The Roadmap for Curing Malignant Mesothelioma

As the Chairman of the Scientific Advisory Board for the Mesothelioma Applied Research Foundation (MARF), I represent a group of physicians and scientists whose sole mission is to find a cure for mesothelioma. As recently as ten years ago, my colleagues who deal with other malignancies would find such a statement "laughable" since the conventional wisdom of that time was that there is no treatment for mesothelioma and since the disease has such a smaller population of sufferers than breast cancer, lung cancer and prostate cancer, there was little need for either a financial or intellectual investment in trying to help these patients.

I can safely say that over the last ten years there has been minimal financial investment for this cause; however, the intellectual investment by a few focused centers, many of which are represented on the MARF board of directors and scientific advisory board, is beginning to pay incredible dividends.

What has happened over these last ten years that convinces me and my collaborators that mesothelioma could be a potentially curable disease if an infusion of funds were available for such an effort? To me, it's an incredible story which frankly is one of the best kept secrets in oncology.

But here is where science and clinical excellence merge! Very preliminary data suggest that there are genes which specifically are involved in the pathways which govern whether a patient will respond to Alimta. In other words, the presence or absence of certain genes in the tumor of the patient before treatment may predict whether an individual will be sensitive or not to Alimta. The implications are that we may be on the threshold of "designer" therapies for mesothelioma. With adequate funding, the attainable "holy grail" for such a situation is for researchers to study the genes and proteins of patients given certain therapies and see if certain gene signatures are associated with significant treatment responses. Different signatures would demand different, but specific, treatment options. Patients would be spared useless, insensitive treatments, and have a higher chance for successful treatment.

1. Better understanding of the molecular basis for mesothelioma can lead to clinical trials that make sense

   A key example of this genetic "educational experience" in mesothelioma is illustrated by the finding from our lab and others that this tumor likes to make blood vessels, i.e. a phenomenon called angiogenesis. This discovery came at a time when many drug companies were developing new compounds which can target this "blood vessel" pathway with the hypothesis that if you stopped the blood vessel formation, you could starve the tumor and it would die. MARF has been at the forefront in supporting such efforts to translate these basic molecular findings into a hospital bedside therapy. Dr. Hedy Kindler (another MARF doctor) performed a clinical trial using Avastin and chemotherapy based on these hypotheses from our lab and others, and these exciting results will be published soon.

   1. The story of how asbestos actually turns a mesothelial cell into a mesothelioma is beginning to be understood. This first started as a series of hit or miss experiments in the 1990's which gave insights into certain genes which have helped us classify the disease better (i.e. the Wilms Tumor gene) or corresponded to missing regions of chromosomes that we now recognize as tumor suppressor genes (i.e. the neurofibromatosis gene).
   2. Now instead of simply looking at one or two genes, we can look at as many as 42,000 at one time. In fact, our laboratory as well as that of my MARF colleague Dr. Rafael Bueno, has published on the ability to take a patient's tumor and predict when that patient will reoccur with disease and also whether his survival time is short or long. This biomarker test is in its infancy stage but the key elements of these analyses are that they pinpoint genes and pathways which give insight into how the disease progresses. Having knowledge of such pathways, we can now target them and potentially have patients live longer.
   3. The same theory of impacting on blood vessels matured into a completed clinical trial from our institution which was presented at the American Society of Clinical Oncology recently where patients were given a pill which reduced levels of the proteins which stimulate blood vessels (VEGF) by lowering the serum copper. The results of surgery and this oral pill were striking in patients with Stage I and II disease, and this is now being considered for a national trial by the Southwest Oncology Group.
2. Large Clinical Trials have proven that newer chemotherapies for mesothelioma prolongs life and improves the Quality of Life
   1. Ten years ago we were happy to have a response rate in mesothelioma of 10-15%. Medical oncologists would groan when confronted with a mesothelioma patient. Nobody would have predicted that a drug combination would result in a 41% response rate and significantly increase the life of non-surgical mesothelioma patients. Not only were these goals accomplished, but they were accomplished with the largest trial in mesothelioma patients, accumulated in a Multicenter international setting by Dr. Nick Vogelzang, one of the members of the Board of Directors. To be able to mount such a successful trial which led to approval of Alimta for these patients was unheard of for this disease, and has infused enthusiasm internationally for more trials with newer agents which can be combined with Alimta.
   2. Ten years ago we were happy to have a response rate in mesothelioma of 10-15%. Medical oncologists would groan when confronted with a mesothelioma patient. Nobody would have predicted that a drug combination would result in a 41% response rate and significantly increase the life of non-surgical mesothelioma patients. Not only were these goals accomplished, but they were accomplished with the largest trial in mesothelioma patients, accumulated in a Multicenter international setting by Dr. Nick Vogelzang, one of the members of the Board of Directors. To be able to mount such a successful trial which led to approval of Alimta for these patients was unheard of for this disease, and has infused enthusiasm internationally for more trials with newer agents which can be combined with Alimta.


3. Surgeons, Medical Oncologists, and Radiation Oncologists are no longer working in treatment silos, but are combining their expertise to help mesothelioma patients live longer with less chance of recurrence.
   1. There is a paucity of mesothelioma centers in the United States, and up until two years ago, there was not a concerted effort for these "powerhouses" to unite to answer basic questions regarding mesothelioma treatment. This isolation ended with the development of a national trial which involves both MARF institutions and non-MARF centers investigating the role of chemotherapy before operation for mesothelioma . This collegial experiment is working in that accrual of patients is faster than expected and this allows for early evaluation of results.
   2. This collaboration however, does not in any way stifle individual center initiatives to develop novel treatment methods which are benefiting patients. Dr. Valerie Rusch and her radiotherapy colleagues clearly demonstrated the benefit of adding radiation therapy after an extrapleural pneumonectomy in that the chance of local progression was significantly less than expected. Drs. Roy Smythe (also of MARF) and Craig Stevens at the MD Anderson Hospital have extended these results with promising data using even more targeted radiotherapy after the operation with extraordinarily low recurrence rates in the chest. This sort of cooperation between disciplines for this disease was unheard of 10 years ago.
   3. Intracavitary therapies at the time of the operation are being pioneered by Drs. David and Paul Sugarbaker, as well as by Dr. Robert Taub (MARF). These sort of trials require an incredibly complex choreography of patient expertise and planning, and represent the surgeon and the medical oncologist extending the use of their therapies to higher than expected dose intensities. The only analogy that we have for such treatments harkens back to the days when lymphoma began to be treated aggressively with multiagent chemotherapy at the National Cancer Institute, and lymphoma now is one of our success stories in oncology.
   4. Genetic manipulation to target certain genes is a reality in mesothelioma and Drs. Stephen Albelda and Dan Sterman at the University of Pennsylvania are combining their gene therapies with conventional chemotherapies. Their preliminary data are demonstrating long term cures in preclinical experiments.
4. Not only is there hope to cure established mesothelioma, but with the knowledge gained from the study of genes (genomics) and proteins (proteomics) we are discovering pathways in which cells are "on their way" to becoming a mesothelioma.
   1. It is a well known fact that mesothelioma takes years to become manifest from the time of the original insult. The transformation of a mesothelial cell to mesothelioma is not an "all or none" event but a series of changes in the genes and proteins which could potentially be reversible. If we can detect those changes which inexorably lead to the disease but are at a point of reversibility, it is possible that the number of mesotheliomas that would require compensation would be drastically reduced since, in essence, they have been "nipped in the bud." This is the theory of "chemoprevention" which, in reality, could be "oncoprevention" if the clinician intercepts and aborts the cancer pathway early enough. This area of research is as promising as it is underfunded.
   2. There are already exciting data that have us closer to detecting "early" mesothelioma in a potentially curable state before there is invasion and spread. The new marker Serum Mesothelin Related Protein (SMRP), published in Lancet by Robinson et al., is the subject of study by MARF. Our laboratory has confirmed that this marker is specific for mesothelioma, and unpublished data from Australia even hints that a rise in the level means that mesothelioma may be present. Our laboratory has shown that with successful treatment of mesothelioma the levels of the marker decrease to normal. One can imagine that if we are able to successfully give a preventive agent which reverses the maturing of a mesothelioma cell such that this novel SMRP marker decreased to normal in a high risk asbestos exposed population, we would abort the overt manifestations of the disease and potentially "cure the patient before the disease even started." With a marker for the disease, we certainly can begin this effort to develop agents which will target pathways which will reverse the growth of the tumor and result in a fall in the marker, which potentially can lead to total eradication of the tumor.

Please do not confuse my enthusiasm as a cavalier effort to simplify the state of the art for mesothelioma in 2004. Although the learning curve for uncovering the secrets of mesothelioma is now in a rapid ascent, it was only through the hard work, faith, and diligence of incredibly dedicated individuals that this learning curve appeared at all for there was no ?state of the art? for mesothelioma in 1994. The individuals involved in this work are still the leaders in the field and they are conscripting an ever increasing number of talented young investigators. These young investigators will lead the way for developing novel therapies to cure this disease, and the only way to maintain this momentum is to tap into available funding, as well as recruit new sources of funding, to support their effort

If there is any doubt in your mind that we can find a cure for mesothelioma, I humbly remind you that 10 years ago it would have seemed remarkable for somebody to say that we could perform heart surgery using robotics; or that we could clone a sheep; or that we could find a single genetic defect (KIT) for a tumor and treat it and make pounds of tumor melt away with a single drug targeting that defect (Gleevec); or an oral drug targeting a receptor in lung cancer (Iressa) could result in a complete response.

We at MARF are optimists in the battle against negativity for mesothelioma, and we feel that money would be well invested in the support of translational research efforts to find the cure for this disease. We study and treat the disease because we welcome the challenge to help these unfortunates even when others think we are tilting at windmills. I, for one, firmly believe that we are exposing these windmills now for what they really are, and we are finding that they are vulnerable. Having the resources to fortify and expand our armamentarium with funding directed towards these efforts will only hasten the victory.