Innovations in cancer treatments start with discoveries in the laboratory – which is where Fox Chase Cancer Center has made powerful inroads for more than 100 years to advance care for patients in the local community and throughout the world.
Together with Temple Health, Fox Chase offers one of the most comprehensive mesothelioma programs in the United States, and the only one of its type in the region. This world-class center for the treatment of malignant mesothelioma, lung cancer and other pleural conditions drives cutting-edge research and improved outcomes for patients battling these very challenging diseases.
Among those leading the way toward more effective treatments for mesothelioma – and working to stop this deadly disease before it even starts – are the collaborative efforts from the very bright minds of Dr. Joseph Testa and Dr. Joseph Friedberg.
Dr. Testa, the Chief of Genomic Medicine at Fox Chase who holds the Carol & Kenneth E. Weg Chair in Human Genetics, is an internationally renowned mesothelioma researcher who has made numerous groundbreaking discoveries in the field. Dr. Friedberg, the Co-Director of the Mesothelioma and Pleural Disease Program and Thoracic Surgeon-in-Chief at Temple Health, has driven tremendous advancements in treating lung-related disease through his highly innovative thinking. As these two research pioneers have joined forces on several groundbreaking projects, they continue to dedicate themselves to making mesothelioma a potentially treatable, chronic disease instead of a rare cancer with no known cure.
Dr. Testa and Dr. Friedberg are key members of a Fox Chase-Temple research team that received a three-year, $1.2 million contract to study sulforaphane, derived from broccoli and other cruciferous vegetables, on which Dr. Friedberg conducted initial research several years ago. Sulforaphane shows promise as a cancer preventive agent for patients who are at higher genetic risk for asbestos-associated malignant mesothelioma through the BAP1 tumor predisposition syndrome. The BAP1 gene mutation and its role in predisposing to mesothelioma, as it turns out, is a discovery from Dr. Testa’s own research.
About 80 percent of cases of malignant mesothelioma – an incurable cancer of the mesothelial lining that surrounds the internal organs – occur in the chest. Of these, asbestos exposure is the most common cause. No preventive methods or treatments are currently available for people at risk of developing malignant mesothelioma, but Drs. Testa and Friedberg are aiming to change that.
“Because advanced cancers such as malignant mesothelioma develop resistance to therapy, there is an urgent need to identify successful preventive measures,” says Dr. Testa, the project’s principal investigator. And since there is frequently a long delay between asbestos exposure and cancer development – Dr. Friedberg has even treated patients who were exposed during World War II – any method of prevention would likely need to be administered for decades. That makes long-term safety especially critical.
Sulforaphane is characterized by the presence of an isothiocyanate moiety, a substance that is highly reactive and thought to be responsible for some of its cancer-preventive properties, Dr. Testa says. It can play a role in altering or reversing histone and DNA modifications, miRNA regulation, and signaling pathways that are involved in DNA damage and repair, inflammation, immune suppression, and other processes of cancer initiation, promotion and progression.
Funded through the National Cancer Institute’s PREVENT Cancer Preclinical Drug Development Program, the study assesses the ability of sulforaphane and Avmacol, a commercially available broccoli seed and sprout extract, to prevent asbestos-associated malignant mesothelioma. Drs. Testa and Friedberg hope to determine whether these agents prevent or significantly reduce the incidence and progression of malignant mesothelioma and prolong survival, as well as identify biomarkers in banked tissue specimens to further assess effectiveness. Finally, they will study whether it is safe to administer sulforaphane and Avmacol over a long period of time.
“When your mom told you to eat your vegetables, that was actually really good advice,” Dr. Friedberg says with a smile. “I routinely see patients who had the same exposure to asbestos as their family member who I am treating for mesothelioma. Right now, we have nothing to offer them but surveillance. Now, imagine if we are able to prove in the laboratory that we can prevent the formation of mesothelioma with a simple, nontoxic substance like this, and we can tell people: ‘Here's something you can take that can’t hurt, and it may help you not end up with this terrible cancer.’ What greater legacy could you have?”
Success in these preclinical studies in an animal model would ideally lead to clinical trials in humans. These would include asbestos workers and people in the military, where asbestos has been used as a fire retardant; genetically predisposed individuals; and members of households where individuals developed the disease after handling asbestos-laden work clothes of occupationally exposed patients. In addition, in some parts of the world, there is no protection from or regulation of asbestos.
Dr. Testa, who has worked for 25 years with Philadelphia-area asbestos workers and seen many of their struggles first-hand, says: “We're all trying to do the right thing to protect people from getting this disease. Oncologists are making a lot of inroads and we believe mesothelioma can be treated more effectively in the future, but it's still better not to get it in the first place. If we can find a way to prevent it from ever happening, that's the best thing we can do.”
Drs. Testa and Friedberg, who have long respected each other’s work from afar but were able to begin personally collaborating only in recent years, each have a long list of discoveries that have furthered efforts worldwide to understand the biology of the disease, drive new treatments, and possibly prevent mesothelioma and other pleural diseases.
Drawing from his decades of work in genetics and gene–environment interactions, Dr. Testa and collaborators were first to demonstrate that heritable mutations can influence the risk of asbestos-induced mesothelioma. Dr. Testa and his lab have identified three major players involved in human mesothelioma, the BAP1, CDKN2A (encoding p16INK4A and p14ARF), and NF2 tumor suppressor genes, and went on to verify the importance of these genes in asbestos-induced mesothelioma through investigations in transgenic mouse models they developed.
Another published study led by Dr. Testa focused on a new drug candidate called SC144 that contributed to success in delaying or preventing tumor growth and prolonging survival in mice by blocking key inflammation pathways after asbestos exposure. In Dr. Friedberg’s own words, Dr. Testa is “a world authority and one of the inventors and masters of the animal model for asbestos-induced cancers.”
Dr. Testa conceived and supervised a recent study that identified a mutated gene known as LRRK2 that may predispose some families to the carcinogenic effects of asbestos and act as a novel tumor suppressor gene in malignant mesothelioma. His research also has found that the presence or absence of the receptor-interacting protein kinase 3 (RIPK3), which is involved in the inflammatory process, can help determine the effectiveness of drugs in cases of malignant mesothelioma.
Meanwhile, Dr. Friedberg has led significant advancements for current mesothelioma treatment with his research showing that a less invasive, “lung-sparing” surgical procedure, followed by photodynamic therapy (PDT) to boost the immune response and kill remaining cancer cells, was better for patients and often resulted in higher survival rates compared with radical surgery known as extrapleural pneumonectomy.
The median survival rate for mesothelioma patients is 12-18 months. In Dr. Friedberg’s study, however, the median survival rate was 35 months. Lung-sparing surgery, once an uncommon procedure, is now an area of expertise for the Mesothelioma and Pleural Disease Program.
Starting with an idea that was sparked by using Fix-a-Flat aerosol sealant to repair a deflated tire, Dr. Friedberg is also driving major innovations in detection and treatment of pulmonary air leaks. These can occur during surgery, a biopsy, or even spontaneously. He concepted and has continued to research the use of an inhaled sealant for the pulmonary system as he aims to minimize these common and very expensive drivers of prolonged hospitalizations, which can also be life-threatening.
Among other key projects, Dr. Friedberg is studying new ways to leverage the abdominal cavity for respiration in support of weakened lungs, primarily through the use of medical perfluorocarbons; and he has developed a completely novel treatment called photobrachytherapy that fights cancer through a combination of substances and techniques.
Now, the search for newer and better ways to fight mesothelioma is continuing. The Temple-Fox Chase program aims to offer surgical and nonsurgical trials for patients with every subtype and presentation of this rare and deadly disease.
Clinical trials in the works include the use of PDT as well as radiodynamic therapy (RDT). Both involve the use of a photosensitizing drug, 5-ALA, that accumulates in cancer cells and briefly renders patients light-sensitive. When activated by light, the drug triggers a series of reactions that are effective at directly killing cancer cells and stimulating a tumor-directed immune response.
The trial of RDT, available in the Western Hemisphere only at Fox Chase, employs a racetrack microtron that generates high-energy photons. These can trigger a PDT-like reaction, but without the limitations of the restricted depth of penetration imposed by conventional PDT, which uses visible light as the stimulating energy.
A plan is also in place to join a preeminent mesothelioma program in Lille, France, for the European IMPALA study, in which PDT will be used to amplify and focus the effect of concomitant immunotherapy.
Both doctors say Fox Chase has established a culture that drives increased collaboration on new solutions for cancer in a close-knit, patient-centric setting. The cross-disciplinary emphasis and clinical trial expertise that bring researchers and physicians together have a significant compounding effect that drives better patient care and real bench-to-bedside results.
“You become a surgeon because you want to fix problems, right? There are few problems bigger than mesothelioma – it is arguably one of the worst cancers known to man,” Dr. Friedberg says. “It certainly is rewarding to try to save lives one at a time, but to make a real impact across the board, it has to be through science and the type of work that Dr. Testa does at Fox Chase. It's a partnership, it's a team like everything else that we do here. And to me, it means everything to do this together.”
The Mesothelioma and Pleural Disease Program establishes a world-class center of excellence to combat mesothelioma and other serious lung diseases. As research is accelerating to detect, treat and prevent this terrible cancer, new treatments and techniques are becoming available that are likely not only to prolong life, but also to maintain quality of life.
Fox Chase, with its long and storied history of breakthrough research, continues to lead the field with seminal scientific discoveries that have key translational implications. The insights gleaned from these laboratory studies can be directly applied to patient care while safely evaluating new approaches to preventing and treating cancer through clinical trials, which may eventually drive standard protocols with far-reaching implications.
That is the ultimate goal of the exhaustive studies by researchers like Drs. Testa and Friedberg – and a key benefit of Fox Chase’s elite standing as an NCI-designated Comprehensive Cancer Center, currently one of only 51 in the nation. Our extraordinarily talented scientists thrive in an environment that is ideal for making fundamentally important discoveries.
With support from the partnership with Temple Health’s oncology research, treatment and prevention programs, Fox Chase Cancer Center makes a world of difference in Northeast Philadelphia and all other communities that we serve.
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