Oral MMPI Shows Promise as An Inhibitor of Angiogenesis

LOS ANGELES--While the flurry of media attention on antiangiogenesis drugs has focused on angiostatin and endostatin, other such agents are further along in development. One of them, BAY 12-9566, has stopped tumor growth in patients for up to 11 months in an ongoing trial, Louise Grochow, MD, said at an ASCO session on novel approaches in drug development.

BAY 12-9566 is a novel matrix metalloproteinase inhibitor (MMPI) that directly inhibits MMP-2 and MMP-9 at achievable nanomolar concentrations. In preclinical trials, BAY 12-9566 has demonstrated antiangiogenesis and antiprolif-erative effects, including reduction in tumor growth and decreased metastatic potential, said Dr. Grochow, associate professor of oncology, Johns Hopkins Oncology Center.

This phase I trial has enrolled 27 solid tumor patients whose cancers had not responded to standard therapy. Each was treated with oral doses of BAY 12-9566--100 mg/d escalating up to 1,600 mg/d (400 mg four times daily or 800 mg twice daily). The first 6 patients were treated for 4 weeks followed by a 2-week rest; subsequent patients received continuous daily doses unless disease progressed or toxicity intervened.

Dr. Grochow reported that treatment has been well tolerated. Changes in liver enzymes and mild thrombocytopenia at the highest doses were reversible after dose reduction. No patients have developed the diffuse arthralgia that has been seen in trials of some other MMPIs, she said. One patient developed back pain due to vertebral bone loss that is potentially treatment related. It may be that the MMPI prevented the absorption of cortical and trabecular bone, she said.

Tumor measurements obtained every 8 weeks have shown 14 patients to have no tumor growth for at least 4 months, and 5 patients to have stable disease for 7 to 11 months, she said. The cohort included primarily colorectal cancer patients but also patients with breast, cervical, ovarian, and a variety of other solid tumors. All had received prior chemotherapy, and some had also received radiotherapy.

Dr. Grochow pointed out that the trial’s endpoint (ability to achieve an acceptable drug exposure) was "nonstandard" for a phase I trial; toxicity was not an endpoint because none was expected. "Our target exposure was 100 mg/L, and we got 50% greater than that," she said.

Dr. Grochow concluded that chronic oral doses of BAY 12-9566 are well tolerated with minimal reversible toxicities at doses up to 800 mg twice a day. Steady-state plasma levels can be sustained at levels shown to be active in preclinical models, she said.

"There is legitimate reason for excitement about these new agents," Dr. Grochow told Oncology News International. She emphasized that while endostatin and angiostatin, because they are complex proteins (peptides), have to be administered parenterally, some of the MMPIs, like BAY 12-9566, AG3340, and marimastat are orally available.

"What is interesting about the experience with BAY 12-9566," she said, "is that you get growth inhibition and some cytotoxic effects as well." She said that in animal models, stopping administration resulted in renewed tumor growth, and resuming dosing once again stopped growth.

Karen Kumor, MD, Bayer’s international clinical project manager for BAY 12-9566, noted that the MMPIs are further along in testing than endostatin and angiostatin. "The MMPIs are smaller molecules and are easier to synthesize and administer," she said.

Development of the MMPIs represents a novel approach to inhibiting oncogenesis. "The metalloproteases were discovered within the last 7 to 8 years in arthritis research. They are involved in remodeling of the extracellular matrix. In order for a cell mass to grow, it has to get through this tough matrix," Dr. Kumor explained.

The metalloproteases, in their normal function, break down matrix to allow embryogenesis, vessel formation, and wound healing. An extraordinary number of diseases, she observed, have been discovered to be associated with excesses of matrix metalloproteases.

Invading tumor cells, through a signaling process, engage the normal surrounding matrix cells and induce them to produce the digestive proteases that break down structures and create room for the tumor mass to expand. The MMPIs interdict this process, inhibiting angiogen-esis, cell proliferation, metastasis, and angio-genesis, thus preventing endothelial cell invasion without affecting normal endothelial cell proliferation.

While BAY 12-9566 is very selective for MMP-2 and MMP-9, other MMPIs target MMP-1 and MMP-13 as well. These are collegenase proteins that may be important for joint structural integrity, Dr. Grochow said, adding that "inhibiting them may lead to joint structure problems," as have been seen with some other MMPIs.

Another possible explanation for the joint problems experienced in patients in clinical trials of agents targeting the collagenase MMPs is that they may induce inflammatory cytokines.

Clinical experience in humans has suggested that the MMPIs are best given after cytoreduction. "You reduce the tumor with radiation or chemotherapy, and then this drug is given to prevent further spread and metastasis--to keep any remaining cancer cells so small that they do not develop," Dr. Kumor said.

BAY 12-9566 is now in phase II-III trials for lung cancer, pancreatic cancer, and ovarian cancer in Europe, the United States, and Canada. In addition, a trial of the agent in combination with a cytotoxic agent is planned, Dr. Kumor said.