Tobey J. MacDonald, M.D.
For over 50 years, the field of cancer therapy has been dominated by the concept that the tumor must be the selected target of the chemotherapy delivered. Therefore, any drug with the ability to directly kill tumor cells in the laboratory was by definition a candidate for use as chemotherapy in humans. However, because of the high mutation rate of cancer cells (genetic instability), repeated exposures to chemotherapy often results in a population of residual tumor cells that have become resistant to the effects of the chemotherapy. It is this genetic instability and the development of resistance to therapy that has most hindered our success in finding a cure for childhood brain tumors.
It was also readily apparent that normal cells of the body are susceptible to the effects of chemotherapy. These changes in the normal cells or organs of the body are referred to as the side effects of the drug and are responsible for limiting the amount of chemotherapy that can be safely administered. However, recent discoveries that alterations in specific functions of normal cells can also inhibit tumor growth has led to enthusiasm for the development of drugs that target normal cells. Moreover, since normal cells are not prone to the genetic instability seen in tumor cells, resistance to drugs that effect their function is unlikely to occur. With this approach, oncologists no longer need to restrict their attention to the individual cancer cell, but may focus on the entire tissue environment as potential targets of therapy.
Angiogenesis Inhibition — One of the most promising avenues in this field of cancer research is the study of a group of drugs called Angiogenesis Inhibitors (AIs). These are drugs that block the development of normal new blood vessels, a process known as angiogenesis. By blocking the development of new blood vessels, researchers are hoping to cut off the supply of oxygen and nutrients to the tumor. Although the blood vessels of tumors have been studied since the early 1800s, it is only in the past few years that this approach as an effective therapy has become realistic. The concept of cancer anti-angiogenic therapy stems from the work of Dr. Judah Folkman, a pediatric surgeon at the Children’s Hospital in Boston, in the early 1970s. Dr. Folkman was the first to emphasize that solid tumors cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters) without inducing the formation of new blood vessels to supply the nutritional and other needs of the tumor. He then recognized that inhibiting the growth of tumor blood vessels should lead to effective methods in attacking malignancy. This theory, now confirmed by a large body of experimental evidence, implies that tumors can potentially be starved to death by inhibiting their blood supply.
How AI’s work — In normal tissue, new blood vessels are formed in response to signals generated during tissue growth and repair (wound healing), during the normal female reproductive cycle, and during the development of the fetus in pregnancy. About 15 proteins are known to activate new blood vessel growth. Of these, the most potent is called Vascular Endothelial Growth Factor (VEGF). Other important ones include Fibroblast Growth Factors (FGF), angiogenin, Epidermal Growth Factor (EGF), Placental Growth Factor (PIGF), Platelet Derived Growth Factor PDGF), and Tumor Necrosis Factor Alpha (TNF-alpha) to name a few. In cancerous tissue, tumor cells produce their own VEGF and other chemical signals that induce the existing blood vessels in the surrounding tumor environment to make new blood vessels for the growing tumor. Endothelial cells, the cells that form the walls of blood vessels, are the source of new (blood vessels. In response to these chemical signals, endothelial cells divide and grow, breakdown their surrounding tissue barriers with enzymes called matrix Metalloproteinases (MMPs), and migrate toward the tumor to form a connection to the body’s blood supply. Each of the steps in this process is a potential target for AIs to block. Some of the naturally occurring inhibitors of angiogenesis include angiostatin, endostatin, interferons, platelet factor 4, thrombospondin, transforming growth factor beta, and tissue inhibitor of metalloproteinase.
In general, four strategies are being used by investigators to design anti-angiogenesis agents:
Block the ability of endothelial cells to break down their surrounding tissue barriers
Inhibit normal endothelial cells directly
Block the chemical signals that stimulate angiogenesis
Block the action of proteins called integrins that are on the surface of endothelial cells and are responsible for the continued survival of endothelial cells undergoing angiogenesis.
AIs in clinical trials –Today, about 20 angiogenesis inhibitors are being tested in adult human cancer trials (see below). Most are in early Phase I or II adult human clinical studies. Some are in or entering Phase III testing. With the exception of thalidomide, pediatric studies with angiogenesis inhibitors have not been started. The first group-sponsored pediatric trial will be conducted by member institutions of the Pediatric Brain Tumor Consortium (PBTC) in early 2000. This will be a phase I trial with the VEGF blocking compound, SU5416. In Phase I/II trials, a limited number of people are given the drug to determine its safety, dosage, side effects, and preliminary activity. In Phase III trials, hundreds of people around the country are involved in studies to determine how effective the drug is. Since all of these trials are in the early stages, commenting on their usefulness against tumors in humans would be premature, but all have been shown to retard tumor growth either in the test tube or in animals. The following AIs are currently in trial or about to begin and are grouped according to their method of inhibition, which is denoted by one of the four corresponding numbered strategies listed above:
Marimastat, AG3340, COL-3, Neovastat, BMS-275291
TNP-470, Thalidomide, Squalamine, Combretastin A-4 Prodrug, Endostatin
SU5416, SU6668, PTK787/ZK 22584, Interferon-alpha, Anti-VEGF Antibody
EMD121974
CAI, Interleukin-12, and IM862 are also in clinical trials; however, their mechanism of inhibition is unknown.
Some of the differences between standard chemotherapy and anti-angiogenesis therapy are the result of AIs targeting dividing endothelial cells rather than tumor cells. AIs are not as likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss. Also, AIs may not necessarily kill tumors, but rather hold them in check indefinitely. Therefore, it may be necessary to continue therapy with AIs for the life of the individual or use in combination with other standard chemotherapy drugs.
Conclusion — In summary, AIs offer an exciting new approach to the treatment of childhood tumors. Potential important benefits over standard chemotherapy are the lack of resistance to therapy and the lack of significant side effects on other normal tissues. How realistic are the prospects of anti-angiogenesis therapy? The final answers will come only through the completion and analysis of ongoing clinical trials.
Tobey MacDonald, M.D. is a pediatric oncologist, now located at Emory University Health Sciences Center (2009), previously the Clinical Director of Neuro-Oncology at the Children’s National Medical Center, Washington, D.C. and was an Assistant Professor in Pediatrics at The George Washington University School of Medicine in Washington, DC. His research interests include childhood central nervous system tumors; tumor integrin-host interactions important to CNS tumor invasion and angiogenesis; genetic regulation of tumor invasion and angiogenesis; translational therapeutics for biological targets of CNS tumor invasions and angiogenesis. He also finds time to serve as on the Medical/Scientific Advisory Board of the Childhood Brain Tumor Foundation, www.childhoodbraintumor.org and donated his time to write this article. Contact us for permission to reprint.
This article was written for the Childhood Brain Tumor Foundation, Germantown, MD.