21 September 2018

Biomarker in ovarian cancer patients linked to longer survival

Protein Research

High levels of the protein CT45 is associated with longer survival in patients with advanced ovarian cancer. The discovery published today in the scientific journal Cell is made by researchers from Germany, the USA  and Denmark.

Despite aggressive treatment involving surgery and chemotherapy, about 85 percent of women with high-grade wide-spread ovarian cancer will have a recurrence of their disease. This leads to further treatment, but never to a cure. About 15 percent of patients, however, do not have a recurrence but remain disease free for years.

Research teams from the the Max Planck Institute of Biochemistry in Martinsried/Munich, Germany, the University of Chicago Medicine and the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen, have now published a new study in the biomedical journal Cell. Here they examine why some women survive and others do not. They find an independent prognostic factor that predicts how patients will respond to treatment. The factor is a protein that is  called cancer/testis antigen CT45.

“Our goal was to find reliable biomarkers that could predict how patients will respond to treatment and why this is the case,” says the study’s co-lead-author Matthias Mann, research director and professor at the Department of Proteomics at the Novo Nordic Foundation Center for Protein Research and  the Max-Planck Institute for Biochemistry in Martinsried near Munich in Germany. The team analyzed more than 9,000 proteins and identified CT45 as an independent prognostic factor for patients with high-grade serous ovarian cancer.

“Using mass spectrometry, we can identify, for the first time, almost all of the proteins in the tumor tissue of the patients,” Mann says. “Our highly sensitive methods now enable us to profile thousands of proteins simultaneously, allowing us to search for the proteins that are critical in various diseases by comparing archived tissue samples.”

Biomarker closely linked to treatment success
The team of physicians and scientists found that patients with high levels of CT45 in their tumors had extended disease-free survival. Data from long-term survivors with high levels of CT45 averaged 2,754 days, compared to only 366 days for patients who did not have high levels of CT45.

The study authors attribute their discovery to the emerging field of multi-level cancer proteomics, which they have pioneered. The researchers relied on minute pieces of tissue acquired from the University of Chicago ovarian cancer tissue bank, which has been following patient outcomes for 20 years.

They used pieces of these samples to isolate, identify and characterize thousands of proteins. The most interesting of those proteins was CT45. They determined that higher levels of this biomarker were closely linked to treatment success.

“Our work highlights the advantage of analyzing archived biobank samples with proteomics. This way, we can look back to the past in a way because we know exactly how the patient reacted to chemotherapy”, explains Fabian Coscia, first author of the study and Postdoc at the Novo Nordisk Foundation Center for Protein Research.

CT45 could be relevant for longer survival
To validate their initial findings, the researchers studied tissues collected from more than 200 patients from the University of Chicago by the co-leader of the study Ernst Lengyel, MD, PhD, an ovarian cancer specialist and chairman of the Department of Obstetrics and Gynecology. They found no CT45 at all in 82 of those patient samples, but they found high levels in 42 patients, all of whom had much longer disease-free survival. A larger study, using sequence data from The Cancer Genome Atlas, confirmed their initial results, leading to their conclusion that “CT45 expression is a novel prognostic indicator for advanced stage high grade serous ovarian cancer.”

Little is was known about CT45’s role in cellular functions before this study. The authors therefore used proteomics to understand the molecular mechanisms that improved responses to chemotherapy. They found that the standard chemotherapy for ovarian cancer, carboplatin, caused DNA damage, particularly in tumor cells expressing high levels of CT45. This lead to cell death in tissue culture and tumor reduction in treated mice. Using a previously acquired proteomic ‘cellular wiring diagram’, they found that CT45 is a novel member of a DNA repair complex, setting them on the right path to elucidate this proteins cellular role.  

They also found two peptides from CT45-positive ovarian cancer cells that stimulated an immune response against the cancer. T cells collected from a CT45-positive patient with high-grade ovarian cancer were able to kill cancer cells in vitro.

The clinical implications from this study could be significant and CT45 may be particularly relevant to achieving long-term survival.

The study was funded by the National Cancer Institute, the Harris Family Foundation, the Körber Foundation, the Max-Planck Society for the Advancement of Science, the Novo Nordisk Foundation, the Danish Cancer Society, and the Ovarian Cancer Research Fund Alliance (OCRFA).

Additional authors besides Matthias Mann and Fabian Coscia are Ernst Lengyel, MD, PhD, an ovarian cancer specialist and chairman of the Department of Obstetrics and Gynecology at the University of Chicago, Anthony Montag, Diane Yamada, Alyssa Johnson, Jaikumar Duraiswamy, Bradley Ashcroft and Kristen Wroblewski from the OB/GYN Department at the University of Chicago; Michal Bassani-Sternberg and Michael Wierer from the Max Planck Institute of Biochemistry; and Blanca López-Méndez, Jakob Nilsson and Andreas Mund from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen, Denmark.

Read the study.


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