Study Finds Proteins That May Kill Cancer

More than 200 people packed the Fairchild Biochemistry Lecture Hall Friday afternoon to hear Children's Hospital researcher M. Judah Folkman speak about his research which identifies human proteins that may be used as drugs to shrink cancer tumors.

The speech, "Strategies for Discovery of Endogenous Angiogensis Inhibitors," was the 12th Annual Pfizer Lecture in honor of Konrad E. Bloch.

Folkman's research centers around using proteins to block the growth of the blood vessels which feed cancerous tumors. Injections of two such proteins--angiostatin and endostatin--into mice with cancerous tumors eventually hampered the growth of the tumors. The proteins caused the tumors to shrink, and eventually, to stop growing back.

"The combination of angiostatin and endostatin appears to eliminate tumors in mice," beyond detectable levels, Folkman said.

Folkman began to consider the possibility of using angiostatin and endostatin together in 1996 as a first-stage therapy to eliminate cancer tumors.

His most recent work has shown that successive injections of the inhibitors in mice cause the tumors to shrink at the same rate, but they take longer to grow back each time. After several successive rounds, the tumors do not grow back at all.

"There are many approaches to treating cancer," said Jack L. Strominger '46-'47, Higgins professor of biochemistry. "His [finding] is novel--it is based on the realization that, when a tumor mass grows, it can't survive without a blood supply to feed it."

Strominger said the discovery found natural inhibitors to angiogenesis--the mechanisms by which new blood vessels grow.

Unlike other drugs, the proteins do not cause the tumors to develop resistance since the proteins are found naturally in the regulatory system. Because of this, the proteins are some of the most powerful anticancer drugs in existence, Folkman said.

"The development of resistance is a major problem in cancer therapy," said Strominger, who created the lecture series and secured its funding from Pfizer, a pharmaceutical company. "You would be 10 miles ahead in the game if there is no resistance."

When Folkman proposed the idea that tumor growth depends on a close presence of blood vessels in 1971, few medical experts took him seriously. Now, Folkman's research is on the forefront of establishing effective anti-cancer drugs.

Folkman said his entire career has been dedicated to the study of growth of blood vessels.

"My work has been focused on the problems of what controls the growth of the microvesicles in the body," he said. "In the past 25 years, it has been discovered that tumors [in the body] must recruit from the host vascular endothelial cells...and without, virtually all tumors remain stuck, sometimes for years, at a small size."

Without blood vessels as feeding tubes, the tumors are malnourished and cannot spread throughout the body. Vascular endothelial cells make up a layer of cells that line blood vessels.

"[O]nce angiogenic, the tumors become very dangerous and potentially lethal [and grow aggressively,]" Folkman said. "The proteins which the tumor cells deploy to recruit the vascular endothelial cells began to be identified 12 years ago."

As the proteins that stimulate the growth of these endothelial cells were discovered, inhibitors that could be used as drugs also were identified.

About 10 years ago, the first inhibitor was discovered. Clinical trials began in 1992 to establish the use of the inhibitor--TNP-470--as a cancer drug, largely as an adjunct after chemotherapy.

"Tumor growth could be slowed significantly, but not reversed [using TNP-470]," Folkman said. "Nevertheless, for the first time, there was no drug resistance."

About two years ago, it was discovered that tumor growth could be slowed almost completely by using normal proteins to signal the vascular endothelial cells which line blood vessels.

"For the first time, it became possible to shut off angiogenesis and cause [tumor] regression," Folkman said. "This was caused by a specific signal which only talks to endothelial cells."

The proteins are part of the larger regulatory system that maintains the layer of endothelial cells in blood vessels. The cells rarely divide, and are normally replaced by a completely new set every three years. However, when they are stimulated by the proteins sent out by the cancerous tumors, the cells' turnover rate skyrockets to every four days, fueling the growth of the vessels to feed the tumors.

"When anything in the body grows, there are factors that promote and factors that inhibit the growth," said Strominger. "The balance between the two determines the rate of growth."

Folkman said that existing tumors actually provide inhibitors for growth of blood vessels elsewhere in the body--this spread is known as metastases.

"It is well known that some tumors suppress the growth of metastases," Folkman said. "Our question was [that] if tumor size is ultimately controlled by endothelial proliferation, could a primary tumor suppress growth of a distant metastasis by delivering an endothelial inhibitor to it through the circulation?"

Folkman's group showed that mice which had tumors with naturally occurring inhibitors had lower metastases than those with surgically removed tumors.

In the past, the spread of cancer even after tumors had been removed was blamed on stress induced by the surgery, not the removal of natural inhibitors.

Folkman's group began to consider using angiostatin as a treatment to maintain dormancy of the tumors two years ago.

Since then, Folkman's group has demonstrated that these natural inhibitors can be injected into tumors, causing them to shrink. This creates the possibility of using the inhibitors as a first-line therapy against cancer. These results are unpublished.

According to Folkman, over 60 pharmaceutical companies are focusing on angiogenesis for cancer therapeutics, and large-scale clinical trials of some of the first inhibitors are likely to occur in the near future.

The drugs may have side effects, however, such as reducing the rate at which wounds heal and preventing fetus development. However, Folkman said the side effects are minimal when contrasted to those caused by chemotherapy: hair and weight loss, nausea and diarrhea.