Counting to 125: The Painstaking Journey to a Landmark Ovarian Cancer Biomarker

Published: Tuesday, Oct 11, 2016
 Robert C. Bast Jr, MD

Robert C. Bast Jr, MD

Discovering the first useful blood biomarker for ovarian cancer involved an element of serendipity as well as a lot of hard work, said Robert C. Bast Jr, MD, a master of translational research who continues to break new ground in the battle against cancer more than 35 years after the now famous CA-125 assay for ovarian cancer was developed.

“The 125 really refers to the number of promising hybridomas that we screened to find a murine monoclonal antibody that would bind selectively to human ovarian cancer cells,” he said. At Harvard Medical School, Bast and Robert C. Knapp, MD, developed the first monoclonal antibody against ovarian cancer in an attempt to provide more effective treatment for the disease. “The 125th clone looked promising for therapy until we found that the cancer cells actually shed the antigen to which the antibody bound,” Bast recalled in an interview.

“That was a problem, because if you are going to inject antibodies intravenously or even intra-abdominally, shed antigen might neutralize the antibodies before they could bind to cancer cells,” he said. “With Bob Knapp, we attempted to make lemonade out of lemons, reasoning that if you could use the antibody to measure shed antigen, then that might provide a biomarker to monitor response of ovarian cancer to therapy.”

The two men were onto something. There were no useful biomarkers for ovarian cancer at the time. They found that rising levels of CA-125 can indicate growth of ovarian cancer during treatment and falling levels can signal a response to therapy. Rising CA-125 could also detect disease recurrence several months prior to detection by symptoms or physical exam.

“With the CA-125 test, you could measure total tumor burden body-wide, even where there were numerous small cancer nodules too small to image. That improved monitoring, so an oncologist could tell whether the cancer was responding or not responding to chemotherapy,” said Bast.

“In this regard, CA-125 resembles other biomarkers that have been developed over the last 60 years, like PSA in prostate cancer, CEA in colorectal cancer, HCG in choriocarcinoma, and AFP in testicular cancer. Those are markers that go up or go down with tumor burden, and CA-125 is very similar,” said Bast, who is now vice president for translational research at The University of Texas MD Anderson Cancer Center in Houston.

Over the years, CA-125 has been applied to fill other unmet needs in ovarian cancer care, including as an aid in surgical management of the disease. There are now FDA-approved CA-125– based blood tests that can assure referral of >90% of patients to a gynecologic oncology surgeon. Through monitoring and triage, CA-125 has contributed to the care of hundreds of thousands of women with ovarian cancer worldwide.

For his work in ovarian cancer, particularly the discovery of CA-125, Bast was honored with a Giants of Cancer Care award in the Gynecologic Malignancies category in 2015.

Focusing on New Treatments

Bast has pursued his theories about ovarian cancer with tenacity. “Bast, as an individual, was an unbelievably hard worker,” said Knapp, recalling those days in the 1970s when he and Bast worked together on the monoclonal antibody effort. “He was a driver. He drove himself. He drove the technicians. Timewise, he would be there until he felt a particular part of the project was completed. I don’t think he knew if it was 12 o’clock or it was 9 o’clock. He was amazing. He just worked.” In recent years, Bast has continued his work in ovarian cancer by seeking ways to improve upon the performance of paclitaxel. Although paclitaxel is given routinely to all women with newly diagnosed ovarian cancer, fewer than half respond to the agent. Bast’s group found that the enzyme SIK2 (salt-induced kinase 2) is critical to the process of cell division and that, when its presence is reduced, cells become more sensitive to paclitaxel. Bast gives much of the credit for this discovery to postdoctoral fellow Ahmed Ashour Ahmed, MBBCH, MD, PhD, who is now a professor at the University of Oxford.

In addition, Bast and his fellow researchers at MD Anderson have explored ways to eliminate dormant cancer cells and have developed the first inducible model for dormancy in ovarian cancer driven by re-expression of the gene ARHI (DIRAS3), which is downregulated in 60% of ovarian cancers. Re-expression of ARHI not only establishes dormancy, but also induces autophagy, a process by which cells consume their own organelles to generate energy that could sustain nutritionally challenged dormant ovarian cancer cells in small scars on the peritoneal surface.

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