While serving in the Navy at the Naval Medical Research Institute in Bethesda, Folkman observes that tumor cells do not grow when fed by blood substitutes, but do grow when implanted into mice. He theorizes that tumors are angiogenesis-dependent.
The New England Journal of Medicine publishes Folkman's hypothesis that tumors are angiogenesis-dependent.
Vascular endothelial cells are grown in vitro in Folkman's lab by Michael Gimbrone, M.D. This success becomes the foundation for future experiments to test substances that can stimulate or inhibit blood vessel growth.
Bruce Zetter, Ph.D., identifies the first angiogenesis inhibitor, interferon-alpha. This protein, occurring naturally in the body, is also known for its antiviral activity.
After serving as Children's Hospital's Surgeon-in-Chief for 14 years, Folkman steps down to devote all his time to surgical research.
Basic fibroblast growth factor (bFGF) is purified as the first angiogenic molecule by Michael Klagsbrun, Ph.D., and Yuen Shing, Ph.D.
Folkman proposes the concept of an angiogenic "switch" when the balance of pro-angiogenic and anti-angiogenic compounds in a tumor cell shifts, causing the tumor to "turn on" angiogenesis and begin growing.
Interferon alpha becomes the first angiogenesis inhibitor to cause complete remission of a tumor, a hemangioma (a benign tumor formed by clusters of blood vessels). The drug enters clinical trials in infants with sight- or life-threatening hemangiomas. Today, interferon-alpha is used in many children when these severe hemangiomas fail conventional therapy.
Donald Ingber, M.D., Ph.D., accidentally discovers a fungus that produces an angiogenesis inhibitor, fumagillin. This leads to the development of the synthetic compound TNP-470, the broadest-spectrum angiogenesis inhibitor known. TNP-470 enters clinical trials in 1992, and is later reformulated under the name caplostatin.
In a study published in Cell, Folkman, Michael S. O'Reilly, M.D., and colleagues demonstrate how the removal of a malignant primary tumor in mice spurs the growth of remote tumors, or metastases. O'Reilly identifies a protein in the primary tumor that inhibits angiogenesis in the metastases. He names the protein angiostatin. This powerful natural angiogenesis inhibitor is now in Phase II clinical trials.
Robert D'Amato, M.D., Ph.D. reports that 2-methoxyestradiol (2ME2), a compound found in the urine of women near the end of pregnancy, is a potent angiogenesis inhibitor. The compound is now in Phase I and II clinical trials for a variety of cancers under the trade name Panzem. D'Amato also discovers that the once-abandoned drug thalidomide is a potent anti-angiogenic agent.
Thalidomide enters clinical trials for age-related macular degeneration. Today, it is being studied in at least 50 trials for a variety of cancers, and Celgene has licensed several thalidomide analogs from Children's Hospital and EntreMed.
In a January issue of Cell, O'Reilly reports the discovery of a second naturally-occurring angiogenesis inhibitor, endostatin. In a groundbreaking paper in Nature, O'Reilly, Folkman, and Thomas Boehm, M.D., demonstrate that endostatin can cause tumors to regress in mice without inducing drug resistance, a common problem with chemotherapy. (Endostatin, like other angiogenesis inhibitors, targets endothelial cells, which have a low mutation rate, making them less likely to develop drug resistance than tumor cells.) Though not currently commercially available in the U.S., endostatin went through Phase III trials in China and was approved there in September 2005.
The New England Journal of Medicine publishes the first report of a complete and sustained cancer remission in a human by an angiogenesis inhibitor (TNP-470).
Marsha Moses, Ph.D., in the Vascular Biology Program reports in Cancer Research that a urine assay for matrix metalloproteinases (MMPs) can predict whether a cancer will progress and metastasize. The presence of MMPs, a family of enzymes required for angiogenesis, indicates that angiogenesis has been "turned on." Based on this finding, a number of noninvasive tests are under clinical development that could be used to detect a cancer before it can be visualized radioscopically, and to guide treatment with angiogenesis inhibitors.
Karen Moulton, M.D., in Folkman's lab reports in Circulation that endostatin or TNP-470 administration reduces the formation of atherosclerotic plaque, the gummy substance that clogs arteries, causing heart disease. Plaque contains living cells that require a blood supply, and angiogenesis is known to occur within the inner coating of vessels with atherosclerotic lesions. In mice bred to have human-like plaque formation, endostatin treatment inhibited plaque growth by 85%, and TNP-470 by 70%.
A study by Folkman and Timothy Browder, M.D., published in Cancer Research, demonstrates that giving lower, frequent doses of standard chemotherapy drugs can suppress angiogenesis by inhibiting endothelial-cell growth in the vascular bed of a tumor, thereby suppressing the tumor itself. In mice, this approach suppressed growth of lung and breast tumors three times more effectively than a conventional chemotherapy regimen, and avoided drug resistance. Conventional chemotherapy is given at "maximum tolerated doses" with resting periods in between; the new approach eliminates the resting periods so that endothelial cells cannot recover and resume angiogenesis. Browder's demonstration has changed thinking about chemotherapy and has spawned clinical trials in the U.S., Canada, and Europe of what is now called "metronomic chemotherapy" or "chemotherapy lite."
Robert D'Amato, M.D., Ph.D., publishes a paper in the FASEB Journal demonstrating genetic variability in an individual's ability to grow new blood vessels. Intrigued by the fact that almost no African-Americans develop macular degeneration (abnormal blood-vessel growth in the retina leading to blindness), D'Amato exposed the corneas of black and white mice to angiogenic compounds. The black mice were ten times more likely to show inhibited angiogenesis than the white mice.
A study from Folkman's lab, published in the Journal of the National Cancer Institute, demonstrates that cells within a single tumor can vary in their angiogenic activity. Tumor tissue from a human liposarcoma, transplanted into mice, gave rise to three kinds of tumors: highly angiogenic and fast-growing tumors, weakly angiogenic and slow-growing tumors, and nonangiogenic and stable tumors. The presence of some tumor cells with little or no angiogenic activity suggests an explanation for dormant metastases, late tumor recurrence, and changes in rate of tumor progression, and offers a model for testing whether the angiogenic switch can be prevented.
Maria Rupnick, M.D., Ph.D., in Folkman's lab publishes a study in the Proceedings of the National Academy of Sciences showing that angiogenesis inhibitors can control the growth of fat tissue in mice. The study demonstrates that angiogenesis can control the size of any tissue mass, cancerous or not, and also suggests a possible treatment for obesity.
Researchers from Duke University report a landmark Phase III trial of the angiogenesis inhibitor Avastin, a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). In a study of 925 patients with advanced colon cancer, Avastin increased median survival by 30% when compared with standard chemotherapy alone
The New England Journal of Medicine publishes a Phase II study from the National Institutes of Health showing that Avastin prolonged time to disease progression in metastatic kidney cancer by an average of 2 months. The probability of being progression-free at eight months was 30% for patients on high-dose Avastin, 14% for those on low-dose Avastin, and 5% for patients taking placebo.
A trial of Avastin and "metronomic" chemotherapy for women with advanced metastatic breast cancer, using small daily doses of standard chemotherapy drugs, begins at the Dana-Farber Cancer Institute.
Avastin is approved by the Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer in conjunction with standard chemotherapy.
The first complete Phase III clinical trial results for thalidomide are presented at the American Society of Clinical Oncology (ASCO) annual meeting. They show an 80% response rate in patients newly diagnosed with multiple myeloma when thalidomide is added to dexamethasone, as compared with 53% with dexamethasone alone.
Marsha Moses, PhD, Roopali Roy, PhD, and colleagues in the Vascular Biology Program report in the Journal of Biological Chemistry that an angiogenic protein called ADAM 12, when found in urine, is an early sentinel of breast cancer. Tests of urine samples from breast cancer patients found that 94% contained ADAM 12, as compared with only 15% of samples from 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.
The FDA approves Macugen, an anti-VEGF drug that inhibits angiogenesis, developed by Anthony Adamis, M.D., a former Vascular Biology Program investigator. The approval follows two clinical trials showing that the drug significantly slowed vision loss in patients with the "wet" form of age-related macular degeneration.
Researchers from China report the results of Phase III trials of endostatin, conducted in nearly 500 patients with late-stage non-small-cell lung cancer, at the ASCO annual meeting. Patients who had endostatin added to their chemotherapy regimen had increased time to disease progression.
Endostatin receives marketing approval in China.
Folkman and pediatric oncologist Giannoula Klement, M.D., report that a panel of biomarkers in platelets that may permit very early diagnosis of cancer. Working with mice bearing human tumors, they found that platelets took up angiogenesis regulatory proteins secreted by these tumors. The so-called "platelet angiogenesis proteome" is currently in clinical trials for the early detection of recurrent microscopic cancers. The lab is also investigating whether platelet profiles can detect the recurrence of neovascular ("wet") age-related macular degeneration or diabetic retinopathy before it can be seen on ophthalmoscopy.
Randy Watnick, PhD, a principal investigator in the Vascular Biology Program, reports his discovery that tumors prepare distant sites to accept metastases by selectively repressing thrombospondin, a natural angiogenesis inhibitor. The finding raises the possibility that drugs that stop this process could keep metastases from taking hold.
The FDA approves thalidomide (Thalomid, Celgene Corporation) in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma.
The FDA approves the anti-VEGF, anti-angiogenic drug Lucentis for the treatment of neovascular ("wet") age-related macular degeneration, after one-year data showed it to not only slow vision loss but to actually restore vision in some patients. Lucentis-treated patients gained an average of 7 letters in visual acuity on an eye chart while the control group lost an average of 10.5. Twenty-five percent 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, versus about 5% of controls.
Oxford Biomedica, Inc., licences rights to the endostatin and angiostatin genes for the treatment of cancer with anti-angiogenic gene therapy. The company previously licencedlicensed these genes for the treatment of "wet" age-related macular degeneration (AMD) and other eye diseases. Its candidate product, RetinoStat, is expected to enter clinical development in 2008 for wet AMD.
Last updated September 2007.