Scorpion Venom Hints It May Sting Gliomas

LOS ANGELES, July 31 -- A synthetic version of the venom of a deadly insect is being tried to help patients with glioblastoma multiforme, according to researchers here.

A peptide called chlorotoxin -- found in the venom of the giant yellow Israeli scorpion Leiurus quinquestriatus - has the unusual property of crossing the blood-brain barrier and binding to tumor cells, but not normal cells, according to Adam Mamelak, M.D., a neurosurgeon at Cedars-Sinai Medical Center here.

Preclinical studies suggested that combining the peptide with radioactive iodine might be a useful way of attacking gliomas, a tumor type whose prognosis has not improved in two decades, Dr. Mamelak and colleagues reported in the August issue of the Journal of Clinical Oncology.

And in a Phase I safety trial, the researchers said, the combination of the synthetic peptide - dubbed TM-601 -- and iodine¹³¹ was well-tolerated, with no apparent dose-limiting toxicities. While the study was not designed to evaluate efficacy, the treatment appeared to have an anti-tumor effect, said Dr. Mamelak and colleagues. A Phase II dose-finding study is under way.

"We're using the TM-601 primarily as a carrier to transport radioactive iodine to glioma cells," Dr. Mamelak said, adding there are data to suggest that the peptide may have an antitumor effect on its own, although that remains to be demonstrated.

"If studies continue to confirm this, we may be able to use it in conjunction with other treatments, such as chemotherapy, because there may be a synergistic effect," he said. "TM-601's ability to impede cancer growth could allow us to reduce the dose of chemotherapy to achieve a therapeutic effect."

The researchers enrolled 17 patients with glioblastoma multiforme and one with anaplastic astrocytoma, with documented recurrent disease and a Karnofsky performance status of at least 60%, who were eligible for cytoreductive craniotomy. During the surgery, an intracavitary catheter with a subcutaneous reservoir was placed in the tumor cavity.

Two weeks later, patients received the peptide, carrying 10 milliCuries of radioactive iodine, at one of three doses -- 0.25, 0.50, or 1.0 mg.

There were no clinically significant acute adverse events during the infusion of the combination at any dose level and most events reported during observation were mild to moderate, the researchers said. Four patients had serious adverse events that might have been related to the study drug, including infection, paresis, and cerebral edema.

Radiographic follow-up 90 days after the infusion was available for 16 patients. Seven had stable disease and nine had progressive disease. Long-term follow-up was available for six patients - one had a partial response (defined as at least a 50% decrease in tumor volume from baseline), four had stable disease and one was progressing.

Two patients -- one with stable disease and the one with a partial response -- went on to achieve a complete radiographic response without evidence of disease for 32 and 30 months, respectively, Dr. Mamelak and colleagues reported. As of March 2006, both were alive 37 and 39 months after surgery.

A phase II trial has been initiated using escalating peptide and radiation doses with multiple injections for patients with high-grade glioma.

The study was supported by TransMolecular Inc. of Cambridge, Mass., which is developing TM-601. Dr. Mamelak owns stock in the company and several members of the study team were either employees of the company or had consulted for the company.