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Anti-Angiogenesis: Starving Tumors

By Sean Henahan, Access Excellence

San Diego, CA (5/6/98)- Researchers have been working for decades to develop treatments for cancer based on blocking tumor blood supply. Now a series of animal and clinical studies suggest this work is starting to pay off.

The creation of new blood vessels, known as angiogenesis, is an essential component of  embryonic development, menstruation and wound repair. It is also a critical element in tumor formation and growth. Cancer cells secrete a number of  angiogenesis factors encouraging new blood vessels to sprout,  providing essential nutrients for a  tumor to grow. Left unchecked, cells inside the tumor will eventually enter the blood stream through the same blood vessels that feed it, spreading around the body in a process known as metastasis.

mouse studyThe most well known researcher in the angiogenesis field is Dr. Judah Folkman. He has been working at Harvard University for 30 years to unlock the secrets of cancer and blood vessel formation. His research began with an investigation of how thalidomide caused birth defects. He determined that the notorious drug appeared to inhibit embryonic blood vessel formation. Reasoning that this kind of agent might prove useful in the fight against cancer, he began studying tumor growth.

His work led to the current excitement generated by the announcement that two genetically engineered proteins, angiostatin and endostatin eliminated tumors in mice. Researchers reported that the proteins eliminated forms of colon, prostate, breast and brain cancers in the animal experiments. Angiostatin is a naturally occurring protein believed to inhibit tumor growth by blocking blood vessel formation. It is related to fibrinogen. Endostatin also appears to block new blood vessel growth in tumors. blocking the metastatic process.

The new proteins will have to be evaluated much more thoroughly before they can be used in human studies. Many potential cancer treatments that looked promising in animal studies have not panned out in the clinic. A series of human studies will be required to first test the safety of the new drugs, then the potential efficacy against cancer. This process will take at least two years.

Clinical Studies Now Underway

A number of  other immunotherapeutic approaches to cancer treatment directed against biological elements of tumor growth and metastasis are already in clinical trials. Early clinical data from some of these trials were presented at the 11th International Conference on Monoclonal Antibodies for Cancer.

"Changes occur early on in the angiogenic process when tumors produce angiogenic cytokines, so attacking something common to the endothelium may offer a new strategy. If we can inhibit the ability of blood vessels to invade tumor, we can eliminate the tumor's ability to access the blood supply as well as perturb its ability to get tumor cells into the circulation," noted David Cheresh, MD, Scripps Research Institute, La Jolla, CA.

Cheresh, who has been involved for many years in the development of anti-integrin antibodies to disrupt tumor angiogenesis, believes the alphaVbeta3 receptor, part of the integrin family, should offer a good target for antiangiogenic therapy.

Cheresh and colleagues at the Sidney Kimmel Cancer Center recently completed a clinical trial of a humanized antibody targeting the alphaVbeta3 integrin receptor. Fifteen patients with late stage, progressive metastatic cancer were treated with the antibody once week for six weeks. Preliminary results showed no toxicity or serious side effects and some patients did respond to the treatment.

"The early results indicate that the antibody treatment is safe and possibly effective when given to right patients. Moreover, we've shown it can be given on a prolonged basis, which is an important consideration with the antiangiogenic approach. As opposed to an anticancer approach, the antiangiogenic approach would have to be administered over a long period of time," said Cheresh.

VEGF

A number of researchers are working on antiangiogenesis approaches that involve inhibition of  vascular endothelial growth factor or VEGF.  Many human tumors overexpress VEGF mRNA, including those involving the CNS, urinary tract, ovaries and endometrium. Animal studies have confirmed that anti-VEGF antibodies do indeed inhibit tumor vascularity and growth.

These observations led to the development of a chimeric humanized antibody targeting VEGF. Clinical studies are now in progress with the anti-VEGF antibody alone and in conjunction with standard chemotherapy regimens

"The early results look promising, with significant reductions in tumor size, and few side effects. Neovascularization is an essential piece in tumorogenic cascade. The idea of blocking angiogenesis has broad application across tumor types. I believe this kind of agent will lend itself to a complementary treatment approach where we might attack the tumor with chemotherapy, and the vasculature with the antibody," said Gwen Fyfe, MD, a researcher at Genentech.

Researchers are also evaluating another monoclonal antibody that targets C225, another receptor associated angiogenesis. In animal studies the C225 antibody decreased tumor growth and increased survival in mice with  renal cell carcinoma. This agent is now being tested in humans, and has been given as a single agent as well as in combination with various chemotherapy regimens, in combination with radiation and as a single agent therapy following surgery.

These studies reflect a growing consensus among cancer researchers that the new generation of immunotherapeutic anti-cancer agents will not replace current treatments, but rather will complement and enhance them.
 


Related information on the Internet
Molecular Biology of Cancer
CNN Video: Expert Reaction
 Early Angiogenesis Cancer Research
 Virtual Embryo
 Antibodies vs. Lymphoma
 Fight Tumors with Tumors

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