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Angiogenesis: Blood Vessel Growth and the Treatment of Disease

Capillaries--tiny blood vessels--extend into all the tissues of the body, replenishing nutrients and carrying off waste products. Under most conditions, capillaries do not increase in size or number because the endothelial cells that line these narrow tubes or vessels do not divide. But in certain circumstances they do, such as during menstruation or in wound repair. This proliferation of endothelial cells, causing the formation of new capillaries, is called angiogenesis or neovascularization. It is typically tightly controlled and short-lived, usually "turning off" one to three weeks after its function has been accomplished.

Judah Folkman, M.D., director of the Vascular Biology Program at Children's Hospital Boston, first speculated in the 1960s that angiogenesis is also integral to the complex biology that enables and encourages the growth of tumors and other forms of cancer. Folkman has spent the last four decades validating this hypothesis, beginning with a seminal paper published in The New England Journal of Medicine in 1971. In this paper, he proposed the revolutionary concept that tumors are unable to grow beyond a certain size unless they have a dedicated blood supply, and that "successful" tumors secrete an unknown substance (which he then called tumor angiogenesis factor, or TAF) that encourages new blood vessel growth. The process of angiogenesis, Folkman argued, helps transform a tumor from a small cluster of mutated cells to a large, malignant growth.

More than thirty years later, angiogenesis inhibitors and stimulators present powerful new weapons in the armamentarium against cancer and a host of other illnesses, including heart and eye disease. Angiogenesis inhibitor therapy works on Folkman's elegant principle that, rather than waging a toxic chemical and radiation battle with a tumor, one could starve it into submission by shutting down its blood supply. Today, at least 50 angiogenesis inhibitors are in clinical trials around the world, and more than 1,000 laboratories in universities and industry are conducting angiogenesis research.

The newest horizon in angiogenesis research is early detection of the moment when previously dormant, harmless tumors "switch on" angiogenesis and become a threat. Folkman hopes to be able to detect this switch by monitoring "biomarkers" in the blood or urine, and then treat the patient with nontoxic angiogenesis inhibitors. Several biomarkers discovered in the Vascular Biology Program are now in clinical development. Ultimately, the goal is to delay -- or even block -- the switch by giving nontoxic angiogenesis inhibitors preventively, preventing a cancer from starting at all.

Angiogenic Switches: Turning Them On and Off
Folkman's first approach to understanding how tumors "turn on" angiogenesis was to search for an actual angiogenic protein produced by a tumor. To make this search possible, Folkman needed research tools and tests that could demonstrate such a protein's presence. The first step was the ability to grow blood vessel endothelial cells in vitro so that vessel growth could be easily monitored under different experimental conditions. This was accomplished for the first time in the early 1970s by Folkman and his student, Michael A. Gimbrone, Jr., M.D., now Chair of Pathology and Director of Vascular Research at The Brigham and Women's Hospital.

A second tool consisted of tiny polymer beads that could be implanted into the corneas of laboratory animals, releasing their contents over a period of days. Potential angiogenic proteins could be incorporated into the beads, and those that stimulated new blood vessel growth in the cornea could then be further purified and studied. This work was done in the mid-1970s with Robert Langer, Ph.D., now professor of Chemical and Biomedical Engineering at M.I.T, when he was a post-doctoral fellow in Folkman's lab. A third technique was the implantation of angiogenic proteins into chicken embryos cultured in dishes, where capillary growth could be easily observed.

By the late 1970s, Folkman's lab was working intensively to isolate and characterize an angiogenic protein from a tumor. Success came in 1983 when Michael Klagsbrun, Ph.D., and Yuen Shing, Ph.D., completely purified the first angiogenic protein from a tumor, basic fibroblast growth factor (bFGF). Other angiogenic proteins were subsequently discovered in other laboratories, including angiogenin, and vascular permeability factor (now called vascular endothelial growth factor, or VEGF) in the lab of Harold Dvorak, M.D., Pathologist-in-Chief at Beth Israel Deaconess Medical Center and professor at Harvard Medical School.

At least 16 angiogenic proteins have now been discovered by labs in the United States and Europe; of these, VEGF is the most specific stimulator of vascular endothelial-cell proliferation. It's now known that tumor cells can trigger production of more than one kind of angiogenic protein, affecting different parts of the cellular signaling process leading to angiogenesis. It's also now known that these compounds are maintained on "standby," releasable when angiogenesis is needed for bodily functions--or when it is induced by a tumor.

"Off" switches
By the 1980s, Folkman's team turned its attention to the search for molecules that could turn off angiogenesis in tumors. This was a daunting task: no such molecules were known, and few scientists believed they even existed.

The first angiogenesis inhibitor to be identified was interferon-alpha, a natural protein in the body known for its antiviral activity. Bruce R. Zetter, Ph.D., in Folkman's lab showed in the early 1980s that interferon-alpha could also stop endothelial cells from moving and migrating toward a tumor; other scientists then showed the protein's anti-angiogenic activity. Interferon-alpha entered clinical trials for the treatment of life-threatening hemangiomas (masses of blood capillaries) in children in 1989.

Folkman and two colleagues -- Alan Ezekowitz, M.B., Ch.B., D.Phil., now a senior vice president at Merck Research Laboratories, and John B. Mulliken, M.D., director of the Craniofacial Center at Children's Hospital Boston -- developed the most extensive clinical experience with this new anti-angiogenic therapy for children. Interferon-alpha was subsequently used in children's hospitals worldwide for severe hemangiomas that failed to respond to conventional therapy. It is currently most useful for certain tumors such as high-grade giant cell tumors in adults and children over the age of 1.
Other early angiogenesis inhibitors from Folkman's lab included:
  • TNP-470, a synthetic version of an angiogenesis inhibitor discovered accidentally by Donald E. Ingber, M.D., Ph.D., in 1985. (Ingber isolated the original inhibitor from a mold contaminating a culture dish.) TNP-470 entered clinical trials for cancer patients in 1992, showing activity against an unusually broad spectrum of cancers. It has now been reformulated to eliminate the neurotoxicity observed in some clinical studies. The new formulation, known as caplostatin, does not cross the blood-brain barrier. Other TNP-470 derivatives are under development. To read more, http://focus.hms.harvard.edu/2004/March19_2004/oncology.html and here http://www.news.harvard.edu/gazette/2004/02.26/01-tnp.html.

  • Thalidomide, which was shown to be an angiogenesis inhibitor in 1994 by Robert J. D'Amato, M.D., Ph.D. Once taken off the market because it caused severe birth defects, thalidomide and related compounds are being studied in at least 50 clinical trials for a variety of cancers. Several thousand patients with multiple myeloma that resisted all conventional chemotherapy have had complete remissions on thalidomide. In May, 2006, the U.S. Food and Drug Administration (FDA) approved the use of thalidomide to treat multiple myeloma. To read more, . http://www.childrenshospital.org/chnews/10-04-04/story.html
Natural Inhibitors
In 1989, Folkman had a novel hypothesis that led to the discovery of the most potent angiogenesis inhibitors known. Some primary tumors, he knew, are able to suppress the growth of their remote metastases. Folkman hypothesized that while these tumors secrete short-acting, highly potent angiogenic stimulators locally, they simultaneously secrete low levels of long-lasting angiogenic inhibitors into the circulation. One such inhibitor, thrombospondin, had already been found to be secreted by tumor cells by Noel Bouck, Ph.D., at Northwestern University.

Michael S. O'Reilly, M.D. (now at the MD Anderson Cancer Center) pursued Folkman's idea, and ultimately purified three more inhibitor proteins from tumor-bearing animals: angiostatin in 1994, endostatin in 1996, and anti-angiogenic antithrombin (aaAT) in 1998. These proteins caused animal tumors to regress to a microscopic size, where they often remained dormant indefinitely, even after prolonged therapy was discontinued. Another compound, 2-methoxyestradiol (2ME2), was reported by Robert D'Amato to be a potent angiogenesis inhibitor in 1994. This steroid, a metabolite of estrogen, is found in women's urine near the end of pregnancy.

These novel angiogenesis inhibitors, occurring naturally in the body, have shown no toxicity. Moreover, tumors do not become resistant to them as they do to conventional chemotherapy agents. This is because the inhibitors don't target cancer cells, which develop resistance rapidly because of a high mutation rate, but instead target endothelial cells, which rarely mutate. The body makes more than two dozen molecules known to defend against angiogenesis, according to the Angiogenesis Foundation.
From the Lab to the Clinic
At least 50 angiogenesis inhibitors - including endostatin, angiostatin, 2ME2 (Panzem), and a thrombospondin analog -- are in clinical trials today for cancer, including a variety of drugs that have been discovered to have unexpected anti-angiogenic effects. These include the anti-inflammatory drug celecoxib (Celebrex); rosiglitazone (Avandia), a drug commonly used to treat Type 2 diabetes; doxycycline, a common antibiotic; and some cancer drugs that also have other mechanisms of action, including Erbitux, Herceptin, Velcade and Tarceva. Even some conventional chemotherapy drugs have demonstrated anti-angiogenic effects when given in frequent, smaller doses (see Anti-Angiogenic Chemotherapy below). Folkman envisions that someday angiogenesis inhibitors will be used together or in combination with conventional anticancer therapies such as chemotherapy, radiotherapy, immunotherapy, gene therapy, or vaccine therapy.

Clinical trials are beginning to show promising results.
  • Endostatin and angiostatin have led to long-term disease stabilization and improved quality of life in a small group of patients, with a return of strength, weight, and hair growth--and virtually no toxicity. In China, Phase III trials of endostatin were conducted in nearly 500 patients with late-stage non-small-cell lung cancer. Researchers reported at the 2005 American Society of Clinical Oncology (ASCO) annual meeting that patients who had endostatin added to their chemotherapy regimen had increased time to disease progression. In September, 2005, endostatin was approved for marketing in China. To read more, go to http://www.asco.org/ac/1,1003,_12-002636-00_18-0034-00_19-0031990,00.asp and http://www.childrenshospital.org/dream/dream_spring06/rising_star.html.

  • Avastin was approved by the FDA in 2004 for the treatment of metastatic colorectal cancernd was approved in 2006 for advanced non-small-cell lung cancer, both in combination with standard chemotherapy. Reports have also found that Avastin slows the progression of advanced breast cancer (http://www.cancer.gov/newscenter/pressreleases/AvastinBreast).


  • In May 2006, FDA approved thalidomide for the treatment of multiple myeloma after Phase III clinical trials showed an 80% response rate in patients newly diagnosed with multiple myeloma when thalidomide is added to dexamethasone, as compared with 53% with dexamethasone alone. A dozen Phase III trials are continuing around the world, with one third to one half of multiple myeloma patients responding. Australia was the first country to approve thalidomide for multiple myeloma, in December 2003. For more on thalidomide, go to http://www.childrenshospital.org/chnews/10-04-04/story.html.

Angiogenesis: Other Potential Clinical Applications
While the potential of using angiogenesis inhibitors to treat cancer has garnered much attention and excitement, the same class of drugs has also proved useful in treating other diseases caused by abnormal blood-vessel growth. According to the Angiogenesis Foundation, more than 70 such diseases have been identified, from macular degeneration to endometriosis.

Equally exciting is the potential application of angiogenic stimulators to treating coronary heart disease, the single largest killer of men and women in the United States today. Angiogenesis-stimulating growth factors are now being tested in facilities in Boston, New York, Germany and other medical centers around the world. These centers are developing ways to grow collateral blood vessels--in effect, creating a biological coronary bypass graft--to introduce new blood flow in damaged heart muscle. Angiogenic stimulators are also being used in peripheral vascular disease and to promote wound healing.


Eye Diseases

Angiogenesis plays a pivotal role in the development of diabetic retinopathy and age-related macular degeneration, both of which are major causes of blindness, as well as retinopathy of prematurity in preterm infants. As these disorders progress, the blood vessels of the eye not only proliferate excessively, but the new vessels are weak and leaky and prone to hemorrhage. In both macular degeneration and diabetic retinopathy, new abnormal vessels bleed and cause blindness.


In the early 1990s, Anthony Adamis, M.D., in the Folkman Lab discovered with collaborators at the Joslin Clinic and the Mass Eye and Ear Infirmary that the naturally occurring angiogenic protein VEGF is the critical factor in the development of new blood vessels in both diseases. By inhibiting VEGF, scientists hypothesized they could prevent the development of new blood vessels in the eye. Their hypothesis was borne out by subsequent research and, as a result, several anti-VEGF drugs are now in clinical trials for patients with these eye diseases, and two have been approved by the FDA.

Macugen (pegaptanib sodium injection) received FDA approval in December, 2004, after two clinical trials showed that it significantly slowed vision loss in patients with the "wet" form of age-related macular degeneration (AMD).

Lucentis (ranibizumab, Genentech, Inc.), was approved for "wet" AMD in June, 2006, following a promising Phase III clinical trial. One-year data presented at the annual meeting of the American Society of Retina Specialists in 2005 showed that 25% of patients treated with a low dose of Lucentis and 34% of those treated with a higher dose gained at least 15 letters in visual acuity on an eye chart, as compared to about 5% of controls. Lucentis-treated patients gained an average of 7 letters, while the control group lost an average of 10.5.


Cardiovascular Disease

In the early 1980s, scientists at Children's identified and purified bFGF the first of many potent angiogenesis inducers. Subsequently, other angiogenic proteins such as VEFG which stimulate the formation of new blood vessels, were discovered by investigators. It was not surprising that before long researchers in the field of cardiology had envisioned the therapeutic potential of such compounds stimulating the growth of arterial vessels.

When an artery becomes significantly obstructed due to atherosclerosis, a condition in which a fatty substance called plaque builds up on the vessel wall, the body normally responds by developing collateral vessels that help to compensate for the reduced blood flow. Researchers at institutions in Germany and the US demonstrated in animal models that administering angiogenesis inducers stimulated the development of additional collateral vessels and improved blood flow to the heart. More recently, this strategy has been used with some success in patients with significantly blocked coronary vessels, providing a possible alternative to opening the clogged artery with balloon angioplasty and stents or with bypass surgery.

Another approach to angiogenesis is based on inhibiting, rather than stimulating angiogenesis, as reported by Karen Moulton, M.D., in the Folkman Lab. Earlier research had determined that plaques, like tumors, require the nourishment provided by new blood vessels in order to grow to a size that can cause a problem. Her studies in mice have determined that two angiogenesis inhibitors discovered at Children's, TNP-470 and endostatin, reduced the growth of arterial plaque significantly. Current work is directed at identifying the factors responsible for the formation of new vessels into the plaque. The use of angiogenesis inhibitors to cut off the blood supply to the plaques may someday provide a novel way to prevent atherosclerosis and its complications, including heart attack, stroke, and peripheral vascular disease. To read more, go to http://www.hno.harvard.edu/gazette/1999/04.29/cancer.drug.html


Obesity

Fat, or adipose tissue, is one of the few tissues in the body that can grow and regress throughout life. To researchers in the Folkman Lab, it seemed likely that angiogenesis had to be taking place as body fat increased, and that the new fat cells would die if angiogenesis were inhibited.

To test this hypothesis, Maria Rupnick, MD, PhD, and colleagues gave angiogenesis inhibitors to a strain of severely obese mice and to mice of normal weight. The new blood vessels in obese mice regressed and, in the process, fat cells died. As a result, the obese mice shed a significant percentage of their weight while on the angiogenesis inhibitors, but they regained it when the drugs were stopped. The angiogenesis inhibitors had little effect on the normal mice.

Rupnick's research established for the first time that the growth of at least one type of healthy tissue is controlled by angiogenesis. And, although preliminary, it may suggest a new approach to combating obesity. To read more, go to http://www.childrenshospital.org/chnews/archive/08-30-02/mice.html


Vascular Anomalies

Vascular anomalies are birthmarks of two major types: vascular malformations, or tangles of irregular blood vessels, and vascular tumors, most commonly hemangiomas. Hemangiomas are benign tumors in which cells that line the blood vessels proliferate wildly, resulting in a tangled thicket of blood vessels. Approximately 1 out of 100 newborns develop at least 1 hemangioma and approximately 25% of premature babies develop hemangiomas.

Typically, hemangiomas exhibit a fairly predictable pattern of growth. They grow rapidly for the first 6 to 12 months of life, after which they begin a much slower process of shrinking, or involution, which may take from one to seven years. By the time a child reaches about 12 years of age, involution is almost always complete. For this reason, most hemangiomas require no treatment.

However, some hemangiomas develop near the eyes or on vital organs, where, if they become large enough, they may pose a threat to the child's vision or life. These often require treatment with interferon alpha, the first antiangiogenic agent to be used in humans after Bruce R. Zetter, Ph.D., in Folkman's Lab discovered its antiangiogenic properties in the 1980s. However, interferon isn't universally effective.

Pioneering work by Folkman and his colleagues in the Vascular Biology Program is helping direct studies of how hemangiomas grow and regress and how vascular malformations begin and expand. Joyce Bischoff, Ph.D., and colleagues are discovering factors that stimulate the growth of endothelial cells. Inhibiting abnormal endothelial cell proliferation in hemangiomas could help children who do not respond to current therapies.

In addition, research in the lab of Marsha Moses, Ph.D., suggests that urine testing for angiogenic compounds known as matrix metalloproteinases (MMPs) can help monitor hemangiomas and other vascular anomalies and predict those about to become a serious threat. The lab's findings also suggest, for the first time, that angiogenesis plays a role in the progression of vascular malformations, raising the possibility of curbing these difficult-to-treat anomalies with MMP inhibitors or other anti-angiogenic drugs. To read more, go to http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel147.html


Infertility

Researchers in the Folkman Lab were the first to determine that certain angiogenesis inhibitors could block the female reproductive cycle at several key stages, suggesting an entirely new role for these compounds. Currently, they are studying various antiangiogenic agents as potential forms of contraception. If this research is successful, it would offer a nonhormonal method of birth control and could become an inexpensive option for developing countries concerned about overpopulation.

Robert D'Amato, MD, Christian Becker, M.D., Ofer Fainaru, M.D., Ph.D., and others in the Folkman Lab are looking at whether angiogenesis inhibitors may have a role in treating endometriosis, which is characterized by the migration of tissue from the lining of the uterus to the ovaries, urethra and other pelvic structures. The migrant tissue waxes and wanes just as the endometrium does during the menstrual cycle. As it grows, it can interfere with ovarian function and become a source of pain. Angiogenesis inhibitors may be able to "starve" the unwanted tissue by robbing it of its rich blood supply.

Other angiogenesis-dependent diseases and disorgers include:
  • Rheumatoid arthritis
  • Crohn's disease
  • Psoriasis
  • Uterine fibroids
  • Benign prostatic hypertrophy
  • Preeclampsia
  • Certain diseases of premature infants


New Horizons in Angiogenesis Research
Today, Folkman and his colleagues at Children's are advancing angiogenesis research on several exciting fronts.


Preventing the "Angiogenic Switch"

Using mice as a model, Folkman and colleagues have tracked when different types of tumors "switch" and become angiogenic, and have found that the switch frequently occurs at a predictable time for a given tumor type. A major current focus of Folkman's lab today is on preventing the "angiogenic switch" from happening at all.

Cancer -- without disease
A large majority of people, once they reach a certain age, have tumors, but they remain small and dormant. Most never become angiogenic. The evidence for this comes from autopsy studies of people who died of trauma and never had cancer in their lifetime (Black and Welch, New Engl J Med, 1993). Only a small fraction of these tumors will switch on angiogenesis and progress to an invasive cancer. For example, only 1% of men in their 60s have clinically apparent prostate cancer, whereas 46% have detectable small prostate tumors. Similarly, only 1% of women in their 40s have clinical breast cancer, whereas almost 40% have detectable breast tumors (mostly ductal carcinoma in situ).

Folkman's goal is to be able to delay the angiogenic switch--perhaps indefinitely--by giving naturally-occurring, nontoxic angiogenesis inhibitors preventively. Therapy could be offered to people with a genetically increased risk for cancer (such as women carrying the BRCA1 gene), people with a personal or family history of cancer, and perhaps anyone in whom a simple blood or urine test indicates that a tumor somewhere in the body has switched on angiogenesis. Such tests are indeed under development:
  • Marsha Moses, Ph.D., has developed non-invasive diagnostic and prognostic urine tests for cancer that are based on the detection of biomarkers -- compounds required for angiogenesis, tumor growth, and metastasis. The first of these biomarkers are members of a family of enzymes known as the matrix metalloproteinases (MMPs).Tests based on the MMPs are now in clinical development. A more recent study involved a biomarker called ADAM 12. Tests of urine samples donated by 71 breast cancer patients found that 94 percent contained ADAM 12, as compared with only 15 percent of samples from 46 healthy controls. The likelihood of testing positive, and levels of ADAM 12 in the urine, were lowest in women with very early breast cancer and highest in women with advanced, metastatic breast cancer. Other urinary cancer markers will be announced in the coming year. To read more, go to http://www.childrenshospital.org/dream/DreamRsch2005/moses.html
  • Folkman and pediatric oncologist Giannoula Klement, MD, have found that proteomic analysis of circulating blood platelets may be useful in early cancer detection. Platelets, Klement discovered, take up and sequester the proteins that tumors secrete to regulate angiogenesis. Using mass spectroscopy--a technique that can detect, identify and quantify minute amounts of proteins--Klement and Folkman have been able to "profile" a platelet's contents at different stages of tumor growth. Changes in the platelet protein profile can be analyzed to track very early tumor development, even before the proteins can be detected in the blood plasma. To read more, go to http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel195.html "Treating the biomarker" Folkman envisions a day when patients are treated with angiogenesis inhibitors long before the tumor can be visualized by radiologists and long before symptoms appear. Doctors can then monitor the results of treatment with additional urine or blood tests. This idea, which Folkman calls "treating the biomarker," may someday transform cancer into a non-threatening condition manageable with nontoxic drugs. To read more, go to http://www.pulitzer.org/year/2005/beat-reporting/works/marcus9.html

    Folkman draws an analogy with infections. "Before antibiotics, people who had infections developed abscesses. Then the surgeons would drain the abscess -- if they could find it," he said in a 2005 interview with Newsweek. "In 1941, penicillin comes along. Suddenly, doctors don't need to know precisely where the abscess is because they can just look at biomarkers in the blood and treat the patient with an antibiotic."

    The Folkman Lab is also investigating what causes a tumor to stay dormant, and what causes it to undergo the angiogenic switch. For example, Nava Almog, Ph.D., in the lab has identified genes whose activity is increased or decreased during the angiogenic switch. Based on these discoveries, Almog and Moses are developing molecular and biochemical interventions to prevent the switch from occurring, halting a budding cancer before it becomes invasive.


    Down Syndrome, Endostatin, and Disease Protection

    As people with Down syndrome begin to live longer, it's been observed that they virtually never develop cancers, other than testicular cancer and a rare form of leukemia. Nor do they develop diabetic retinopathy, even though they have diabetes at the same incidence as the normal population. People with Down syndrome, or trisomy 21, have been discovered to have a two-fold higher level of circulating endostatin than other individuals: their extra chromosome 21 also endows them with increased natural protection from angiogenesis. Chromosome 21 contains the gene that codes for collagen XVIII, which is the parent molecule of endostatin.


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    The Nerve-Vascular Connection

    Researchers in the lab of Michael Klagsbrun, Ph.D., have discovered that molecules originally thought to guide growing nerve fibers to their destinations also can inhibit blood vessel growth and could be another type of naturally-occurring angiogenesis inhibitor. Ultimately, the example of nervous-system development may help scientists understand how endothelial cells are guided during angiogenesis.

    For example, in 1998, Klagsbrun's lab reported that the angiogenesis stimulator VEGF also binds to neuropilin, a receptor on endothelial cells that is also involved in nerve guidance. Further studies showed that neuropilin enhances VEGF signaling and function, making it a good target for trying to inhibit cancer growth. In 2006, Children's granted Genentech an exclusive license to anti-cancer technologies based on neuropilin. Read more at http://www.childrenshospital.org/research/Site2029/mainpageS2029P27sublevel29.html


    Recently, Klagsbrun's lab showed that semaphorins, also involved in nerve guidance, are potent angiogenesis inhibitors, completely inhibiting tumor metastasis in mice.


    Genetic Differences in Angiogenesis

    It is well known that African-Americans rarely develop the wet form of macular degeneration, a condition leading to blindness caused by an excess of angiogenesis in the retina. Similarly, African-Americans rarely develop hemangiomas. Intrigued by these observations, Robert D'Amato, M.D., Ph.D., began studying genetic differences in angiogenesis in black and white mice, and has found a difference tied to the pathway for making the skin pigment melanin. When D'Amato and his colleagues knocked out a key gene in this pathway, the result was albino mice whose blood vessels grew faster. These observations suggest that people may have different genetic susceptibilities to angiogenesis that could provide leads for new treatment approaches. To read more, go to http://www.hno.harvard.edu/gazette/2003/02.06/01-thalidomide.html


    Anti-Angiogenic Chemotherapy

    Standard chemotherapy relies on high doses--the maximum a patient can tolerate -- given over a short period of time. The toxicity of these regimens requires a resting period between treatments, to allow the patient's own cells to recover. But during the rest periods, the tumor cells often mutate and become drug-resistant, while endothelial cells in the tumor bed also recover and begin making angiogenic compounds. Thus the tumor can begin to grow again.

    Timothy Browder, M.D., in the Folkman Lab discovered that if standard chemotherapy drugs are instead given at low, frequently repeated doses, the treatment is less toxic, avoids acquired drug resistance, and has anti-angiogenic effects that prevent vessel regrowth and inhibit tumor resurgence much more effectively than standard regimens. Adding a second angiogenesis inhibitor augments these effects. At first, this paradigm shift in thinking was rejected and even ridiculed. But today, constant, low-dose chemotherapy--also known as "metronomic" therapy or "chemotherapy lite"--is under active study around the world. In the summer of 2003, the Dana-Farber Cancer Institute began a clinical trial in women with advanced breast cancer, using a combination of low-dose chemotherapy drugs and the angiogenesis inhibitor Avastin. To read more, gp tp http://www.dana-farber.org/abo/news/publications/turning-point/summer-fall-2003/research-notes3.asp


    New insights into metastasis
    Randy Watnick, PhD, a principal investigator in the Vascular Biology Program, has made the startling discovery that tumors prepare distant sites to accept metastases by selectively repressing the natural angiogenesis inhibitor thrombospondin - helping the metastatic tumor cells attract a blood supply. Drugs that stop this process might one day keep metastases from taking hold.


    Lymphangiogenesis

    The lymphatic system collects fluids that leak from tissues and blood vessels and returns them to the circulation. Lymphatic vessels have been implicated in various diseases including lymphedema and systemic sclerosis, and lymphatic vessels also provide a conduit by which tumor cells can metastasize. Arja Kaipainen, M.D., Ph.D., in Folkman's lab has found that some angiogenesis inhibitors also inhibit lymphangiogenesis, and might become possible treatments for tumor metastasis and other diseases involving lymph-vessel abnormalities.

    The angiogenic horizon is pushed forward with each new study, clinical trial, and discovery of mechanisms that regulate the complex biology creating and halting the formation of the body's tiny blood vessels--advancing concepts originally envisioned by Judah Folkman more than 45 years ago.

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    Last updated September 2006
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