OHSU Knight Cancer Institute researcher: study may result in more targeted drugs for GIST

November 13, 2008

PORTLAND, Ore. - According to Oregon Health & Science University Knight Cancer Institute researchers, there is strong evidence that patients can have varying clinical responses to medications depending on the specific makeup of their cancer. The study, which focused on, gastrointestinal stromal tumors, also called GIST, found that the genetic variations in their disease appear to determine which medications will be most effective.

"What these findings mean is that we can begin to develop an individualized approach to the treatment of GIST. We can tailor therapy based on the genetic makeup of the tumor," said Michael Heinrich, M.D., interim head of hematology/medical oncology, and section chief of hematology /medical oncology, Portland Veterans Affairs Medical Center. Heinrich is co-author with Christopher Corless, M.D., Ph.D., vice chairman for research and professor of pathology and OHSU Knight Cancer Institute member.

The data was published in two papers in the Journal of Clinical Oncology. The journal also published an editorial about this research.

Gleevec, (imatinib), the FDA-approved first line of treatment for GIST, was initially developed by OHSU Knight Cancer Institute Director Brian Druker, M.D., to treat chronic myeloid leukemia. Heinrich further pioneered the use of Gleevec for GIST. In GIST, Gleevec targets mutations of the KIT or PDGFRA enzymes KIT mutations are found in 80 percent to 85 percent of tumors; PDGFRA mutations are found in about 5percent of tumors; and no mutations of KIT or PDGFRA are found in 10 percent to 15 percent of tumors, so called wild-type tumors.

In the first study, Heinrich analyzed tumor specimens from almost 400 GIST patients who were treated with Gleevec. The presence and type of mutation predicted their response to Gleevec: patients with a certain type of KIT mutation -- KIT exon 11, which is present in 70 percent of GIST patients -- had the best response to Gleevec, followed by wild-type GISTs, and then GIST with KIT exon 9 mutations. In addition, evidence indicates that patients with exon 9-mutant GIST did better if they receive double the usual daily dose of Gleevec. In contrast, patients with other types of GIST, do equally well on the standard daily dose of Gleevec.

Although the vast majority of GISTs respond well to Gleevec treatment, over time tumors can become resistant and regrow. To combat this problem, a second drug, Sutent (sunitinib), was tested in clinical studies and shown to be active in treating Gleevec-resistant GIST. Like Gleevec, Sutent targets KIT and PDGFRA enzymes. However, unlike Gleevec, Sutent can also block blood vessel formation in GISTs.

To better understand how Sutent works, Heinrich's team analyzed tumor samples from 78 subjects treated with Sutent as part of a phase I/II clinical study. These results were reported in a second article in the journal. Notably, trial participants whose tumors have KIT exon 9-mutations or wild-type tumors, had better survival during Sutent treatment, when compared with patients whose tumors had KIT exon 11-mutant tumors. Using laboratory methods, Heinrich's team found that Sutent was more potent than Gleevec for inhibiting the aberrant KIT enzyme activity in KIT exon 9-mutant and wild-type tumors.

In addition, Heinrich's team found that a common cause of Gleevec-resistance in GIST is the development of new mutations that block the ability of Gleevec to inhibit the rogue KIT enzyme. In a test tube system, Sutent can inhibit some but not all of these resistance mutations.

"In GIST the KIT enzyme acts like a car motor that is stuck running at full speed. Gleevec acts like a key that allows the motor to be turned off. Unfortunately, over time, GIST cells can further change the lock by mutating, so that Gleevec can't turn off the motor. Sutent is a different kind of key that can work on some Gleevec-resistant tumors. But it only works on some secondary mutations. We need other keys, or other drugs, to attack all of the possible resistance mutations," Heinrich said.

"We knew that Sutent worked, but these results help show us why it works. These early data show that there are differences in how certain mutations and genes respond to therapy. By finding the original defect, we can predict better an individual tumor's response to Sutent."

Heinrich said that larger studies are needed to confirm these results, as well as better, quicker testing methods for these gene mutations.

Oregon Health & Science University

Love on the Line
by Deeanne Gist (Author)

Rural switchboard operator Georgie Gail is proud of her independence in a man's world ... which makes it twice as vexing when the telephone company sends a man to look over her shoulder.

Dashing Luke Palmer is more than he appears though. He's a Texas Ranger working undercover to infiltrate a notorious gang of train robbers. Repairing telephones and tangling with this tempestuous woman is the last thing he wants to do. But when his stakeout puts Georgie in peril, he realizes more than his job is on the line.

Measure of a Lady, The: A Novel
by Deeanne Gist (Author)

Rachel van Buren arrives in Gold Rush San Francisco with two wishes: to protect her younger siblings and to return east as soon as possible. Both goals prove more difficult than she could imagine as her brother and sister are lured by the city's dangerous freedom and a missionary-turned-gambler stakes a claim on her heart. Rachel won't give up without a fight though, and soon all will learn an eloquent but humorous lesson about what truly makes a lady. Speak Politely. Even when you're the only respectable woman around, protesting the decadence of a city lost to gold fever. Dress Modestly. Wear your sunbonnet at all times. Ensure nobody sees your work boots muddied by the San Francisco streets. Remain Devoted to Family. Protect your siblings from the lures of the city, even...

Maid to Match
by Deeanne Gist (Author)

From the day she arrives at the Biltmore, Tillie Reese is dazzled--by the riches of the Vanderbilts and by Mack Danvers, a mountain man turned footman. When Tillie is enlisted to help tame Mack's rugged behavior by tutoring him in the ways of refined society, the resulting sparks threaten Tillie's efforts to be chosen as Edith Vanderbilt's lady's maid. But the stakes rise even higher when Mack and Tillie become entangled in a cover-up at the town orphanage. They could both lose their jobs...and their hearts.

Trouble with Brides, The
by Deeanne Gist (Author)

Get three historical romances in one omnibus edition from award-winning, bestselling author Deeanne Gist. This special edition introduces new and value-minded readers to Dee's unbeatable blend of laugh-out-loud humor, poignant drama, and irresistible romance. Includes three of Dee's most popular novels: A Bride Most Begrudging (more than 170,000 sold!), Courting Trouble, and Deep in the Heart of Trouble.

A Bride in the Bargain
by Deeanne Gist (Author)

In 1860s Seattle, a man with a wife could secure himself 640 acres of timberland. But because of his wife's untimely death, Joe Denton finds himself about to lose half of his claim. Still in mourning, his best solution is to buy one of those Mercer girls arriving from the East. A woman he'll marry in name but keep around mostly as a cook.

Anna Ivey's journey west with Asa Mercer's girls is an escape from the griefs of her past. She's not supposed to be a bride, though, just a cook for the girls. But when they land, she's handed to Joe Denton and the two find themselves in a knotty situation. She refuses to wed him and he's about to lose his land. With only a few months left, can Joe convince this provoking--but beguiling--easterner to be his bride?

Beguiled
by Deeanne Gist (Author), J. Mark Bertrand (Author)

When novelists Deeanne Gist and J. Mark Bertrand first met in a Houston critique group, they never expected where friendship would take them. She wrote romance; he wrote crime novels. But growing respect for each other's work culminated in the decision to try blending their talents into this wonderfully engaging story merging romance and mystery. Rylee Monroe walks dogs in old-money Charleston, a part of the city recently targeted by a daring thief. Logan Woods works the crime beat for the local paper but dreams of a life as a nonfiction writer. When the string of robberies takes a strange twist, Logan sees the making of a once-in-a-lifetime book that seems to circle around this charming, eye-catching dogwalker. But pursuing the truth means ignoring that he seems to be falling for her....

Deep in the Heart of Trouble
by Deeanne Gist (Author)

Humorous romance from a best-selling, Christy-award-winning author. A sequel to Courting Trouble, set in Texas in the 1890's.

Courting Trouble
by Deeanne Gist (Author)

Bestselling, Christy award-winning author's humorous romance--a 30-year-old single woman who draws up a list of the eligible bachelors in 1890's Texas.

Bride Most Begrudging, A (Thorndike Christian Historical Fiction)
by Bethany House Publishers

When Lady Constance Morrow finds herself held against her will aboard a ship bound for the American colonies?a ship filled with "tobacco brides" and felons she is quite sure that as soon as she arrives she will find a reasonable man who will believe her father is an earl and send her back on the next ship to England. Instead she meets Drew O'Connor, a determined Colonial farmer who is nearly as headstrong as she is. Drew wins Constance as his bride but soon realizes he has taken on much more than he bargained for

100 Questions & Answers About Gastrointestinal Stromal Tumor(GIST)
by Ronald DeMatteo (Author), Marina Symcox (Author), George D. Demetri (Author)

Whether you're a newly diagnosed GI Stromal patient, a survivor, or a friend or relative of either, this book offers help. The only text to provide the doctor's and patient's views, 100 Questions & Answers About Gastrointestinal Stromal Tumor (GIST) gives you authoritative, practical answers to your questions about treatment options, post-treatment quality of life, sources of support, and much more. This book is an invaluable resource for anyone coping with the physical and emotional turmoil of this frightening disease.