Matrix metalloproteinases in tumor progression: Past, present, future teaches valuable lessons

Anaheim, Calif. - Lessons can be learned from the failure of matrix metalloproteinases inhibitors (MMPIs) to make a difference in halting tumor progression in clinical trials, according to the president of the American Association for Cancer Research (AACR).

Speaking here at the AACR annual meeting, Lynn M. Matrisian, Ph.D, professor and chair of the department of cancer biology at Vanderbilt University, Nashville, Tenn., discussed the preclinical and clinical experiences with MMPs.

"There was a discrepancy between what we expected and what we saw, Dr. Matrisian says. "We now know that you can't cause regression of an established tumor with an MMP inhibitor. That's how the clinical trials were designed, to have an impact on stage four cancers; that is patients in advanced stages."

Dr. Matrisian, who is the Ingram Distinguished Professor of Research, says that the experience with these enzymes, which are oncogene-related genes, proved the experience in the laboratory cannot always translate into clinical trials.

In the laboratory, the inhibition occurred at the time of the onset of the tumor, whereas in the clinical trials the drug was administered in late-stage disease. The clinical trials involved cases of pancreatic cancer as well as non-small cell lung cancer and small cell lung cancer whereas the preclinical work involved subcutaneous xenografts and genetic models of tumors of the breast and colon. Researchers developed synthetic MMP inhibitors to decrease experimental and spontaneous metastasis in the 1990's in response to the discovery that MMP activity contributed to tumor metastasis.

The clinical trials that compared an MMP inhibitor to standard treatment found no improvement or worse performance. When an MMP inhibitor was matched against placebo, there was no difference in outcome or the MMP inhibitor fared worse. The results provided a lesson that animal model design should recapitulate clinical trial design.

"We extrapolated from animal studies and that led us in the wrong direction," Dr. Matrisian tells Dermatology Times. "MMPs are complex. We always assumed that they made matters worse by contributing to tumor progression, and that was dogma. Nobody ever published things that didn't support the dogma. There was a publication bias, and negative results were underrepresented in the literature. Now that the clinical trials have failed, that information has come out. We have to look at the consequences of not being honest."

Indeed, since the failure of the clinical trials to show positive response, studies have been published pointing to the ability of MMPs to cleave plasminogen to make angiostatin, Dr. Matrisian notes.

Lesson learned

One of the lessons learned from past mistakes is that target modulation assays are crucial to determining the maximum, tolerable and efficacious dose that should be administered.

"In the trials, we had no assay to determine if the drugs were modulating the activity of the enzymes in the tumor," Dr. Matrisian says. "As a consequence, we don't know if we gave appropriate doses to be efficacious. Without the assay, we don't have that information. If we are going to be conducting a clinical trial, we have to establish the assay up front. When you conduct a clinical trial, it is important to know that you are hitting the target, and that you are monitoring that."

Dr. Matrisian says that some data are now pointing to future opportunities for MMP inhibitors. Some of the latest experiments, for instance, have involved using MMPIs and COX-2 inhibitors, which have demonstrated inhibition of tumor multiplicity in mouse models.