cells and constitute the second of the two types of cells that form the walls of blood vessels in tumors.
Drugs that inhibit VEGF can stop angiogenesis and even cause regression of blood vessels in certain tumors. Consequently these inhibitors are a promising recent addition to drugs used in treating cancer. One VEGF inhibitor has been approved for clinical use, and many others are in clinical trials. However, little is known about the action of PDGF-B inhibitors because these agents were not available until recently. There is indirect evidence suggesting that inhibitors of PDGF-B could inhibit angiogenesis. There is also evidence that PDGF-B inhibitors complement the action of other anti-cancer drugs, but the mechanism of the benefit is unclear.
Data from our pilot experiments show that PDGF-B inhibitors can reduce the number of pericytes and the number of blood vessels in a lung cancer model in mice. Pericytes began to regress after only 1 day of treatment. Endothelial cells of some tumor blood vessels regressed a few days later, suggesting that loss of pericytes resulted in the loss of endothelial cells and the blood vessels they lined. Two novel inhibitors of PDGF-B were used to obtain these results. Both had the same effect. Neither had been used previously in studies of lung cancer.
The experiments described in this application will extend our preliminary results with the goal of developing a more complete understanding of the role of PDGF-B in maintaining the vasculature of lung cancer. We will examine the cellular effects of selective PDGF-B inhibitors on tumor vessels, with a particular focus on pericytes, in three different models of lung cancer in mice.
By understanding the action of PDGF-B inhibitors on tumors, the potential usefulness of these agents in lung cancer can be better assessed. Our finding of the potent action of PDGF-B inhibitors on pericytes in tumors has promising implications because many blood vessels in tumors are left without these cells. This change may reflect a greater vulnerability of pericyte-free tumor vessels to other anti-cancer drugs. Further supportive data from the planned experiments would add to the rationale for using PDGF-B inhibitors in the treatment of lung cancer. |
|Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of PDGF-B by selective aptamer AX102.
|Periodical: Cancer Research
|Authors: Sennino B, Falcon BL, McCauley D, Le T, McCauley T, Kurz JC, Haskell A, Epstein DM, Mc Don