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Judah Folkman on Isolating the ‘Angiogenic Switch’

Hyer, Richard

doi: 10.1097/01.COT.0000287230.90184.86
Lynn Sage Breast Cancer Symposium

CHICAGO—In his Distinguished Lecturer Speech at the Lynn Sage Breast Cancer Symposium here, M. Judah Folkman, MD, reminded the audience that it isn't just a matter of finding the tumor; one must also isolate the angiogenic switch.

In a free-ranging speech, Dr. Folkman, Andrus Professor of Pediatric Surgery and Professor of Cell Biology at Harvard Medical School, discussed the state of the science in locating angiogenesis inhibitors, including the endogenous, genetically regulated ones that act as tumor-suppressor genes.

The action of many angiogenesis inhibitors can now be increased with small-molecule drugs that can be administered orally.

He also discussed the existence in human tumors of both angiogenic and non-angiogenic cells. Non-angiogenic human tumor cells implanted into SCID mice develop into harmless tumors. However, a predictable percentage switch over at a predictable time, and if accurate biomarkers can be developed to detect them, human cancer can be treated earlier.

Accurate is the key word. Autopsies of 1.8 million auto accident deaths reveal small breast cancers in situ in 39% of women over age 40. But in the living population, breast cancer will be diagnosed in only 1% of women in this age range, for the rest of their lives. According to Dr. Folkman, that gap represents the angiogenic switch.

As biomarkers continue to improve, diagnosis may occur years earlier—quite possibly even before the cancer's location can be determined. “Then what will doctors do?,” Dr. Folkman asked rhetorically.

The “occult” primary tumor is now the rare exception, he said, but in the future, doctors may often have to warn patients that they will develop cancer in a site not yet known.



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Calcitonin as Predictor of Medullary Thyroid Cancer

Dr. Folkman described the case of a boy living in London who was found to have medullary cancer of the thyroid. After surgery, doctors forecast that the cancer would recur in the chest within 10 years.

The boy is now seven years past surgery, and indeed, his calcitonin levels have continued to rise. Calcitonin has a specificity of 98% as a biomarker for this cancer, Dr. Folkman said. Doctors still forecast recurrence, now within three to four years.

Dr. Folkman observed that the case demonstrates the existence of both early biomarkers and clinically silent cancer growth. Many cancers can grow for years without forming a tumor or becoming otherwise symptomatic, he noted.

Substantial data describe clinically silent cancers of the breast, colon, and pancreas. “This comes from back calculations of doubling times, time to recurrence, patients who refuse therapy or choose to discontinue because of severe reactions; as well as misdiagnoses,” Dr. Folkman said.

Tumors stop expanding at 1 mm or less, he said, and cannot continue to expand until the angiogenic switch is made. It could conceivably be interrupted, given a biomarker of sufficient accuracy.

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Pinpointing Tumor Location

Meanwhile, treatment with angiogenesis inhibitors continues apace. Antiangiogenic therapy is now a fourth modality, after surgery, radiotherapy, and chemotherapy. All four are tied to location, but Dr. Folkman envisions a future where antiangiogenic therapy can be used before the location has been pinpointed and the tumor has begun to cause damage.

Sixty percent of human breast cancers make only vascular endothelial growth factor when they start, but in time they make more angiogenic factors. Angiogenesis inhibitors already come in three broad types: those that block one angiogenic factor, those that block two or three, and the broad-spectrum inhibitors.

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Safest Angiogenesis Inhibitors Found in Blood

The safest angiogenesis inhibitors are found in blood, Dr. Folkman said. Sixteen have now been identified.

He described the experiments of Raghu Kalluri, PhD, at Beth Israel Deaconess Medical Center in Boston, which led to discovery of the small peptide tumstatin.

This is in the alpha 3 chain of collagen type 4, which lines all blood vessels. Tumstatin is composed of about 232 amino acids, and circulates in humans and mice at about 336 ng/ml. Dr. Kalluri removed the tumstatin, and tumors in the mice grew up to 400% faster. He then gave tumstatin back at the physiologic level, and the tumors returned to the wild type. Then he gave more, and they regressed.

“This fulfills the classic paradigm of a tumor-suppressor protein, like p53, except that tumstatin is a purely anti-angiogenic protein,” Dr. Folkman said. “It has no other known functions, whereas p53 blocks angiogenesis four ways.”

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Clinical Clues In Down Syndrome

Clues to blood-borne angiogenesis are most evident, he said, in patients with Down Syndrome, who can live to age 70 without getting glioblastoma or cancers of the breast, prostate, or colon.

Many Down patients are found to have three copies of chromosome 21, the trisome, as well as an extra copy of collagen 18, inside of which is endostatin.

In fact, their level of endostatin is almost twice that of the normal population, and this appears to protect them. Down patients have the same amount of diabetes as non-Down individuals, but without diabetic retinopathy. Nor do they have plaque.

The angiogenesis inhibitor celecoxib raises endostatin almost to the Down level. The common antibiotic doxycycline, which is chemically modified tetracycline, increases thrombospondin and lowers the metalloproteinases used by endothelial cells for tumor growth, he said.

The latter is another example of an oral drug approved by the FDA that has also been found to increase the level of endogenous inhibitors.

Progress is being made on other fronts as well, Dr. Folkman said. In late October, a paper published by Olga Volpert and colleagues in Molecular Cancer Research described how exogenous thrombospondin-1 or its peptide derivative ABT510 reverses an angiogenic switch.

“Abbott Laboratories took the big molecule thrombospondin and a small peptide of about nine amino acids, and made it into the drug ABT510,” he explained.

“It's in clinical trial, reducing bulky tumor. Adding Avandia [rosiglitazone] increases the receptor for thrombospondin, and increases anti-angiogenesis and decreases tumor growth.”

Still, he reminded the audience of the need to develop biomarkers based on angiogenesis. “Every tumor removed from the operating room has two populations. About 80% are angiogenic, and the rest are not. Without the angiogenic switch, the tumor's harmless,” said Dr. Folkman.

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ADAM 12 Biomarker

In closing, he discussed the work of Marcia Moses, MD, who has found a biomarker in urine indicating early breast cancer. It is an enzyme called ADAM 12, a metalloproteinase made by blood vessel endothelial cells when they're driven by tumor.

The research was reported at the most recent AACR Annual Meeting (abstract #3286), and subsequently published in September in the Journal of Biological Chemistry. The enzyme detects breast cancer as early as or earlier than a mammogram, with high accuracy, Dr. Folkman said.

“All of this taken together means that as new cancer therapies become less toxic, they can be used earlier and earlier. These include angiogenesis inhibitors as well as vaccines, immunotherapy, telomerase inhibitors, apoptosis inhibitors, among others. They don't hurt your bone marrow, don't cause diarrhea, don't cause your hair to fall out, you don't lose weight, and you can go back to work.”

“There's a paradigm shift: The drugs are not as toxic, and can be used earlier. That leads to a whole new world. For the first time, toxicity and efficacy are disconnected. It used to be thought that in order to kill a cancer, you had to use a drug that made the patient sick. Now the fourth modality can be used earlier.”

© 2005 Lippincott Williams & Wilkins, Inc.
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