Malignant pleural mesothelioma is a deadly malignancy caused by asbestos that affects more than 3,000 individuals in the United States each year. The five-year survival of mesothelioma has increased to about 10 percent at five years with aggressive multimodality therapy, but a report published in Nature Genetics this week provides new hope for more effective treatments.
Dr. David Sugarbaker, professor of surgery and director of the Mesothelioma Treatment Center and Lung Institute at Baylor College of Medicine, co-authored this study with physician-researchers from the International Mesothelioma Program at Brigham and Women's Hospital, a program founded by Sugarbaker. As part of the program, Sugarbaker developed a tissue bank in initial efforts to promote genetic discoveries in mesothelioma. Using samples from this tissue bank, this study was conducted in collaboration with colleagues at the International Mesothelioma Program and scientists from Genentech. This study compared tumor samples to paired normal tissue samples. After more than 10 years of research they have been able to characterize the mutational profiles in patients with mesothelioma.
This study identified several clinically actionable mutations and will most likely result in new clinical therapies that would target these mutations. The mutations found in this study have also been identified in other malignancies and provide targets for currently available drugs and biological therapy. In all, the research revealed more than 2,500 alterations and 10 mutated genes. Sugarbaker and his colleagues showed that several of the targeted mutations discovered could be matched to each individual patient and could serve as more specific targets for new and existing immunotherapies in mesothelioma.
“This research increases our understanding of mesothelioma biology and can significantly improve treatment based on mutational profiling of individual patient cancers. It will allow us to translate this knowledge into the clinic in real-time,” said Sugarbaker. “Each patient now has the potential to benefit from effective therapies that otherwise may be relevant to only a small percentage of patients."
The study also found that patients with the sarcomatoid type of malignant pleural mesothelioma, a particularly aggressive form of mesothelioma, expressed a protein called PD-L1. Expression of this protein indicates a specific target for a powerful cancer immunotherapy pathway. Baylor College of Medicine is currently carrying out an immunotherapy clinical trial targeting PD-L1 inpatients with pleural mesothelioma.
The Mesothelioma Treatment Center at Baylor treats more than 150 patients with mesothelioma per year from all over the world including Russia, China, Denmark, India and South America and Europe. Each of these patients will go through aggressive genetic testing in order to assess whether some of the more targetable mutations exist within the patient’s tumor. Identifying particular targets in particular patients would likely result in cancer therapy that, rather than being effective in only 5 to 10 percent of cases, would be effective in an overwhelming percentage, if the therapy can be paired to the correct patient.
The Baylor College of Medicine Human Genome Sequencing Center currently provides genetic testing for patients seen at the Mesothelioma Treatment Center at In Houston.
“The Baylor Human Genome Sequencing Center, one of the nation’s largest genomic centers, will provide a powerful platform with which we will continue to investigate and identify potentially actionable new mutations. We will continue to move aggressively to provide this analysis to our patients coming to the MTC in order to pursue more effective therapies for every patient,” said Sugarbaker.
Other scientists who contributed to this work are Raphael Bueno, Eric W. Stawiski, Leonard D. Goldstein, Steffen Durinck, Assunta De Rienzo, Zora Modrusan, Florian Gnad, Thong T. Nguyen, Bijay S. Jaiswal, Lucian R. Chirieac, Daniele Sciaranghella, Nhien Dao, Corinne E. Gustafson, Kiara J. Munir, Amitabha Chaudhuri, Ravi Gupta, Joseph Guillory, Karen Toy, Connie Ha, Ying-Jiun Chen, Jeremy Stinson, Subhra Chaudhuri, Na Zhang, Thomas D. Wu, Frederic J. de Sauvage, William G. Richards, and Somasekar Seshagiri.
This work was funded jointly by philanthropic donations to the International Mesothelioma Program, industry grants from Genentech, and grants from the National Cancer Institute.