Radioactice scorpion venom (!) for brain cancer

[heblaj01]

A description of the mode of action of this experimental drug (TM-601) to treat gliomas (currently in phase II trial) in this article:

Radioactive Scorpion Venom For Fighting Cancer

Source: Health Physics Society Posted: June 27, 2006

Health physicists are establishing safe procedures for a promising experimental brain-cancer therapy which uses a radioactive version of a protein found in scorpion venom. For many, this will conjure images of Spiderman's nemesis, the Scorpion. The purpose of this work is not science fiction, but rather to help to develop a promising new therapy for brain cancer. The venom of the yellow Israeli scorpion preferentially attaches to the cells of a type of essentially incurable brain cancers known as gliomas.

Responding to this urgent problem, scientists at the Transmolecular Corporation in Cambridge, Massachusetts created a radioactive version of this scorpion venom. Called TM-601, it contains an artificial version of the venom protein, attached to a radioactive substance called iodine-131 (I-131). When it enters the bloodstream, the compound attaches to the glioma cells, then the I-131 releases radiation that kills the cell.

This compound has enabled an experimental treatment for high-grade gliomas, found in 17,000 people in the US every year and usually causing death in the first year of diagnosis. Patients would simply be injected with the compound in an outpatient procedure, without needing chemotherapy or traditional radiotherapy. The first, early human trials of the venom therapy showed promising signs for treating the tumor and prolonging survival rates for patients.

At the Health Physics Society meeting this week in Providence, Rhode Island, Alan M. Jackson of the Henry Ford Health System in Detroit will report that he and his colleagues recently established safe procedures for the therapy, currently in the second sequence of phase-II human trials, which involve higher doses of radiation than the earliest trials.

"The health physicist has the duty to ensure to ensure that these therapies are conducted both legally and safely," Jackson says. "Obviously, a key objective is to bring these patients home and to ensure that their loved ones and the environment are properly protected."

In the trials, one group of patients received the therapy three times over three weeks, while the other group received the therapy 6 times over 6 weeks. Each group received the same dose of radioactive iodine per week, 40 millicuries (mCi). According to Jackson, this is not tremendously high compared to a thyroid cancer treatment, in which patients receive up to 200 mCi in a single treatment.

As Jackson discovered, the TM-601 that does not bind to cells in the body is rapidly excreted in the urine. "Other tissues will receive some dose," he says, "but the vast majority of the dose is delivered to the cancer cells." To prevent the radioactive compound from being absorbed by the thyroid, which has a voracious appetite for iodine, the patients were given large amounts of non-radioactive iodine prior to the therapy to block the thyroid uptake of I-131.

When the patient returns home several hours after the procedure, there are radiation doses to any family members at home due to the presence of radiation in the patient's body. Such radiation exposures to family members, Jackson found, are low and comparable to those from a family member receiving standard thyroid cancer therapy.

Jackson is encouraged by the safety of this procedure and its potential to help patients with brain gliomas. A recent study of the earlier phase II trials showed that patients receiving up to 40 mCi of weekly dose did not show evidence of any adverse reactions attributable to the radiation. The second-sequence phase II trial at Henry Ford involves 3 patients, with a total of 54 patients across the US currently in investigational trials for the therapy.

[heblaj01]

http://www.rxpgnews.com/cancer/brain/article_4744.shtml

Synthetic scorpion venom delivers radioactive iodine to malignant gliomas By Cedars-Sinai Medical Center Jul 30, 2006, 02:45

A new method of delivering a dose of radioactive iodine – using a man-made version of scorpion venom as a carrier – targets deadly brain tumors called gliomas without affecting neighboring tissue or body organs. After a Phase I clinical trial conducted in 18 patients showed the approach to be safe, a larger Phase II trial is underway to assess the effectiveness of multiple doses.

Adam N. Mamelak, M.D., a neurosurgeon at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute, led the Phase I trial and is first author of an article in the August of the Journal of Clinical Oncology.

The key ingredient is TM-601, a synthetic version of a peptide, or protein particle, that naturally occurs in the venom of the Giant Yellow Israeli scorpion. TM-601 binds to glioma cells and has an unusual ability to pass through the blood-brain barrier that blocks most substances from reaching brain tissue from the bloodstream.

"We're using the TM-601 primarily as a carrier to transport radioactive iodine to glioma cells, although there are data to suggest that it may also slow down the growth of tumor cells. 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. In other words, TM-601's ability to impede cancer growth could allow us to reduce the dose of chemotherapy to achieve a therapeutic effect," said Mamelak, who serves as co-director of the Pituitary Center at Cedars-Sinai.

About 17,000 Americans are diagnosed with gliomas each year. The tumors are extremely aggressive and deadly, with only eight percent of patients surviving two years and three percent surviving five years from time of diagnosis. Even when surgery is performed to remove a glioma, some cancer cells invariably remain behind and proliferate.

"Despite advances in surgical technology, radiation therapy and cancer-killing drugs, length of survival has remained virtually unchanged for patients with gliomas," said Keith L. Black, M.D., director of the Maxine Dunitz Neurosurgical Institute and interim chair of Cedars-Sinai's Department of Neurosurgery. "Only in the recent past have we begun to discover some of the molecular, genetic and immunologic mechanisms that enable these deadly cancer cells to evade or defy our treatments, and we are developing innovative approaches, such as this one, that capitalize on these revelations."

Patients who consented to participate in the Phase I study first underwent tumor-removal surgery. Fourteen to 28 days later, a single, low dose of radioactive iodine (131I) attached to TM-601 was injected through a small tube into the cavity from which the tumor had been removed.

Although TM-601 had been tested in earlier laboratory and animal experiments, it had never been given to humans. Therefore, the primary objective of this study was to document that 131I-TM-601 could be administered to humans safely. In addition, the researchers sought to begin to assess the drug's anti-tumor effect and dosing standards. Six patients agreed to receive additional doses at one of three different levels (.25 mg. of TM-601, .5 mg. of TM-601, and 1 mg. of TM-601, each carrying the same amount of iodine).

"In this first human trial, treatment of patients with recurrent high-grade glioma with a single intracavitary dose of 131I-TM-601 was well tolerated to the maximum dose …. Very few adverse side effects occurred during the initial 22-day observation period, suggesting the dosing level of peptide used in this study is safe and well-tolerated in humans," the article states.

While median length of survival for all patients was 27 weeks, two patients, women in their early 40s, had a "complete radiographic response," meaning there was no evidence of residual tumor according to magnetic resonance imaging scans. The patients were still alive beyond 33 and 35 months after surgery, despite the low dose of TM-601 and radiation levels that were below expected therapeutic levels.

Analyses also showed that most of the radioactivity delivered by the drug left the region within 24 hours of administration. That which lingered was "tightly localized to the tumor cavity and surrounding regions, suggesting discrete binding to the tumor." The drug was eliminated primarily through the urine, with radiation doses to the thyroid and other vital organs remaining extremely low and harmless.