Antiangiogenesis Tested in Pediatric Tumors

NEW ORLEANS--Researchers at the Dana-Farber Cancer Institute haveinitiated a trial of an angiogenesis inhibitor in children withrecurrent solid tumors, the idea being to stunt the growth ofnew blood vessels that nourish the tumor. Speaking at the AmericanCancer Society Science Writers Seminar, Dr. Stephen Skapek, ofthe Department of Pediatrics, Harvard, said that an agent knownas TNP-470 (formerly AGM-1470) was found to be a "potent"inhibitor of blood vessel growth in immunosuppressed mice andproduced a desirable adverse effects profile.

Based on these preclinical results, a phase I study was begunto assess the pharmacokinetics and safety of TNP-470 in 30 patients,aged 2 to 20 years. Three children have been enrolled to date,with diagnoses of recurrent medulloblastoma, CNS sarcoma, andEwing's sarcoma. They will be given the agent intravenously threetimes a week and assessed at 8 weeks.

Dr. Skapek and his colleagues are particularly interested in thedrug's effect on brain tumors. Despite recent therapeutic advances,fewer than 50% of children with brain tumors are cured; therefore,the search for novel agents to treat these children remains ahigh priority, he said.

The mechanism of action of TNP-470 is unclear (see below). Dr.Skapek said the drug was developed when fumagillin, a similarnaturally occurring chemical made by Aspergillus, was "serendipitously"found to be a potent inhibitor of new blood vessel growth.

Although TNP-470 and fumagillin are chemically similar, TNP-470is more potent and has fewer side effects than its biologicalcousin, and is more potent than other analogs to which it hasbeen compared in cell cultures, he said.

Laboratory animals receiving the drug demonstrated mild weightloss, mild suppression of white blood cells and platelets, andmild evidence of microscopic hemorrhage in various tissues.

Fortunately, the blockage of angiogenesis does not interfere withthe efficacy of chemotherapeutic agents, which depend upon bloodflow for delivery. "Preclinical studies are showing thatyou actually get increased delivery of cytotoxic drugs to thetumor when you use TNP-470," Dr. Skapek said. "By inhibitingnew blood vessel formation, the agent seems to decompress existingvessels."

The clinical usefulness of this approach is far from clear, headded. "Even the strongest proponents of antiangiogenic therapyrecognize that it is likely to be of greatest benefit as an adjunctto other standard treatment modalities," he said.

Angiogenesis Is Regulated by Proteins

It has recently become clear, largely through the work of Dr.Judah Folkman at Children's Hospital and Harvard Medical School,that the malignant tumor cell's ability to grow uncontrolled andmetastasize is related to the tumor's ability to control the growthof new blood vessels, Dr. Stephen Skapek said at an American CancerSociety seminar (see story above).

Angiogenesis is regulated by a balance of factors, primarily proteinsthat either stimulate or inhibit angiogenesis, such as basic fibroblastgrowth factor and vascular permeability factor/vascular endothelialgrowth factor.

Whether TNP-470 works directly on these proteins is unclear, hesaid, and the drug's mechanism is, at this point, largely undetermined.