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

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.

Focusing on New Treatments

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.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.

Looking at the Big Picture

Comparison of primary and positive second-look surgical specimens—examined at later stages of the disease—suggests that ovarian cancer cells are present in less than 20% of primary cases, but in more than 80% of second-look specimens from the same patients. Later-stage specimens also express ARHI and are undergoing autophagy. Thus, antiautophagic therapy might eliminate dormant, drug resistant cancer cells that remain after primary surgery and chemotherapy.Bast is very enthusiastic about this current era in cancer research, which he says is moving rapidly and appears to be on the brink of significant advances in patient care.

However, he stressed that bringing down the societal cost of cancer therapies is a difficult, but necessary, challenge. “One of the challenges we face is to be more efficient in developing effective targeted drugs. Of 20 new oncologic agents that are moved into clinical trials from pharma, 19 will fail, and it is not because the FDA is being particularly strict. Drugs are being approved that only extend progression-free survival by a few months,” said Bast.

“Our preclinical models are simply not adequately predictive of efficacy in patients. Much more attention needs to be devoted to developing and validating highly predictive preclinical models and choosing targets wisely, as well as to discovering biomarkers with high negative predictive value, comparable to estrogen and progesterone receptors in predicting lack of response to hormonal therapy in breast cancer.

Concerns About Future of Research

“If we could predict with high accuracy who would not respond to costly therapy, we could cut costs by more than half in most cases, spare patients from toxicity, and provide them with the agents that are more likely to help. Academe should take a more active role in developing such biomarkers,” Bast said.He lamented, however, the impact on young investigators of the current poor state of funding for biomedical research, and said this is discouraging physicians from becoming researchers. “It never occurred to me that I could not support my family and send my daughter to college, and still be a scientist and a physician. I think these days, young physicians are really wondering whether there is a future in biomedical research,” he said.

Recent efforts by Congress to restore cuts in National Institutes of Health funding are extremely important. At MD Anderson, Bast coordinates programs to develop the careers of physician-scientists in laboratory-based research and clinicianinvestigators in hypothesis-driven clinical trials. He is also involved in graduate and postdoctoral programs to ensure that doctoral students get more exposure to human biology and to clinical research so that their skills in translational research can be maximized.

“When I was going through medical school at Harvard, there was a strong commitment to provide doctoral candidates access to medical knowledge, and they spent the first 2 years taking medical school classes so that they knew anatomy and physiology and microbiology and pharmacology— all of the things that physicians learn. Over the last 40 years, that has completely changed, due in large part to the fact that there is so much fundamental science to master. Most PhD curricula include very little medicine,” Bast said.

At the Graduate School of Biomedical Sciences, a joint venture of MD Anderson and the University of Texas Health, courses are being established for graduate students in human biology and pathophysiology, clinically relevant cancer biology, translational cancer research, clinical trial design and execution, cancer immunotherapy, and clinical oncology.

Opportunities are provided for graduate students and postdoctoral fellows to shadow surgeons, radiation therapists, medical oncologists, pathologists, and imaging specialists, often caring for patients with the type of cancer that the trainees are studying in the laboratory.

Bast said a realization of the urgent need for solutions is partly behind his dedication to the craft of oncology practice and research. “I care for patients every week. It is not a huge number, probably only a couple of hundred in total, but I think that caring for cancer patients really keeps you focused and shows that our progress can never be fast enough from a patient’s perspective. It reminds you every week why you are doing what you are doing, and also I really enjoy caring for patients and practicing oncology.”

In preparing a recent grant application, Bast calculated that he has mentored at least 190 undergraduates, graduate and medical students, clinical and postdoctoral fellows, and established faculty members over the years, many of whom were truly exceptional. He feels that he has also been particularly fortunate to work with other members of the faculty at Harvard University, Duke University, and MD Anderson.

It is to these individuals that he gives much of the credit for the advances in medicine with which he has been involved. “I think that it is impossible to accomplish a lot without working collaboratively with great people around you. You also have to give young people space to develop and to work on their own projects, and that has been a principle of mine—to try to encourage people to develop their own careers and to try to find people who are highly motivated, if not driven, to do something about cancer and to help them accomplish that goal, however I can,” he said. His most enduring contribution to medical science, however, may be the development of the CA-125 blood test. Knapp gives him all of the credit. Without Bast, he said, there would be no CA-125. “He was the one who did it all.”