Angiogenesis Inhibitors -- New Approach to Cancer, KS Treatments. Interview with Donald Ingber, M. D., Ph.D., Harvard Me

An entirely new kind of cancer treatment has been successful in animal tests and is now being prepared for human trials. This new class of drugs works by blocking angiogenesis -- the growth of blood vessels which tumors need to nourish themselves. These drugs may be useful against most if not all solid tumors, whether AIDS-related or not -- and also against Kaposi's sarcoma (KS).

The two leading drugs of this class are (1) AGM-1470, being developed by Donald Ingber, M. D., Ph.D., and Judah Folkman, M. D., at Harvard Medical School, working with scientists at Takeda Chemical Industries, Ltd., in Osaka, Japan, and (2) SP-PG, developed by Daiichi Pharmaceutical Co., Ltd., in Tokyo, and tested for KS in animals by Robert Gallo, M. D., and others at the U. S. National Cancer Institute. In addition, several major U. S. pharmaceutical companies are developing other anti- angiogenesis drugs. This article will look at AGM-1470 as an example of this new class of potential cancer and KS treatments.

Background -- Angiogenesis in Cancer and KS

"Angiogenesis" means growth of new blood vessels. Cancers which form solid tumors must be able to turn on the body's machinery to grow new blood vessels, or else the tumor cannot nourish itself and therefore cannot grow to more than about one cubic millimeter in size -- usually too small to be harmful.

Angiogenesis not only allows solid tumors to grow, it also makes them more dangerous because they are more likely to metastasize -- spread elsewhere in the body through the bloodstream. The new blood vessels in the tumor increase the chance of cancer cells getting into the blood, especially since the tumor's blood vessels are often imperfectly formed. A recent study reported that human breast cancers which became metastatic had many more blood vessels than those which did not (1).

In normal adults, new blood vessel growth occurs only in wound healing and other special situations. If a drug could stop new blood vessels from forming, it could be taken for life to stop further growth of existing tumors -- with short interruptions when necessary for wound healing.

What about Kaposi's sarcoma? Although this disease is often called a cancer, it is usually not a true malignancy. Instead, KS lesions are caused by abnormal growth of blood vessels (in other words, angiogenesis). So a drug which stopped this growth should be useful as a KS treatment, as well as a cancer treatment.

Why do the blood vessels grow when they should not? The cause seems to be a disorder of chemicals called growth factors, chemicals which serve as messengers between cells, and can act in very small amounts to affect cell growth. In KS, certain cells seem to be transformed so that they produce abnormal growth factors, causing blood-vessel growth and producing the KS lesions. In cancer, the tumor cells produce growth factors which cause the new blood-vessel growth, which nourishes the tumor. (Not all tumors can produce the growth factors which cause blood-vessel growth, but those which cannot usually do not cause problems, and are seldom noticed.)

Almost every cell in the human body contains all the body's genes -- including, for example, the genes required for the various steps of the process of growing new blood vessels. Fortunately, most of the genes are turned off most of the time. Scientists are intensely interested in understanding what regulates the genes, but so far most of the answers are not known. Today there is great interest in growth factors -- about 100 are known so far -- because they have major effects in regulating (or disregulating) cells.

Blood-vessel growth is caused by activities of the endothelial cells which line the blood vessels; it is a complex process requiring a number of steps. The abnormal blood vessels seen in cancer consist of normal endothelial cells (which remain normal, although they have malfunctioned because of abnormally high levels of growth factors).

AGM-1470 does not appear to affect the growth factors themselves. Nor does it attack all growing cells, as cancer chemotherapy does. Instead, AGM-1470 acts on normal endothelial cells to prevent new blood vessels from starting to grow, and on growing vessels to inhibit their further expansion.

Angiogenesis and AGM-1470

Angiogenesis was first proposed as a target for cancer drugs in the early 1970s by Judah Folkman, M. D., of Harvard Medical School. The idea first met with disbelief and skepticism, probably because it is so different from other approaches for treating cancer. And in the beginning, there was no way to develop anti-angiogenesis drugs, because no one knew how to test potential drugs for their effect on blood-vessel growth. Dr. Folkman first had to learn how to culture blood vessels, and then needed to develop practical assays (tests) for the activity of candidate drugs.

The discovery of AGM-1470 started with a laboratory accident. Dr. Ingber (see interview below) was culturing capillary endothelial cells when one dish became contaminated with a fungus. Dr. Ingber noticed that the fungus produced a substance which induced cell rounding, which his previous work showed was associated with inhibition of capillary growth. Further research showed that this substance was fumagillin, a drug developed in the 1950s for treating amebas and other intestinal parasites, but largely abandoned today. (It is not used in the United States, but may still be used as a medicine in a few countries.)

Use of Dr. Folkman's assays confirmed that fumagillin could inhibit angiogenesis. However, animal tests showed that this drug was not promising as a cancer treatment, because the doses required were toxic; animals lost weight and the drug had to be discontinued. Drs. Ingber and Folkman then began working with Takeda Chemical Industries, which had the facilities to synthesize hundreds of chemical variants of fumagillin for further testing. The best fumagillin analog to emerge from this process was AGM-1470.

AGM-1470 has been found effective against a number of solid mouse tumors, including breast cancer, colon cancer, and melanoma; against tumors in three different animal species -- mice, rats, and rabbits; and also against human tumors implanted into immune-deficient mice. It has worked against every solid tumor tested so far. The cancers do not disappear, but they stop growing, and metastasis is greatly suppressed. Studies are now underway to determine if AGM-1470 could be combined with conventional cancer treatments; the latter would shrink the tumors, while AGM-1470 would prevent further growth.

In the animal tests so far, little or no toxicity has been seen. In contrast to fumagillin, AGM-1470 allows animals to gain weight, even while the tumors are shrinking.

One advantage of AGM-1470 and other anti-angiogenesis drugs is that there is no problem with the blood-brain barrier, with tissue absorption, or with any other barrier to getting the drug to the site of action. Since these drugs act at the endothelial cells which line the blood vessels, they only need get into the bloodstream (e.g. by injection) to be delivered directly to their site of action everywhere in the body.

Also, for reasons explained in the interview below, drug resistance would not be expected to be a serious problem with this class of drugs, as it is with cancer chemotherapy. No drug resistance to AGM-1470 has yet been found; more exacting tests are now ongoing to see if any may exist.

A technical article by Dr. Ingber, Dr. Folkman, and others was published last December (2), and an article by Takeda scientists was published in February 1991 (3). The U. S. press has largely missed this story of angiogenesis inhibitors as cancer treatments. AIDS TREATMENT NEWS mentioned Dr. Ingber's work briefly, in a section on anti-angiogenesis research in Michelle Roland's special issue on KS (issue #122, March 1, 1991). We hope that this article, and the interview below, will help alert the press and the public to a major emerging development in the treatment of both KS and cancer.

References

1. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis -- correlation in invasive breast carcinoma. New England Journal of Medicine. January 3,1991; volume 324, number 1, pages 1-8.

2. Ingber D, Fujita T, Kishimoto S, and others. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature. December 6, 1990; volume 348, pages 555- 557.

3. Kusaka M, Sudo K, Fujita T, and others. Potent anti- angiogenetic action of AGM-1470: Comparison to the fumagillin parent. Biochemical and Biophysical Research Communications. February 14, 1991; volume 174, number 3, pages 1070-1076.