Cancer Cure Anticipated

Due to the pioneering research of Dr. M. Judah Folkman, Dyckman Professor of Pediatric Surgery at Children's Hospital and Professor of Anatomy and Cellular Biology at Harvard Medical School (HMS), a possible cancer treatment may soon be available.

Cancer Growth

In 1971, Folkman garnered widespread skepticism from the scientific community when he became the first person to suggest that cancer growth is regulated by a switch that is turned on or off by the balance of angiogenesis factors and inhibitors.

Angiogenesis is the process by which capillaries develop and grow.

For nearly thirty years, Folkman and his laboratory partners have been working on a process called anti-angiogenesis, which has proven effective against all types of cancer and successfully eradicated tumors in small animals.

The theory is that cancer growth is de- pendent upon capillary growth, and that if onecan stop capillary growth, cancer growth will haltas well.

"We've not seen a mouse tumor that we cannotregress," Folkman said in a speech before theNational Institutes of Health last year.

Folkman and his colleagues at HMS have isolatedangiogenesis inhibitors, also known asanti-angiogenesis factors, which have been testedupon animals. TNP470 was the first inhibitorisolated from a fungus. Four more inhibitors havebeen subsequently discovered in the human body.

In a report published in the November 1997issue of Nature, Folkman and his researchteam demonstrated that one of the most powerfulinhibitors they had isolated, endostatin, couldsignificantly shrink tumors in mice.

Folkman says endostatin and angiostatin arerelatively safe compared to other forms ofconventional chemotherapy.

"Chemotherapy has toxic side effects. Forendostatin, we don't have any side effects, nor dowe have any side effects for angiostatin," Folkmansays during an interview in a conference roomadjacent to his office at the Children's Hospital.

A Difficult Road

Folkman basks in praise and acclaim for hisresearch today, but he says this wasn't always thecase.

"I had to pursue it through immense criticismduring the 1970s," he says. "Students, fellowcolleagues would laugh. People would say, `Thosesurgeons shouldn't be doing research'".

Folkman began scientific research at his Ohiohigh school and continued through Ohio StateUniversity to medical school. "Many people inmedicine, to improve the medical field, doscience," Folkman says.

After graduating from HMS in 1957, Folkmanbegan a six-year surgical residency atMassachusetts General Hospital. Drafted in 1960for the U.S. Navy, Folkman was assigned to theNaval Medical Center at Bethesda, Md. It was therethat he first began working on blood substitutes.

Folkman and his fellow researchers found thathemoglobin solutions could support an isolatedthyroid gland in a glass chamber. They thenchecked to see if the thyroid gland could supporttumor growth.

"When we put tumors in, they all stoppedgrowing at a millimeter or less," Folkman says."You could see it. The difference was in thethyroid gland with hemoglobin solutions, theendothelial cells along the blood vessels swelledup and prevented blood vessels from reaching thetumor. But when we moved the tumor to the animal,it grew and killed the animal. In 1961, we saw forthe first time that when you have no bloodvessels, tumors stopped growing."

Folkman's observation became his lifelongpursuit, but the scientific community scoffed athis endeavor. Folkman says this was a blessing indisguise because it enabled him to conductresearch without the competition of his peers.Dividing his time between the operating room andthe research laboratory, Folkman dashed from thehospital to the lab and back each day.

The conventional belief at the time was thattumors did not need blood vessels to grow. Folkmanpursued his convictions that cancer cellsspecifically induce blood vessel growth necessaryfor their own growth.

In 1971, Folkman and his research teampublished a paper that outlined the possibility ofangiogenesis factors and inhibitors.

"At that time, we had only one post-doctoralfellow and two technicians," Folkman says. "Wecould work leisurely. No one believed anythinganyway."

But as Folkman and his colleagues continued topublish more research results showing the link ofangiogenesis to cancer, other scientists began topay attention.

In 1982, when work about the firsttumor-derived angiogenesis factor--lateridentified as fibroblast growth factor--waspublished, researchers swarmed into the field.Biotechnology companies and researchers alikebegan researching angiogenesis with a frenzy.

As a result, Folkman stepped down assurgeon-in-chief at Children's Hospital, a post hehad held for fourteen years, to pursue researchfull-time.

Eradicating Tumors

Recently, the research Folkman began in 1961has led to some of the most promising discoveriesin cancer treatment. The isolation of angiogenesisinhibitors, endostatin and angiostatin, by Dr.Michael O'Reilly, a member of Folkman's researchgroup, has been a major breakthrough.

Using a combination of the two inhibitors,Folkman and his colleagues have eradicated largetumors in mice without causing side effects orsigns of drug resistance.

The development of drug resistance in cancerpatients to their chemotherapy can often be thefinal stage of their condition, but endostatin andangiostatin do not induce such reactions. Evenwith such exciting results, Folkman acknowledgesthat the ultimate step in his research is to beable to provide clinical treatment for humans.

Endostatin and angiostatin are now licensed tothe pharmaceutical industry and await movementinto clinical trials.

The Man Behind the Discovery

Folkman's office is inundated with hundreds ofphone calls from hopeful cancer patients and theirfamily members each day. Some have read in thenewspaper that one of the inhibitors has beenshown to regress leukemia. Others call to seekmedical guidance for cancer.

But Folkman can only say that the two strongestangiogenesis inhibitors have yet to start clinicaltrials. He refers patients to doctors currentlyconducting FDA-approved clinical trials. He notesthat besides angiogenesis inhibitors, many otherpotential treatments are currently in development.But the calls continue while Folkman pursues hisresearch.

Though countless medical organizations havehonored his research, Folkman remains humble abouthis achievements. He gives credit to hiscolleagues and maintains the reserved demeanor ofa man who has devoted years of persistent researchin pursuit of a single idea.

Folkman remains cautiously optimistic about thefuture because he knows that much remains to bedone.

"Proof of principle remains to be seen in theclinic," he says.

Meanwhile, millions of cancer victims and theirloved ones eagerly await more conclusive evidenceon the effects of anti-angiogenesis.

"There are 500,000 patients dying each yearfrom advanced cancer and 1.3 million new cancerpatients each year," Folkman says.Courtesy of The New England Journal ofMedicineCANCER AND THE ANGIOGENIC LINK: An insitu carcinoma grows to form a tumor. There aretwo types of cells: angiogenic tumor cells andnon-angiogenic cells. The cancer spreads to otherparts of the body (metastasis). Either angiogenictumor cells or non-angiogenic cells exist. Theangiogenic tumor cells can rapidly grow and bedetected in the clinic.

"We've not seen a mouse tumor that we cannotregress," Folkman said in a speech before theNational Institutes of Health last year.

Folkman and his colleagues at HMS have isolatedangiogenesis inhibitors, also known asanti-angiogenesis factors, which have been testedupon animals. TNP470 was the first inhibitorisolated from a fungus. Four more inhibitors havebeen subsequently discovered in the human body.

In a report published in the November 1997issue of Nature, Folkman and his researchteam demonstrated that one of the most powerfulinhibitors they had isolated, endostatin, couldsignificantly shrink tumors in mice.

Folkman says endostatin and angiostatin arerelatively safe compared to other forms ofconventional chemotherapy.

"Chemotherapy has toxic side effects. Forendostatin, we don't have any side effects, nor dowe have any side effects for angiostatin," Folkmansays during an interview in a conference roomadjacent to his office at the Children's Hospital.

A Difficult Road

Folkman basks in praise and acclaim for hisresearch today, but he says this wasn't always thecase.

"I had to pursue it through immense criticismduring the 1970s," he says. "Students, fellowcolleagues would laugh. People would say, `Thosesurgeons shouldn't be doing research'".

Folkman began scientific research at his Ohiohigh school and continued through Ohio StateUniversity to medical school. "Many people inmedicine, to improve the medical field, doscience," Folkman says.

After graduating from HMS in 1957, Folkmanbegan a six-year surgical residency atMassachusetts General Hospital. Drafted in 1960for the U.S. Navy, Folkman was assigned to theNaval Medical Center at Bethesda, Md. It was therethat he first began working on blood substitutes.

Folkman and his fellow researchers found thathemoglobin solutions could support an isolatedthyroid gland in a glass chamber. They thenchecked to see if the thyroid gland could supporttumor growth.

"When we put tumors in, they all stoppedgrowing at a millimeter or less," Folkman says."You could see it. The difference was in thethyroid gland with hemoglobin solutions, theendothelial cells along the blood vessels swelledup and prevented blood vessels from reaching thetumor. But when we moved the tumor to the animal,it grew and killed the animal. In 1961, we saw forthe first time that when you have no bloodvessels, tumors stopped growing."

Folkman's observation became his lifelongpursuit, but the scientific community scoffed athis endeavor. Folkman says this was a blessing indisguise because it enabled him to conductresearch without the competition of his peers.Dividing his time between the operating room andthe research laboratory, Folkman dashed from thehospital to the lab and back each day.

The conventional belief at the time was thattumors did not need blood vessels to grow. Folkmanpursued his convictions that cancer cellsspecifically induce blood vessel growth necessaryfor their own growth.

In 1971, Folkman and his research teampublished a paper that outlined the possibility ofangiogenesis factors and inhibitors.

"At that time, we had only one post-doctoralfellow and two technicians," Folkman says. "Wecould work leisurely. No one believed anythinganyway."

But as Folkman and his colleagues continued topublish more research results showing the link ofangiogenesis to cancer, other scientists began topay attention.

In 1982, when work about the firsttumor-derived angiogenesis factor--lateridentified as fibroblast growth factor--waspublished, researchers swarmed into the field.Biotechnology companies and researchers alikebegan researching angiogenesis with a frenzy.

As a result, Folkman stepped down assurgeon-in-chief at Children's Hospital, a post hehad held for fourteen years, to pursue researchfull-time.

Eradicating Tumors

Recently, the research Folkman began in 1961has led to some of the most promising discoveriesin cancer treatment. The isolation of angiogenesisinhibitors, endostatin and angiostatin, by Dr.Michael O'Reilly, a member of Folkman's researchgroup, has been a major breakthrough.

Using a combination of the two inhibitors,Folkman and his colleagues have eradicated largetumors in mice without causing side effects orsigns of drug resistance.

The development of drug resistance in cancerpatients to their chemotherapy can often be thefinal stage of their condition, but endostatin andangiostatin do not induce such reactions. Evenwith such exciting results, Folkman acknowledgesthat the ultimate step in his research is to beable to provide clinical treatment for humans.

Endostatin and angiostatin are now licensed tothe pharmaceutical industry and await movementinto clinical trials.

The Man Behind the Discovery

Folkman's office is inundated with hundreds ofphone calls from hopeful cancer patients and theirfamily members each day. Some have read in thenewspaper that one of the inhibitors has beenshown to regress leukemia. Others call to seekmedical guidance for cancer.

But Folkman can only say that the two strongestangiogenesis inhibitors have yet to start clinicaltrials. He refers patients to doctors currentlyconducting FDA-approved clinical trials. He notesthat besides angiogenesis inhibitors, many otherpotential treatments are currently in development.But the calls continue while Folkman pursues hisresearch.

Though countless medical organizations havehonored his research, Folkman remains humble abouthis achievements. He gives credit to hiscolleagues and maintains the reserved demeanor ofa man who has devoted years of persistent researchin pursuit of a single idea.

Folkman remains cautiously optimistic about thefuture because he knows that much remains to bedone.

"Proof of principle remains to be seen in theclinic," he says.

Meanwhile, millions of cancer victims and theirloved ones eagerly await more conclusive evidenceon the effects of anti-angiogenesis.

"There are 500,000 patients dying each yearfrom advanced cancer and 1.3 million new cancerpatients each year," Folkman says.Courtesy of The New England Journal ofMedicineCANCER AND THE ANGIOGENIC LINK: An insitu carcinoma grows to form a tumor. There aretwo types of cells: angiogenic tumor cells andnon-angiogenic cells. The cancer spreads to otherparts of the body (metastasis). Either angiogenictumor cells or non-angiogenic cells exist. Theangiogenic tumor cells can rapidly grow and bedetected in the clinic.