Mesothelioma: Two New Approaches
Mesothelioma, the deadly respiratory cancer, is now in the cross hairs of two different research approaches by Mayo Clinic investigators and their collaborators. One approach uses a converted virus to carry radioactive iodine to targeted cells; the other explores a new use for an existing drug. Both are innovative searches for better therapies.
Stephen Russell, M.D., Ph.D., conceived using the measles virus vector against mesothelioma.
Pleural malignant mesothelioma is a devastating cancer that attacks the lining of the chest cavity. Asbestos is blamed for the disease's rise worldwide. Exposure comes easily, by breathing airborne particles in areas where it was used for everything from insulation and building materials to auto parts and textiles.
People are exposed to asbestos today when old buildings are demolished and also when silicate particles of any kind are inhaled. Mesothelioma cases have cropped up in recent years in Minnesota's northern Iron Range region, where taconite mining — a significant economic contributor — also poses a proven occupational hazard.
The increased diagnoses of mesothelioma in Minnesota is one reason Mayo and University of Minnesota researchers have partnered to harness a unique therapeutic approach aimed at the disease.
"We've taken a new viral agent, repositioned it for this disease and are advancing it toward the clinic as an entirely novel treatment," says Stephen Russell, M.D., Ph.D., Mayo Clinic molecular researcher.
Dr. Russell is referring to the latest version of the measles virus vector (MV-NIS). It is an engineered version of the measles virus — safe to the patient, but targetable and carrying a toxic payload.
MV-NIS (NIS refers to the inserted gene) codes for the thyroidal sodium iodide symporter, the mechanism that concentrates radioactive iodine into cells that have been infected. Based on this, it is possible to conduct noninvasive imaging studies (SPECT/CT) to follow the virus in the treated patient. If there is substantial radioiodine uptake on these imaging studies, then researchers can administer a more toxic version of radioactive iodine to help the virus destroy the mesothelioma tumor. The addition of the NIS gene is a major genetic change, which transforms the virus into a viable drug candidate.
Mayo has already researched engineered forms of the measles vector against the brain tumor glioblastoma multiform, recurrent ovarian cancer, multiple myeloma and prostate cancer. No other centers are using this virus in clinical trials.
Minnesota Partnership Launches Study
Initial research by Drs. Russell and Robert Kratzke, M.D., of the University of Minnesota, was funded by a grant from the Minnesota Partnership for Biotechnology and Medical Genomics. It marks the first time that a Minnesota Partnership project has promoted an entirely novel treatment into medical practice. It also demonstrates how the Partnership is responding to medical issues within Minnesota. The work was also supported by The Richard M. Schulze Family Foundation.
After the virus killed cancer cells in the lab, it was decided to test the approach in animal models. In mice infected with mesothelioma, the Minnesota Partnership team found that a single injection of measles virus doubled the life span compared to those that didn't receive the virus. Some mice appeared to have been cured.
As a result of the basic findings, Dr. Kratzke and Tobias Peikert, M.D., of Mayo Clinic are leading a Phase I clinical trial in which 12 -36 patients will be divided into two groups. The experimental group will receive the MV-NIS dose, injected into their chest cavities through catheters that also serve to drain excess fluid caused by the disease from around their lungs. The hope is that tumors will shrink significantly. Initially low amounts of measles virus will be used as researchers tweak the dosage for effectiveness and test for toxicity.
"Because of the data Mayo has on the safety of MV-NIS when used for ovarian cancer, we don't anticipate any surprising effects," Dr. Kratzke says. "The only effects we don't know would be anything specific to putting the virus into the chest cavity as opposed to the abdominal cavity."
If successful, measles virus could be combined with chemotherapy, which suppresses the body's immune response, to provide a one-two punch. In such an environment, the virus would have more time to work on cancer cells before the body's defenses shut it down.
A Second Approach
Juan Molina, M.D., Ph.D., will study existing cancer drugs as mesothelioma therapies.
A much larger international clinical trial, led by Julian Molina, M.D., Ph.D., Mayo oncologist, will potentially include more than 500 patients over three years. The effort, which was targeted to begin by year's end, will use the drug pazopanib, made in tablet form under the trade name Votrient by GlaxoSmithKline. The drug already is FDA-approved for treating kidney cancer.
The drug surfaced as a potential treatment for mesothelioma in Dr. Molina's laboratory screening of new FDA-approved drugs on cancers other than what they were approved to treat. Pazopanib is an angiogenesis drug, which means it targets the growth of new blood vessels in cancerous tissue by blocking nutrients and oxygen.
"We took pazopanib and added it to mesothelioma cells that we had in the lab, and we noticed that pazopanib was very effective at killing these cancer cells," says Dr. Molina. "At the time, we were doing a Phase I study here in which we were testing pazopanib for patients who had all tumor types."
An Extra Six Months
A. MRI image of a patient with a left pleural mesothelioma (arrow). Note the reduction in lung capacity.
B. Surgically removed left lung and pleura with mesothelioma encasing the lung (arrow).
A. CT image of malignant pleural mesothelioma.
B. PET/CT image of mesothelioma involving the left lung. Mesothelioma (in red) surrounds the lung.
Based on the drug's potential, the National Cancer Institute funded a region-wide Phase II clinical trial with patients with malignant pleural mesothelioma, led by Mayo Clinic, at member medical centers in the North Central Cancer Treatment Group. The results of the small human study were encouraging.
"The median survival for someone diagnosed with this disease is 9 to 12 months," Dr. Molina says. "We were able to show that pazopanib improved survival in our patients by about six months, to 18.6 months."
This drug approach, like using viruses, is another target-specific alternative to traditional chemotherapy, he says. "Chemotherapy kills every cell in the body that is growing fast, without discriminating whether a cell is a good one or a bad one. These new agents target cancer cells that form new blood vessels really fast."
The approach involves fewer side effects than traditional chemotherapy, Dr. Molina says. A challenge of the clinical trial will be monitoring tumor shrinkage, a task that is not easy because tumors grow in hard-to-see lung lining tissue.
"Traditional chemotherapy for mesothelioma has side effects such as a drop in the blood count, weakness, loss of hair, nausea, vomiting, which all compromise patients' quality-of-life," he says. "With these new kinds of medications, there is no compromise. In fact patients feel better because the pill is having an effect on the tumor."
To monitor how well the drug is working, researchers will employ CT scans of the chest, using a technique that makes the scan appear three dimensional, allowing tumors to be seen from different angles. The scans will be performed every six weeks.
"Currently there are only a handful of clinical trials for mesothelioma," Dr. Molina says. "We are offering this study to patients who have not been treated with any kind of chemotherapy, because what we found in our original study was this pill was better, more effective, than chemotherapy."
Study participants will be divided randomly into a group that will receive about 800 milligrams of pazopanib once daily or a control group in which standard chemotherapy will be used.
"We're not curing mesothelioma with this treatment," Dr. Molina cautioned. "The hope is that four years from now, when we have completed the study and have all the data analyzed, we will be able to tell patients that the standard-of-care for the treatment of mesothelioma is not chemotherapy with all of its side effects. We'd like to say the new standard is this pill you take every day. This standard-of-care will improve your survival by another six months or so without compromising your quality-of-life."