Memorial Sloan-Kettering Cancer Center (MSKCC) is preparing for what it calls “a breakthrough clinical trial” that will test a new drug that uses a MEK inhibitor to target ETV1 in combination with imatinib on a small group of newly diagnosed GIST patients with advanced disease.
We hope to begin recruitment in August, said Dr. William Tap, Section Chief of Sarcoma Oncology at MSKCC. The Phase II trial will be small, with only about 45 participants, and will only have one site at MSKCC in New York City, he said. That’s because “we just want to show that this approach works,” before recruiting for a larger scale trial, Dr. Tap said. There will be a Phase I portion of the trial to define the Phase II doses of the combination regimen.
The trial is unique because most new GIST clinical trials recruit patients that already have taken imatinib, sunitinib or other drugs and have already developed resistance to those drugs. This trial will try to show that treatment with a combination of imatinib and the MEK inhibitor from the start will be even more effective in combating GIST and will reduce the likelihood of secondary mutations that cause resistance.
Novartis Pharmaceuticals is co-developing the MEK inhibitor, MEK162, with Array Biopharma. MEK162 has been through Phase I trials and recently completed a Phase II trial in NRAS-mutant melanoma.
Dr. Tap said the research that opened the way to this new approach was led by his colleague at MSKCC, Dr. Ping Chi. She was able to show that ETV1, a transcription factor, was essential to the survival of GIST; while it was hard to target ETV1 because it didn’t have molecule-binding pockets that could be blocked by drugs, she found a way around this problem by discovering that MEK inhibitors could do that job.
“MEK inhibitors alone doesn’t seem to be great, but by doing combination therapy with imatinib we get a dramatic response,” Dr. Chi said. ETV1 is a master regulator that is highly expressed in all GISTS.
“Ping’s discovery is one of the major discoveries that we have seen in GIST research since the discovery of KIT,” Dr. Tap said.
ETV1 inhibitor takes lead in combination approach to clinical trials
Posted by Phil Avila – May 20, 2013 – News, Research
In 2010, Dr. Chi published a study she led, “ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours,” in Nature.
PITTSBURGH, Aug. 23, 2012 – For the seventh year in a row, researchers from the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, have received funding from the GIST Cancer Research Fund – a patient-driven organization that funds research on gastrointestinal stromal tumors (GISTs). These tumors occur in the gastrointestinal tract and initially can be successfully treated with the targeted therapy drug Gleevec, but rapidly develop resistance to the treatment.
The GCRF has made available the various updates and technical presentations from recently held sponsored events. These include:
- Advances in GIST Diagnosis and Risk Assessment - Adrián Mariño-Enriquez, MD (video)
Advances in GIST Surgery - Chandrajit P. Raut, MD (video)
Clinical Aspects of GIST – Dr. David DeAdamo (video)
Advances in GIST Therapy #2 (KIT/PDGFRA Downstream Targets) - James E. Butrynski, MD (video)
Advances in “Wildtype” and Pediatric GIST - Katherine A. Janeway, MD (video)
GIST Myth Busters - Amy Pilotte, NP and Kathleen Polson, NP (video)
Identifying Vulnerabilities in Drug Resistant GIST - Jonathan A. Fletcher, MD (video)
High-throughput Methods to Identify Drug Targets - Cesar Serrano Garcia, MD (video)
- Advances in Targeted Therapies for non-GIST Sarcomas - Andrew J. Wagner, MD, PhD (video)
- Future Therapeutic Directions for GIST and Conference Wrap Up (video)
- Interoperative Perspectives of Pediatric GIST – Dr. Mike LaQuaglia (video)
Murine models of imatinib-resistant GIST – Dr. Benedikt Bosbach (video)
Update in Pediatric and Wild-type GIST – Dr. Cristina Antonescu (video)
Phase II study of the Hsp90 Inhibitor BIIB021 in GIST – Dr. Mark Dickson (video)
Update in targeting the immune response in GIST – Dr. Ron DeMatteo (video)
Update on CTLA4 clinical trial – Dr. Richard Carvajal (video)
Advanced interventional radiologic techniques for GIST liver metastases - Dr. Karen Brown (video)
GIST Research Update Presentation at 2012 Pittsburgh event.
Presentation from the University of Oregon Meeting
The War on GIST: Life, Death, and Everything In Between - GCRF Research Update 2012 (Michael Heinrich, M.D.)
GIST Research Updates: May 2012, Heinrich & Corless Laboratories
GIST Research Update: Fox Chase Cancer Center (Margaret von Mehren, MD)
Oncogenesis of wild type GIST: some clarity from genetics (Fox Chase Cancer Center - Martin G. Belinsky Ph.D. )
Evaluating new therapies in GIST using in vivo molecular imaging (Fox Chase Cancer Center - Lori Rink, Ph.D.)