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Michigan Oncology Journal Spring 98

Angiogenesis in Cancer

Sofia Merajver, M.D., Ph.D.,
Assistant Professor of Internal Medicine
Director, Breast and Ovarian Risk Evaluation Program

It has been more than 25 years since the initial insight put forth by Dr. Judah Folkman that tumors require new blood vessel growth (angiogenesis) to grow beyond very small lesions (under 1/4 inch). The field of angiogenesis concerns itself with the study not only of tumor-associated vessels but with the origin and remodeling of vessels during development, pregnancy, ovulation, wound repair and processes that require tissue regeneration. Breast cancer provided an important early clinical insight into the workings of angiogenesis. Breast cancer clinicians have recognized that the ability of breast cancer to recur even many years after the original diagnosis and surgery may be due to awakening of the angiogenic capabilities of "dormant" cancer cells. These investigations have led to an increasingly detailed understanding of the molecules and structures involved in angiogenesis. The picture that has emerged is one of a balance between molecules that promote and molecules that impair angiogenesis. As tumors grow and their nutritional needs increase, new blood vessels arise as a consequence of an imbalance between stimulators and inhibitors of angiogenesis. This work is leading to the rapid development of new cancer therapies that address ways to diminish the action of the stimulators of angiogenesis and promote the work of the inhibitors.

Anti-Angiogenesis Therapies
Important substances that impair angiogenesis have been isolated from patients with cancer. Among several examples, angiostatin and endostatin appear to hold promise in anti-tumor therapy. However, these protein drugs are not yet in clinical trials. Their ultimate usefulness in controlling cancer growth still remains unproven, but expectations of success are cautiously high, based on encouraging animal and other laboratory data.

Other avenues of investigation concern the use of antibodies that prevent the action of angiogenesis stimulators by binding to molecules on the surface of blood vessel cells. In this way, these antibodies can block the binding of the stimulators of angiogenesis. One important example in this category is the antibody directed against the receptor for vascular endothelial growth factor (known as anti-VEGF), which is already in clinical trials. Anti-VEGF has been shown to slow down the growth of tumors in several patients, with tolerable side effects. Interestingly, anti-VEGF appears to also help the anti-tumor action of radiotherapy when both modalities are used together. This "cooperation" between treatment modalities is especially hopeful, since it is expected that anti-angiogenesis therapies will be, in general, well tolerated, and thus amenable to combinations with other treatments.

The Role of Copper in Angiogenesis
At the University of Michigan Cancer Center, we have been studying another approach to reducing new blood vessel growth by impairing the action of angiogenesis stimulators. Many studies in model systems have shown that key promoters of angiogenesis require binding to copper in order to function properly. This need for copper is fairly widespread among pro-angiogenic molecules and has been observed to be present in many different types of tumors.

Working together with Dr. George J. Brewer, an expert on the metabolism of trace elements such as copper, we have developed a clinical approach to exploiting the requirement of copper for angiogenesis. Drugs that lower copper levels exist in clinical practice primarily for the purpose of treating a rare hereditary disorder known as Wilson's disease. Patients with this condition do not have the ability to transport copper normally, and thus it accumulates in great quantities in organs such as liver and brain, causing severe malfunction often leading to death. However, with appropriate copper-lowering therapy, Dr. Brewer and others have developed well-tolerated therapies to control the level of copper in patients with Wilson's disease with excellent results. A particularly potent drug to lower copper in the body is the small molecule tetrathiomolybdate (TM) which is safely administered to patients with Wilson's disease.

U-M Clinical Trial with Tetrathiomolybdate (TM)
After completing an animal study that showed that TM was extremely effective in preventing the development of overt mammary tumors in cancer-prone mice, we embarked on a Phase I trial of TM in humans with metastatic cancer. After a year, this trial has now completed accrual. The patients in the trial have tolerated TM extremely well, with nearly no side effects.

It is important to remember that copper is required for many cellular processes, and in fact, absence of copper or very low copper levels would be very harmful to patients. The key observation of our trial is that it is possible to inhibit angiogenesis in many tumor types by lowering the copper to levels that still allow most other cellular processes to proceed relatively undisturbed. In this way, if patients can remain within a well-defined but apparently not too narrow "window" of mild copper deficiency, angiogenesis is brought to a halt without any other major side effects. It is important to point out that copper levels can be easily restored to normal in a matter of hours to days, by simply ceasing administration of TM.

Whereas new blood vessels appear to have a very strong dependence on copper for growth, low copper levels are unlikely to affect existing vessels; however, as tissue turnover eventually occurs, "old" vessels will not be replaced by new vessels, in the setting of copper deficiency. Therefore we postulated that in patients with established tumors, the achievement of chronic disease, and perhaps a very slow decrease in the number of viable tumor cells would be observed in cases in which TM is successful.

In addition, we have observed encouraging hints of cooperativity between TM and Herceptin(r) (anti-HER2 antibody) in breast cancer; TM and radiotherapy in kidney cancer; and TM and interferon in angiosarcoma. We are planning new trials to specifically study the efficacy of TM alone and in combination with other approaches in controlling metastatic sarcoma, breast and kidney cancer, and earlier stages of cancer. Although the results are promising, the exact clinical uses of this approach are yet to be rigorously defined in clinical trials.

Angiogenesis holds significant promise to help render cancer into a chronic or controllable disease or to contribute to its eradication, most likely in combination with other therapeutic modalities. The work in this field constitutes one more example of the concept that knowledge of the molecular and cellular events involved in cancer will lead to new therapies.

Additional References
Irani JL, van Golen K, Lovelace JR, Brewer GJ, Merajver SD. Copper deletion as an anti-angiogenic strategy in HER2-neu transgenic mice. Abstract presented at the AACR's Special Conference, "Angiogenesis and Cancer." 1998.

Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:353-364, 1996.

Folkman J. The influence of angiogenesis research on management of patients with breast cancer. Breast Cancer Res Treat. 36:109-118, 1995.

Folkman J. Angiogenesis inhibitors generated by tumors. Mol Med. 1:120-122, 1995.


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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.