NATURE MEDICINE EMBARGO for 2 p.m. EDT Sunday, August 18,2002
Moores UCSD Cancer Center Researchers
Identify Potent Angiogenesis Inhibitor
Researchers with the Rebecca and John Moores UCSD Cancer Center have identified a potent angiogenesis inhibitor, a naturally occurring hormone called parathyroid hormone-related peptide (PTHrP), which is produced in great quantities by some cancers.
Angiogenesis, the process by which the body forms new blood vessels, is essential to the growth and spread (metastasis) of cancer. The new blood vessels feed the cancer cells with oxygen and nutrients, allowing these cells to grow, invade nearby tissue, spread to other parts of the body, and form new colonies of cancer cells. Angiogenesis also plays a role in rheumatoid arthritis, psoriasis and some eye diseases; and in normal processes such as wound healing and ovulation.
In the study published online August 19 by the journal Nature Medicine, the researchers show that PTHrP inhibits endothelial cell migration, angiogenesis and tumor formation. More importantly, they have identified the way it works, which is by activating protein kinase A (PKA). Protein kinases are regulatory proteins that are responsible for cellular activities such as cell proliferation and migration.
Senior author Judith Varner, Ph.D. (center), with two co-authors from her laboratory, Manjiri Bakre, Ph.D., and staff research associate Yuhong Zhu.
"We've identified a key kinase that, when activated, causes endothelial cells to commit suicide," said the paper's senior author Judith Varner, Ph.D., assistant adjunct professor of medicine with UCSD School of Medicine and member of the Moores UCSD Cancer Center. "But it only causes suicide in endothelial cells that are activated by tumors and other disease states. This mechanism doesn't become activated in normal blood vessels."
Understanding the underlying mechanism is important, Varner says, because it provides a road map that may lead to the development of new drug or gene therapies. In this paper, the researchers tested various methods of local delivery of PTHrP and PKA activation by drug or gene therapy to inhibit angiogenesis.
"We can activate PKA with a common drug called cyclic AMP, and we can also activate it through gene therapy," she said. "We are vigorously pursuing a gene therapy approach and possibly a drug therapy here, at UCSD."
The next step will be to develop a chemically synthesized particle or agent that will deliver the gene or drug only into proliferating endothelial cells. To do so, the researchers must target a receptor expressed only on proliferating endothelial cells and not in large quantities on normal, existing endothelial cells. To that end, Varner is working with a team of UCSD radiologists to develop a bioconjugate, also called a micro- or nano-particle.
"It may sound strange to be working with radiologists on gene therapy," Varner said. "But the same kinds of particles or bioconjugates used for imaging can be used to deliver a gene. You create a micro-particle, attach to it a molecule that will bind to a receptor on the target cell, and use it to deliver DNA directly into that cell. This is an emerging technology in gene therapy and in imaging."
In other work, Varner is collaborating with the same radiology team to develop a cancer-imaging agent designed to find and highlight tiny new tumors and allow clinicians to see metastases.
Besides Varner, co-authors are Manjiri Bakre, Ph.D., staff research associates Yuhong Zhu and Hong Yin, all of Moores UCSD Cancer Center; Doug W. Burton, research specialist with the San Diego Veterans Affairs Healthcare System; and Leonard J. Deftos, M.D., and Robert Terkeltaub, Ph.D., both of the UCSD Department of Medicine and the San Diego Veterans Affairs Healthcare System.
This work was supported by grants from the National Cancer Institute.
For further information about angiogenesis, visit the National Cancer Institute's website:http://newscenter.cancer.gov/sciencebehind/angiogenesis/angio01.htm
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