ASCO GI: Tracking Molecular Targets Essential to of GIST Therapy

ORLANDO, Jan. 30 -- In gastrointestinal stromal tumors (GIST), the central -- and potentially initiating -- oncogenic mechanisms can be identified in virtually all cases, a pathologist said here.

Jonathan Fletcher, M.D., an associate professor of pathology at Harvard Medical School, said that because GIST tumors reveal their molecular secrets so easily, researchers have had extraordinary opportunities to identify ways of combating them.

He described the molecular pathogenesis of GIST at an industry-sponsored satellite symposium titled Current Management of Gastrointestinal Stromal Tumors in the Era of Targeted Therapies, which was presented in conjunction with a gastrointestinal cancer symposium.

Identifying those pathways led to the discovery that Gleevec (imatinib) was highly active against GIST, but even in the Gleevec era management can be challenging said George Demetri, M.D., an associate professor of medicine at Harvard Medical School, and director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

Dr. Demetri, whose talk was described as a Practical Approach to Cutting-Edge Data, said that when faced with a patient who fails to respond to Gleevec, clinicians should first confirm that the patient is taking the medication at the prescribed dose and frequency. Since Gleevec is a pill, it faces the same compliance or adherence problems as hypertension or cholesterol medicines -- as patients begin to feel better, they may become less circumspect about adhering to their medication schedule.

Clinicians should also consider a dose escalation of Gleevec or the possibility that a resection might be needed.

When it comes to treating GIST tumors, Burton Eisenberg, M.D., a professor of surgery at Dartmouth Medical School, and an attending surgeon at Dartmouth-Hitchcock Medical Center, in Lebanon, N.H., said that surgery remained the gold standard.

He acknowledged that there was a role for Gleevec both before and after surgery in a lecture titled, Combining Imatinib with Surgery in GIST: Rationale and Ongoing Trials.

He said, for example, that "doctors should consider resection after Gleevec in limited or stable metastatic disease."

When Gleevec stops controlling GIST tumors, other c-KIT inhibitors are now available to treat the lesions, said David D'Adamo, M.D., Ph.D., of the Memorial Sloan-Kettering Cancer Center in New York.

His talk, Second Generation C-KIT Inhibitors for Management of GIST, described the use of the so-called "son of Gleevec" drugs including Sutent (sunitinib), Nexavar (sorafenib), and AMG and reviewed clinical trials of those drugs.

Dr. D'Adama said that understanding tumor biology often leads to "new hypotheses about treatment."

While many researchers have contended that c-KIT is the driving force behind GIST tumor growth, Sebastian Bauer, M.D., a researcher at the West German Cancer Center in Essen, said there were plenty of other targets to attack as well.

Speaking on the topic, Next Generation of Targeted Agents in Management of GIST: Novel Therapeutic Targets, Dr. Bauer said there was a strong rationale for targeting KIT-downstream kinases such as AKT and mTOR with drugs such as perifosine, everolimus and temsirolimus.

"Many more targets need to be addressed," Dr. Bauer said.

Dr. Fletcher disclosed that he is on the speaker's bureau for and received research funding from Novartis Oncology.

Dr. Demetri said his conflicts include being a paid consultant or adviser for Ariad, Genentech BioOncology, Johnson & Johnson, Novartis Oncology, Pfizer Oncology and Plexxikon, Inc.; and is on the speaker's bureau for Novartis Oncology and Pfizer Oncology; and receives research funding from Ariad, Johnson & Johnson, Novartis Oncology and Pfizer Oncology.

Dr. Eisenberg disclosed that he received financial support from Novartis Oncology. Dr. D'Adamo disclosed that he is on the speaker's bureau of Novartis Oncology and Pfizer Oncology

The satellite symposium was sponsored by Novartis Oncology.

The Gastrointestinal Cancers Symposium was jointly sponsored by American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, the American Gastroenterological Association Institute, and the Society of Surgical Oncology.