A drug originally developed to block the formation of blood vessels in tumors has been shown to overcome resistance to treatment with Gleevec in patients with gastrointestinal stromal tumors (GIST).
Known as SU11248, the drug offers patients with advanced GIST an important new treatment option. The results of this clinical trial may also give researchers fresh insights into the molecular mechanisms controlling the growth of these deadly tumors, according to study results presented at the annual meeting of the American Society for Clinical Oncology in New Orleans, La.
"This drug appears to work when Gleevec does not. Determining how SU11248 shrinks Gleevec-resistant GIST will lead to better diagnosis and targeted therapy," said Michael Heinrich, M.D., member of the Oregon Health & Science University Cancer Institute, associate professor of medicine (hematology and medical oncology) in the OHSU School of Medicine and Portland Veterans Affairs Medical Center, and co-investigator of the study.
The study's principal investigator is George Demetri, M.D., co-director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, and assistant professor of medicine at the Harvard Medical School. Chris Corless, M.D., associate professor of pathology in the OHSU School of Medicine and member of the OHSU Cancer Institute, also participated in this research.
GIST arises in the wall of the stomach, small and large intestine, and is diagnosed in 5,000 to 10,000 Americans annually. Historically, patients with advanced forms of GIST had few treatment options, because surgery, chemotherapy and radiation treatments were ineffective. That changed with the development of the breakthrough drug Gleevec. While it was designed to treat chronic myelogenous leukemia, Gleevec also proved effective in the treatment of GIST. The FDA approved Gleevec for the treatment of GIST in 2002.
However, some GIST patients do not respond to Gleevec. Further, of the 80 percent who do respond, about half of them develop a tolerance for the drug at approximately 18 months, resulting in new tumor growth.
"Many GIST patients have now taken Gleevec long enough for some of their tumors to show signs of resistance," Heinrich said.
The researchers first sought to determine what might be causing patients to develop a tolerance for Gleevec. It was already known that 80 percent to 90 percent of GISTs are associated with abnormal mutations of an enzyme known as KIT and that about 5 percent to 10 percent of GISTs have a mutation of a related enzyme called PDGFRA. Produced by cells, an enzyme is a "signal" for the body to begin or continue a specific biochemical process. In the case of GIST, these mutations signal tumor growth. Heinrich and his collaborators were the first group to identify PDGFRA mutations in these tumors in previous studies.
By studying samples of the cancerous cells from patient biopsies, the researchers noted that Gleevec resistance is associated with the appearance of new mutations of the KIT or PDGFRA enzymes. In other words, the enzymes that were originally responding to Gleevec somehow changed themselves to thwart Gleevec's therapeutic impact. These newly mutated enzymes appear to activate alternative signaling pathways that bypass the original pathways blocked by Gleevec, resulting in the growth of new Gleevec-resistant tumors.
"Gleevec fits into the lock initially and stops the abnormal cell growth, but then the tumor changes the lock," Heinrich said. The search for a new "key" led investigators to SU11248, an existing drug that broadly inhibits enzyme activity. Because the compound was developed as an anti-angiogenesis drug, it also held out the possibility of affecting the mutations at this level as well.
Angiogenesis is a normal biological process in which new blood vessels grow from existing healthy cells. This process works against the body during cancer when it is "turned on" by tumors to feed their growth. Selectively preventing angiogenesis, thus, offers the potential to "starve" a tumor by cutting off its essential support system.
Ninety-eight GIST patients with documented progressive resistance or initial intolerance to Gleevec participated in this Phase I/II clinical trial. The results demonstrated a striking clinical benefit -- in 65 percent of the patients the disease stabilized for at least six months and a partial response was observed in 13 percent of the patients.
While the empirical success of SU11248 points immediately to a new treatment option for GIST patients, the specific mechanisms underlying the response to SU11248 will take more time to fully understand.
Additional research is expected to help to clarify the effectiveness of SU11248 in Gleevec-resistant GIST patients. Based on the positive results from this study, a larger international study of SU11248 has already started. Continuing investigations will also seek to identify the mechanisms by which KIT and PDGFRA enzymes contribute to the development and growth of GISTs. The new research may also shed light on the role of anti-angiogenesis in this circumstance.
"Not only will this research help to identify patients who are most likely to benefit from this therapy, it may also be relevant to developing molecularly targeted therapies for other malignancies," said Heinrich.