Early testing begins for new GIST drug

It’s for people who can’t tolerate Gleevec or had cancer growth on Gleevec

Early human testing has begun on a new drug to see if it can be effective against GIST in patients who couldn't tolerate Gleevec or had cancer growth while on Gleevec.

SU011248, like Gleevec, is a signal transduction inhibitor and comes in capsule form. It is made by Sugen, based in San Francisco, California. Sugen was acquired in August 1999 by Pharmacia Corporation, one of the world's largest multinational pharmaceutical companies.

According to the draft trial protocol, SU011248 was first given to test subjects who didn't have GIST to begin determining the most appropriate and tolerable dose. The phase I (earliest phase of human testing) clinical trial will help determine the best dose for GISTS patients, see how GIST responds to SU011248, and what are the side effects.

According to its Web site (www. sugen.com), Sugen has focused on investigating signal transduction pathways that transmit messages into a cell and its nucleus. These pathways are key to the normal functioning of virtually every type of cell.

Normal cells don't proliferate unless they are signaled to do so by other nearby cells. This ensures that cell and tissue growth is done in an orderly, interdependent manner. Accurate and timely cell signaling — called signal transduction — is key to a healthy balance of cell growth and metabolism.

Many cancers happen, researchers believe, when the cell signaling pathway breaks down, and the cells begin proliferating in an uncontrolled manner.

Of the many cancer-related genes (oncogenes) identified to date, says Sugen's Web site, many appear to be abnormal versions of signaling pathway components, such as tyrosine kinases (TKs), which are enzymes that function as signaling molecules. Other oncogenes include serinethreonine kinases (STKs), the most abuntant molecules found in cells, responsible for controlling the cell cycle, a cell's response to stress, the development of certain cells and tissues, and more.

The close tie between cell signaling aberrations and cancer has led many researchers, including those at Sugen , to think that certain cancers could be classified more effectively by their signaling pathway defects than their mere physical location (e.g., TK or STK rather than breast or lung).

Using this approach, Sugen's Web site says, a suspected cancer might be diagnosed by first sending a tissue sample to a pathology lab. If cancerous, gene or protein expression profiling could be done. If overexpression of a particular TK was found, the doctor could treat the cancer with the appropriate target-specific signal transduction inhibitor.

SU11248 is a small molecule drug — small molecule, because they more easily penetrate cell membranes and the blood-brain barrier, and they can be delivered orally or intravenously. These molecules also tend to be cheaper to make.

Initial results of animal studies for this SU11248 indicate potential activity against some forms of cancer by inhibiting the tumor’s blood supply, thereby inhibiting tumor growth and survival.

Sugen's draft trial protocol and Web site emphasize it is not clear whether this drug will be effective in treating cancer in people.

Future phase II trials, which will look at the efficacy of SU11248, are planned. When these trials are started, they will be listed at ClinicalTrials. gov Web site.

Several Life Raft group members learned about SU11248 at a mid- March meeting with Dr. Robert G. Maki of Memorial Sloan-Kettering Cancer Center in New York City.

Attending the meeting were Norman Scherzer, Tania and Robert Stutman, Dan C., Joan A., Ana Baldor-Bunn's aunt Teresita and her son.

“Dr. Maki showed us slides,” said Robert Stutman, “showing us what GIST looks like and how Gleevec works. He explained everything as he went along so even a layman could understand.”

Dr. Maki also talked about a phase II trial of a drug by Millennium Pharmaceuticals called PS-341 for patients with advanced or metastatic sarcoma (though not specifically GIST).

Right now there are only two places where the trials are being held, said Robert: Dana-Farber Cancer Institute in Boston, Mass., and Memorial Sloan- Kettering. The trials are starting with just a handful of patients.

“Let us hope that these drugs are as successful or more successful than Gleevec,” said Joan.