Angiogenesis

No. 10 in a series providing the latest information on blood cancers

Angiogenesis means the creation of new blood vessels, a critical natural process that occurs in the body both in health and in disease. Blood, carried in the vessels, delivers oxygen and nutrients to and removes waste products from the tissues. When new tissue is formed, blood vessel formation must occur as well. Thus, new tissue formed, for example, with the repair of wounds and the formation of the placenta during pregnancy are normal examples of intense new blood vessel formation (angiogenesis). How the Human Body Controls Angiogenesis The healthy body controls the formation of new blood vessels through a series of on and off switches. The primary on switches are chemicals that stimulate blood vessel formation. The primary off switches are chemicals that inhibit blood vessel-formation. When angiogenic growth factors (on switches) are created in greater amounts than angiogenesis inhibitors (off switches), the balance is tilted in favor of the growth of new blood vessels. When inhibitors are present in greater amounts than stimulators, angiogenesis is stopped. In health, the body maintains a balance of angiogenesis regulators. In some disease states, the organs involved may lose control over angiogenesis. In these conditions, new blood vessels either grow too much or not enough. Angiogenesis and Cancer Like tissues of the body, tumors need a blood supply. They get this through new blood vessel formation that extends into the tumor (angiogenesis). The nutrients and growth factors supplied by these blood vessels allow tumors to grow. Thus, in the search for new approaches to destroy cancer cells, drugs that inhibit angiogenesis are under study.
Published as a public service by The Leukemia & Lymphoma Society 1311 Mamaroneck Avenue White Plains, NY 10605 Information Resource Center (IRC) 800.955.4572

www.LLS.org

IRC 800.955.4572

Angiogenesis/2

Angiogenesis Research in the Fight against Cancer Considerable excitement about angiogenesis as a target for cancer treatment was generated when Dr. Judah Folkman and his colleagues at the Boston Childrens Hospital announced that they had cured mice with tumors using two naturally occurring inhibitors of blood vessel growth called endostatin and angiostatin. When these drugs were studied in clinical trials in humans, the results were disappointing and significant toxicity was noted (including high blood pressure and kidney injury). This has not lessened the interest in developing more effective and less toxic antiangiogenesis agents. In 1999, the National Cancer Institute, designated the development of antiangiogenic therapies a national cancer research priority. The goal of current clinical trials using angiogenesis inhibitors is to inhibit tumor growth and increase patient survival. Cancer cells can release molecules to activate the process of angiogenesis. Scientists now possess a more precise understanding of how blood vessels grow in a cancer. Exploring the steps in angiogenesis has provided targets for the development of new drugs to block blood vessel formation in a tumor. More than a dozen different chemicals have been identified that are signals for the growth of new blood vessels. According to the National Cancer Institute, the two proteins that play a role in blood vessel formation that appear to be the most important for sustaining tumor growth are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor bFGF. VEGF and bFGF are produced by several kinds of cancer cells and by certain types of normal cells, as well. Since the wall of a blood vessel is composed of a) lining cells (endothelium), which are in contact with the flowing blood, b) fibroblasts and the fibers they make and c) smooth muscle cells, which form the wall of the vessel, it is not a surprise that factors that encourage the formation of endothelial cells, fibroblasts, and smooth muscle are potential targets to block angiogenesis. The inhibitors currently being tested to stop the growth of new blood vessels fall into several different categories, depending on their mechanism of action. Some inhibit endothelial cells directly, others inhibit the chemicals that induce angiogenesis, and others block the ability of endothelial cells to penetrate tissues as they attempt to grow into sites needing a blood supply. Researchers are also exploring the targeting of more that one angiogenic mechanism at a time.

www.LLS.org

IRC 800.955.4572

Angiogenesis/3

Antiangiogenic therapy is likely to deliver lower doses of targeted, less toxic drugs over longer periods of time, whereas chemotherapy delivers high doses of toxic drugs in a short period of time. Chemotherapy destroys both normal and cancerous cells in days or weeks, while targeted antiangiogenic therapies may take long periods to achieve their full benefit. Researchers are now exploring whether inhibiting angiogenesis can slow down or prevent the growth and spread of cancer cells in humans. Angiogenic research in the fight against cancer is not limited to drug therapies. Several new technologies, based on research advances in angiogenesis, are currently being developed for the early detection of cancer. One example of this is a scanning device that may sense angiogenesis in a breast tumor, using digital imaging technology. This approach to the early diagnosis of tumor tissue capitalizes on the fact that the tumor may have a more dense collection of blood vessels than neighboring normal, non-growing tissue. The goal is to find breast cancers sooner than is possible with standard x-ray mammograms. In addition, since it uses a light based system, it does not emit X-radiation. Antiangiogenic Drugs in Clinical Trials Cancer clinical trials are conducted by medical scientists to improve the care and treatment of cancer patients. Clinical trials are an important means to develop improved treatment for leukemia, lymphoma and myeloma. They offer patients access to promising new therapies being tested for their potential to increase survival and/or improve quality of life. To help make this determination and protect the patients, a cancer clinical trial is divided into three parts, or phases: Phase I. The first phase of the study tests treatment of a small group of patients to determine the appropriate dose (amount) and best way of giving the treatment, and if any severe toxicity develops. Phase II. Once the appropriate dose and frequency of administration of the drug under study is determined, treatment is given to a larger group of patients to determine whether and how well the treatment works against the disease. Phase III. If the results of phase II studies show effectiveness against the tumor, the treatment is then tested in a phase III trial. Phase III trials usually assign patients randomly to two groups. This permits large numbers of patients with the disease to receive the study treatment (experimental group) and compare its effect to the best standard treatment currently in use (comparison group).
www.LLS.org IRC 800.955.4572

Angiogenesis/4

The Food and Drug Administration (FDA) usually will approve a drug for marketing if in Phase III testing the treatment is found to be effective and meet safety requirements. The goals for new FDA approved therapies and treatments are to be more effective (or equally as effective with less toxic side effects) than standard treatment. To learn more about clinical trials, the Societys Cancer Clinical Trials Fact Sheet may be ordered or accessed online or by calling the Societys Information Resource Center at 800-955-4572. According to the Angiogenesis Foundation, there are over 18 antiangiogenic drugs that have reached the Phase III level of human clinical trial testing. The following are three examples: 1. Thalidomide, banned in the 1960s for causing birth defects when administered to pregnant women, is one of the more promising angiogenesis inhibitor drugs. The Angiogenesis Foundation states that thalidomide targets VEGF, bFGF, and other factors. 2. Bevacizumab is an antibody that neutralizes the vascular endothelial growth factor (VEGF) protein, one of many proteins secreted by tumor cells to promote the development of a new network of blood vessels. By binding to VEGF, bevacizumab prevents it from triggering blood vessel growth, thereby inhibiting tumor growth. 3. Neovastat or oral AE-941, which is manufactured by Aeterna, is an inhibitor of angiogenesis with multiple mechanisms of action. It involves matrix metalloproteinases (MMP 2, 9, 12) which degrade the basement membrane. It also acts on endothelial cells by interfering with the Vascular Endothelial Growth Factor (VEGF) pathway. It induces death of endothelial cells and also increases the level of angiostatin, a naturally occurring angiogenesis inhibitor.

Anti-Angiogenesis Drugs being tested in Leukemia, Lymphoma And Myeloma Several blood cancers also contain an increase in blood vessels to feed the tumor. The finding that an increase in blood vessels is present in the tumor suggests that angiogenesis may be a significant element in the growth of these blood cancers. In a recent review article by Francis J. Giles, MD entitled The Emerging Role of Angiogenesis Inhibitors in Hematologic Malignancies, (A Supplement to Oncology, May 2002, Vold 16. Number 5, Supplement 4). He makes the following points on the state of antiangiogenic science. VEGF, mentioned above, has emerged as the prime target in treating blood cancers. There appears to be a relationship

www.LLS.org

IRC 800.955.4572

Angiogenesis/5

between increased angiogenesis and the prognostic implications for acute and chronic leukemias, myeloma, and hairy cell leukemia and non-Hodgkin lymphoma. Higher levels of proangiogenic factors have been associated with a poor prognosis. In some of the above diseases there seems to be an association between the return to normal levels of blood vessel growth in the bone marrow and the durability of response to treatment. Whether increased blood vessel formation in these blood tumors is a primary factor in these associations is not yet known. Furthermore, the antiangiogenic property of developing therapies has not yet been established as the principal factor accounting for improved outcomes of treatment since these drugs have several effects. Nevertheless these data provide support for the continued exploration of treatment strategies that aim to reduce the activity of proangiogenic factors in blood cancers. Patients with myeloma develop new blood vessels in their marrow, the site of the disease. There has been special interest in using the antiangiogenic drugs in patients with myeloma. Thalidomide, has recently become one of the more promising angiogenesis inhibitor drugs. Thalidomide targets VEGF, bFGF, and other chemical factors. Thalidomide has induced complete responses and improved overall survival in a proportion of patients with advanced myeloma (in which survival is measured in weeks). Thalidomide is now being studied in patients with newly diagnosed myeloma, and in patients with myelodysplastic syndromes and renal cell carcinoma. Thalidomide is also being studied in Phase I and II trials in patients with the following blood cancers: advanced chronic lymphocytic leukemia, low-grade lymphoma, and agnogenic myeloid metaplasia (idiopathic myelofibrosis). Since the drug is already FDA approved for a skin condition, it is available at pharmacies nationwide, and oncologists have been prescribing it for myeloma. Celgene, the company that makes thalidomide is continuing their Phase III trials with patients in various stages of the myeloma, and is expected to seek FDA approval in the spring of 2004. Side Effects of Anti-Angiogenesis Drugs Much remains to be discovered about the side effects of anti-angiogenesis therapy. Anti-angiogenic drugs may be less toxic than conventional chemotherapy drugs and patients may not experience certain of the side effects of chemotherapy such as hair loss, uncontrollable vomiting, or diarrhea. Other side effects have been seen, however. An anti-angiogenic drug would probably stop the normal reproductive cycle in women and would

www.LLS.org

IRC 800.955.4572

Angiogenesis/6

be very dangerous to give to pregnant women. Other side effects in people are being determined. Doctors, scientists and specialists at the FDA will be monitoring these other side effects to better understand the toxicity and risks of these drugs. Questions Yet To Be Answered About Anti-Angiogenesis Therapy Scientists are trying to determine which cancer patients are most likely to benefit from anti-angiogenic drugs, how long treatment will need to be given, and whether tumor cells will escape the drug effect in time and find alternative routes to blood vessel formation. Investigators believe anti-angiogenic therapy may not be used as a single agent, but in conjunction with other therapies. To answer such questions, human clinical trials are currently under way. Researchers, both in private institutions, government laboratories, and drug companies are working to develop agents that will help people with cancer by depriving their tumors of a blood supply. Finding Anti-Angiogenesis Agents Clinical Trials To find out which cancer clinical trials are appropriate for you, begin with discussing clinical trials as a treatment option with your doctor. In addition, you can contact The Leukemia & Lymphoma Societys Information Resource Center (IRC) at (800) 955-4572 to speak with an Information Specialist. (See Resources below). For a listing of anti-angiogenic agents currently being studied, along with their mechanisms of action, you may access the Web site of the National Cancer Institute at www.cancer.gov, enter angiogenesis in the search bar, and then click on the section called Angiogenesis Inhibitors in Clinical Trials. It may well be several years more, investigators believe, before the best use of what appears to be a very exciting new approach to cancer treatment becomes clearly understood and ready for more widespread use. Resources
The Leukemia & Lymphoma Society The Leukemia & Lymphoma Society is a national voluntary health agency with 63 chapters serving all 50 states. It provides education and support services for the public and for cancer treatment professionals. To find the Society chapter nearest you, visit our online chapter finder or contact: The Leukemia & Lymphoma Society 1311 Mamaroneck Avenue White Plains, NY 10605 (800) 955-4572 or www.LLS.org
www.LLS.org IRC 800.955.4572

Angiogenesis/7

Through the Society's Information Resource Center, callers may speak directly with an Information Specialist, Monday-Friday, 9 am- 6 pm, ET at (800) 955-4572. To contact an Information Specialist, click on Live Help (10 am- 5 pm) on the Society's Web site or email us at infocenter@LLS.org . Information Specialists can answer general questions about diagnosis and treatment options, offer guidance and support, and assist with clinical trial searches for leukemia, lymphoma and myeloma. The Societys Web site features a link to the clinical trial searching service of the National Cancer Institute. Clinical trials listings for blood cancers, including abstracts of clinical trial protocols and contact information, are available. The Society provides fact sheets and booklets that can be ordered via the 800 number or through the Free Materials section on the Web site, www.LLS.org .

The Angiogenesis Foundation, www.angio.org, (617) 576-5708 The National Cancer Institute, www.cancer.gov, 800-4-CANCER
This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is distributed as a public service by The Leukemia & Lymphoma Society, with the understanding that The Leukemia & Lymphoma Society is not engaged in rendering medical or other professional services.

FS-10 January 2003

www.LLS.org

IRC 800.955.4572