Sugen offers option when Gleevec fails

Novel compound works when cancer develops resistance to imatinib

WASHINGTON, D.C. – Two new therapies for metastatic cancer are showing significant clinical activity, according to research presented July 14 at the 94th Annual Meeting of the American Association for Cancer Research (AACR).

The studies examined the potential anti-tumor benefits of a combination therapy for colorectal cancer and a multi-targeted oral therapy for Gleevec- (imatinib) resistant gastrointestinal stromal tumors.

In one study, the addition of the antiangiogenesis agent bevacizumab (Avastin) to traditional IFL chemotherapy proved both safe and effective in patients with advanced colorectal cancer, according to researchers at Duke Comprehensive Cancer Center.

“We feel confident that this novel combination will be beneficial for patients with colorectal cancer,” said Dr. Herbert Hurwitz, assistant professor of medicine at Duke, the study’s lead investigator. Continued research is needed, he said, to see if bevacizumab combined with other chemotherapy regimens will apply to other cancers.

In a study of patients with advanced gastrointestinal stromal tumor whose cancer had develop resistance to the standard therapy Gleevec, use of the multi-targeted tyrosine kinase inhibitor SU11248 proved effective for many patients, according to a study at Dana- Farber Cancer Institute in Boston, Mass.

“While imatinib induces objective responses and can control GIST in the majority of patients, the incidence of resistance to imatinib increases over time, and alternative strategies to control this life-threatening disease are needed,” said lead investigator Dr. George Demetri, associate professor of medicine at Harvard Medical School and director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Mass.

Imatinib has captivated the scientific and medical communities by the impressive ability of this oral drug to shrink and control even the most massive abdominal tumors of GIST patients by inhibiting a specific uncontrolled enzyme known as a kinase.

“SU11248 was developed to target multiple signaling “switches” called kinases within cells, and our data indicate that this agent can molecularly target the cancer cells of GIST differently than imatinib, thereby allowing these resistant patients to be successfully treated.”

SU11248 not only targets the tumor cells themselves, but it is also a very powerful anti-angiogenesis agent, blocking the growth of blood vessels that might otherwise feed the tumors.

This phase I study was designed to test the best way in which to administer SU11248, as well as to assess the differences in biological activity between SU11248 and imatinib in GIST patients. Groups of patients were treated at starting doses of 25, 50, or 75 mg per day for two to four weeks, followed by a 14-day rest period. The molecular mechanisms by which SU11248 affects the tumor cells have been carefully studied and these show important differences in the inhibition of uncontrolled signaling molecules such as the KIT receptor tyrosine kinase and related targets in comparison with the standard Gleevec therapy.

Updating previous summaries of this work, Demetri reported on the ongoing results from this active trial. Forty-five patients with GIST have been treated with SU11248. Early results have been reported from 39 of these patients via biopsies and correlative imaging studies. Of these patients, the majority (72 percent) exhibited reductions in tumorassociated metabolic activity as seen via PET scanning.

After one week on SU11248, routine pathology exams (looking at a tumor biopsy sample under a microscope) failed to detect these biological changes; however, by using a more sensitive marker to study the tumors before and after treatment, the researchers were able to see clearly the impact of this therapy: the rate of tumor cell growth (as measured by the Ki-67 proliferation index) decreased in 12 of 17 patients (71 percent) with matched tumor biopsy specimens.

These results have already translated into clinical anti-tumor activity in these imatinib-resistant GIST patients for whom no other therapy existed before.

The development of SU11248 as a potential treatment for imatinibresistant GIST “is an exciting example of the new world of targeted therapy,” Demetri said. “We can analyze cancer cells to identify mutations, then screen drugs in the laboratory that target those specific mutations. The resulting therapies should be more effective and less toxic than traditional chemotherapy, which attacks normal cells as well as cancerous ones.”