A protein called CT45 predicts which ovarian cancer patients will respond to platinum-based chemotherapy and is associated with extended survival in these patients, being a new prognostic marker for ovarian cancer, a study shows.
The findings also suggest that strategies boosting CT45 levels could improve chemotherapy’s efficacy.
The research, “Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer,” appeared in the journal Cell.
About 15% of women with high-grade serous ovarian cancer (HGSOC) — the most common subtype of ovarian cancer — do not experience a recurrence of their disease and remain disease-free for over a decade after aggressive treatments with surgery and platinum-based chemotherapy.
Aiming to discover what drives long-term survival in these patients, a collaboration between the University of Chicago Medicine, the Max Planck Institute of Biochemistry in Germany, and the Novo Nordisk Foundation Center for Protein Research in Denmark used an analytical technique called mass spectrometry to conduct a large-scale protein analysis (proteomics) in ovarian tissue samples of platinum-resistant and platinum-sensitive HGSOC patients.
“Our highly sensitive methods now enable us to profile thousands of proteins simultaneously, allowing us to search for the proteins that are critical to the disease,” Matthias Mann, PhD, the study’s co-lead-author and the Max Planck Institute’s chairman, said in a press release. “Our goal was to find reliable biomarkers that could predict treatment response.”
The results revealed that, of over 9,000 analyzed proteins, patients with high levels of CT45 lived on average seven times longer than those with little or no CT45 — 7.5 years vs. 1 year.
“We believe this is the first example of mass spectrometry-based proteomics leading to the discovery of a prognostic and functionally important cancer biomarker,” Ernst Lengyel, MD, PhD, the study’s co-lead author and chairman of the University of Chicago’s department of obstetrics and gynecology, said. “CT45 was completely unknown until then.”
To validate the initial results, the scientists studied samples from more than 200 patients from the University of Chicago. They observed high levels of CT45 in 42 patients, all with much longer disease-free survival than 82 patients without CT45. Increased overall survival was also associated with higher CT45 expression in 284 HGSOC patients using RNA sequencing data from The Cancer Genome Atlas.
Aiming to better understand the molecular pathways linking the biomarker to improved responses to chemotherapy, the team found that carboplatin — the standard chemotherapy for ovarian cancer — caused DNA damage in mouse tumor cells containing high levels of CT45. This led to cell death in tissue culture and tumor reduction in mice.
“Based on our results, expression of CT45 is expected to improve the efficacy of platinum-based chemotherapy or immunotherapy for patients with advanced-stage ovarian cancer,” the researchers said. “This gives us hope that future strategies that activate CT45 expression in the tumor could make it more sensitive to carboplatin treatment,” said Marion Curtis, PhD, a study author.
The investigators also found that CT45 induced a strong anti-cancer immune response. Immune T-cells collected from a CT45-positive high-grade ovarian cancer patient were able to dose-dependently kill cancer cells in vitro.
“We have evidence that tumor-specific expression of CT45 stimulates the patient’s immune system to fight the cancer, as would a virus or bacterial-infected cells,” Lengyel said. “Our long-term goal is to find new ways to improve patient outcomes based on these exciting insights.”