image: The creation of monoclonal antibody 130A to block the action of a protein called MFAP5 secreted by the cells surrounding and supporting ovarian and pancreatic tumor cells. view more
Credit: Houston Methodist
Known as two of the most lethal cancers, ovarian and pancreatic cancer are often called silent killers since they rarely have early symptoms. As a result, they frequently go undetected until they're too late to effectively treat.
Cancer scientists at Houston Methodist and The University of Texas MD Anderson Cancer Center have been vigilant about looking for more effective late-stage treatments and may have found one.
In a study published online July 22 in the journal Clinical Cancer Research, co-corresponding authors Stephen T.C. Wong, Ph.D., from Houston Methodist Cancer Center and Samuel Mok, Ph.D., from The University of Texas MD Anderson Cancer Center report that they have found a new type of immunotherapy to try in the fight against these two deadly malignancies.
Wong, Mok, and colleagues developed a monoclonal antibody to block the action of a protein secreted by the cells surrounding and supporting tumors in ovarian and pancreatic cancers, called MFAP5. This protein is found at high levels in patients with both these cancers and associated with decreased survival rates.
"We found that blocking MFAP5 enhances the effectiveness of chemotherapy treatments and suppresses tumor growth in ovarian and pancreatic cancers, as well as inhibits progression of these two cancers in mice," said Wong, who is also professor of systems medicine and bioengineering at the Houston Methodist Research Institute. "This new immunotherapy drug targets supporting cells surrounding a tumor rather than just the tumor cells alone. This tumor microenvironment contains newly developed blood vessels and fibrous connective tissue - created through the processes of angiogenesis and fibrosis - that feed and support the tumor."
The MFAP5 protein has been shown to trigger the formation of these surrounding elements that supply and stimulate the tumor, influencing how it grows and spreads. Blocking it prevents new blood vessels and excess tissue from forming within the microenvironment, thereby cutting off the tumor's blood supply and support.
Mok, who is an endowed professor of gynecologic oncology and reproductive medicine at MD Anderson explains, "MFAP5 promotes fibrosis in ovarian and pancreatic cancers, and fibrosis promotes progression, chemoresistance and reduces survival of people with these cancers. By blocking this secretory protein with an antibody, we can treat the tumor by targeting multiple cellular types - fibroblasts and blood vessels -- in the tumor microenvironment."
Now that they have demonstrated the feasibility of using their monoclonal antibody to target MFAP5 as a new cancer treatment regimen, the researchers are in the process of designing and generating a humanized anti-MFAP5 antibody for further development as a therapeutic agent to treat ovarian and pancreatic cancers. Wong said they expect to have it ready by the end of the year for efficacy and toxicity testing, followed by a Phase I clinical trial in the following year.
"The convergence of biological science, computational science, and engineering has allowed us to achieve such translational discovery," Wong said.
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Other researchers collaborating on this paper include Michael J. Birrer of the University of Alabama at Birmingham at Alabama; Tsz-Lun Yeung, Cecilia Leung, Kay-Pong Yip, and Laura Bover at the University of Texas MD Anderson Cancer Center; and Jianting Sheng at the Houston Methodist Cancer Center.
This study was supported in part by grants from NIH (U54CA149196, U54CA151668, U01188388, RO1CA133057, RO1CA142832, RC4CA156551, CA177909 and UH2 TR000943); The University of Texas MD Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence grant P50CA083639 from the NIH; the U.S. Department of Health and Human Services; the Ting Tsung and Wei Fong Chao Foundation; John S. Dunn Research Foundation; Gilder Foundation; the Ovarian Cancer Research Program, US Department of Defense (W81XWH-17-1-0126, W81XWH-17-1-0146 and W81XWH-16-1-0038); and funding support from the Mary K. Chapman Foundation and the Ovarian Cancer Research Fund. The Monoclonal Antibodies Core Facility is supported by the Cancer Center Support Grant NCI P30CA016672.
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For more information: Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer. Clinical Cancer Research (online July 22, 2019). Tsz-Lun Yeung, Cecilia S. Leung, Kay-Pong Yip, Jianting Sheng, Giulio Draetta, Laura Bover, Anirban Maitra, Michael J. Birrer*, Stephen T.C. Wong*, and Samuel C. Mok*
Journal
Clinical Cancer Research