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Fusion proteins that convert VEGF into a cell death factor

Institution: University of California, San Francisco
Investigator(s): Timothy Quinn, M.D.
Award Cycle: 2007 (Cycle 16) Grant #: 16IT-0009 Award: $100,000
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
Each year lung cancer, primarily due to cigarette smoking, kills more Americans than breast cancer, colon cancer, and prostate cancer combined. It has long been hoped that a deeper understanding of the cellular and molecular abnormalities that cause lung cancer will yield new highly effective targeted therapies.

In the past decade scientists have found that lung cancers, and in fact all solid tumors, can grow only if they stimulate the formation of new blood vessels to supply oxygen to the growing tumor, a process called tumor angiogenesis. This discovery has led to new therapies that block tumor angiogenesis in an attempt to “starve” the tumor. One such anti-angiogenic drug that has received much attention blocks the activity of a protein called VEGF. Lung tumors oversecrete VEGF, which stimulates the growth of blood vessels that supply the tumor and allow it to grow. An antibody drug that inactivates VEGF was tested in lung cancer patients, in addition to conventional chemotherapy, and was found to increase survival by two months. This small increase was understandably considered a breakthrough because many other experimental drugs have failed to show any survival benefit. But increased survival of two months – only 60 days – is obviously far short of the hopes of scientists, patients, and their families. Furthermore, the drug only benefited men, not women. There are other drugs being investigated that also block VEGF. While it is possible that one of those other VEGF-blocking agents might work spectacularly better, it is probably more likely that they will produce roughly similar results, if they work at all.

We believe a new approach to exploit the overproduction of VEGF by lung cancers should be investigated. Rather than trying to block VEGF, is it possible to create a non-toxic drug that is activated by VEGF to become a cell-killing drug? Such a drug might be able to selectively kill lung cancer cells because the concentration of VEGF is high within lung cancers. This concept has not previously been investigated.

We created a drug – an artificial protein we call R1FasL – that sticks to VEGF. Preliminary tests using cells in culture show that the R1FasL protein is not toxic in the absence of VEGF. But in the presence of VEGF, as would be found within a lung cancer, the R1FasL protein becomes activated and turns into a cell death factor. We have tested the R1FasL protein on brain cancer cells grown in culture that oversecrete VEGF. Treatment with R1FasL killed the brain cancer cells, and other experiments confirmed that the cells were killed specifically because they oversecrete VEGF. We believe that R1FasL, or a modified version of it, may provide a novel way to turn a lung cancer’s weapon – oversecreted VEGF – against the cancer itself.

The work we propose will have several goals. First, we will create a second artificial protein we call R1TRAIL that might function even better than R1FasL. Second, we will determine if R1FasL or R1TRAIL kills lung cancer cells grown in culture, and determine if the killing activity is enhanced by combining with chemotherapy drugs. Third, we will determine if R1FasL and R1TRAIL are safe when given intravenously to normal mice, as a prelude to future tests in mouse cancer models.

We believe these studies can be performed in a one-year timeline because we have already produced the R1FasL protein drug. It should be possible to quickly determine whether or not this new approach to targeting VEGF shows potential for development into a new therapy for lung cancer.