Three Prominent Researchers Receive GM Foundation Awards

WASHINGTON--Three internationally renowned scientists received the 1997General Motors Cancer Research Foundation Science Awards for their groundbreakingdiscoveries. Each of the award winners was given a gold medal and a $100,000prize during ceremonies held at the Library of Congress.

Herman D. Suit, MD, PhD, Andres Soriano Professor of Radiation Oncologyat Massachusetts General Hospital and Harvard Medical School, won the CharlesF. Kettering medal for outstanding contributions to the treatment of cancer.

The Charles S. Mott medal for outstanding research in cancer causationor prevention went to M. Judah Folkman, MD, Julia Dyckman Andrus Professorof Pediatric Surgery, Harvard Medical School. Paul M. Nurse, PhD, director-generalof the Imperial Cancer Research Fund in London, received the Alfred P.Sloan, Jr., medal for his basic science contributions to cancer research.

The awards are named after former General Motors executives. The Foundationawarded its first prizes in 1979. Since then, 73 scientists have sharedawards or won an award on their own.

Avoiding Amputation in Sarcoma

In 1959, when Dr. Suit began his work on sarcomas at what was then theM.D. Anderson Hospital & Tumor Institute, 60% to 70% of patients withmalignant tumors of the soft tissue of an arm or leg lost the limb to amputation.

Today, thanks to Dr. Suit's pioneering work, "virtually all patientswith soft tissue sarcomas in their extremities are able to avoid amputationby treatment with radiation combined with surgery and sometimes chemotherapy,"the General Motors Foundation said in its awards booklet.

Four decades ago, radiation treatments yielded poor results. "Itwas dogma that sarcomas were radiation resistant," Dr. Suit said inhis Laureate's Lecture prior to the awards ceremony.

However, Dr. Suit hypothesized that these unacceptable outcomes stemmedfrom large tumor size, low radiation doses, and hypoxia (known to resultin radiation resistance) of the sarcoma cells. He tested his thesis using"supervoltage" equipment newly installed at the M.D. AndersonCancer Center.

"Extremity sarcomas were treated under conditions of tourniquet-inducedhypoxia," the GM Foundation noted. The local control rate of softtissue sarcomas irradiated under these conditions after excision was veryhigh. Further, similar tumors treated under conditions of normal bloodflow did equally well.

Analysis of the first 100 soft tissue sarcoma patients managed in thisway showed that local and distant control depended upon tumor grade andsize.

Dr. Suit continued his radiation work after moving to Harvard in 1970.In a collaboration with colleagues at Mass General, using preoperativeradiation (50 Gy), he achieved eradication of the primary sarcoma in 90%of patients, with good functional and cosmetic outcomes.

A study at Mass General of aggressive chemotherapy and radiation administeredprior to conservative surgery in patients with large, intermediate- tohigh-grade sarcomes is now going into a larger phase II intergroup trial.

Currently, Dr. Suit is exploring the use of proton therapy in placeof standard radiation therapy, following years of experimenting with "fractionated"doses given over a period of days. A recent analysis of this approach in180 chon-drosarcoma and 220 chordoma patients showed 10-year tumor-freesurvival rates of 92% and 45%, respectively.

Next year, Dr. Suit will help inaugurate a new proton therapy centerat Mass General, in partnership with the NCI, which will offer treatmentto patients with sarcomas and cancers of the brain, head, and neck, prostate,and bladder, and to children with solid tumors.

Initial Skepticism on Angiogenesis

Dr. Folkman was cited for extensive contributions explaining the roleand importance of angiogenesis in tumor growth. "He realized thatthe tumor and the blood vessel cells within the tumor constituted a highlyintegrated and interdependent ecosystem," the GM Foundation said.

Dr. Folkman published his first paper on tumor angiogenesis in 1971."That paper must have been ahead of its time, because we still haveall the reprints," he quipped during his Laureate's Lecture.

When his laboratory succeeded in purifying basic fibroblast growth factor(bFGF), the first angiogenic molecule, "there was a celebration inour lab and skepticism outside," he said. Since then, 13 other angiogenicmolecules have been discovered by other investigators.

Dr. Folkman and his team went on to discover that malignant cells secreteproteins that cause normally resting endothelial cells to proliferate rapidly--aprocess that once turned on, stays on and feeds the tumor so it continuesto grow. Moreover, the newly dividing endothelial cells also secrete growthfactors that allow tumors cells to invade nearby tissue and metastasize.

More recently, Dr. Folkman discovered angiostatin and endostatin, thetwo most powerful inhibitors of angiogenesis known and, he said, the mostpowerful anticancer drugs ever tested in animals.

"Angiogenesis therapy has now moved from the laboratory into theclinic," the GM Foundation said. Eight angiogenesis inhibitors arenow under investigation in more than 100 clinical trials in the UnitedStates and the United Kingdom. Chief among them is the first angiogenesisinhibitor discovered in Dr. Folkman's Laboratory, TNP-470.

Cyclin-Dependent Kinases

Dr. Nurse was cited both for his discovery of the first cyclin-dependentkinase and for demonstrating its role as the prime regulator of the cellcycle.

"Dr. Nurse identified genes for several important regulators ofcyclin-dependent kinases, and thereby helped to characterize the networkcontrolling entry into cell division," the GM Foundation said. "Hisresearch contributed greatly to the understanding of the altered cell-cycle-controlpathways found in cancers."

His work includes demonstrating that the basic mechanism by which humancells control progression through the cell cycle is closely akin to thatin yeast. In cancer cells, he found that cyclin-dependent kinases are activatedincorrectly and that this may cause premature mitosis and cell divisionbefore all chromosomes are properly replicated and separated. As a result,genetic damage may occur and accelerate the advancement of cancer.

"The work that Dr. Nurse initiated has become of great interestto many laboratories around the world," the GM Foundation said. Scientistsare studying the genes that control cyclin-dependent kinases and the differenttypes of cyclin-dependent kinases and their functions. "It is hopedthat this area of study will provide a new understanding of cancer andpossible targets for future cancer therapies," the Foundation said.