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Discovering the causes of cancer and the means of prevention

Michael Cook Explores Sex Differences, Genetics, and Hormones to Understand Cancer Pathogenesis

by Victoria A. Fisher, M.P.H.

As a tenure-track investigator in the Hormonal and Reproductive Epidemiology Branch (HREB), Michael B. Cook, Ph.D., studies the epidemiology of esophageal adenocarcinoma and prostate cancer. Both types of cancer cause significant mortality in the United States, and Dr. Cook hopes to shed light on their pathogenesis with potential utility for risk prediction.

Journey to Tenure-Track

Michael Cook

Dr. Cook’s scientific goals are rooted in the enigma of the unknown and his desire to solve problems. Mentoring has also played a vital role in shaping his career; a particularly good secondary school teacher encouraged his early interest in science. “I remember that the genetics revolution was under way and the Human Genome Project had begun; it was all very exciting,” he said. “I decided then and there that I was going to study biology and preferably human genetics.”

After earning a bachelor’s degree in genetics from the University of Nottingham in England, Dr. Cook knew that he wanted to continue in the field. “The natural counterpart to genetics is epidemiology,” he said. “I wanted to apply the tools and concepts I had learned while studying genetics to understand disease in human populations.”

Dr. Cook next pursued a Ph.D. in molecular epidemiology from the University of Leeds in England, where he started looking at sex differences in the pathogenesis of esophageal adenocarcinoma. His mentors encouraged his desire to look abroad for postdoctoral positions, and he eventually applied to DCEG and accepted a position within HREB.

Upon arriving at DCEG as a postdoctoral fellow in 2007, Dr. Cook started working with Katherine A. McGlynn, Ph.D., M.P.H., Deputy Chief of HREB, in the area of testicular cancer, particularly focusing on the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) study. He also became heavily involved with the International Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) and in studies with now-former DCEG investigator Dr. Wong-Ho Chow, thanks in part to a post-Thanksgiving dinner conversation with Sanford M. Dawsey, M.D.

“After introducing me to bacon-wrapped turkey, Sandy took me for a walk and asked me what else I was interested in working on in addition to my studies with Dr. McGlynn,” Dr. Cook said. “We discussed my prior work on esophageal adenocarcinoma, and he said he must introduce me to Wong-Ho Chow, who subsequently gave me some great opportunities in esophageal cancer research. Sandy played an important role in starting that collaboration at an early stage in my DCEG career.”

Dr. Cook was promoted to a research fellow in 2008 and to a tenure-track investigator in 2011. During the past several years his research portfolio has diversified; he still spends much of his time working on esophageal adenocarcinoma, but he is now focused on prostate cancer as well.

Esophageal Adenocarcinoma: Sex Differences and Obesity

Dr. Cook uses both classical and molecular epidemiologic approaches in his attempts to understand why as many as seven men for every one woman develop esophageal adenocarcinoma. “No one has been able to explain why such a large sex disparity exists with this malignancy,” he said.

One long-standing theory is that sex steroid hormones, such as androgens, estrogens, and their derivatives, might play a role. Dr. Cook and colleagues are currently investigating whether different levels of sex steroid hormones within men contribute to altered risks of esophageal adenocarcinoma and Barrett esophagus, the metaplasia that precedes cancer. In addition, they are pursuing other hypotheses, including the possibility that both inflammatory cytokines and metabolic syndrome affect risk. Each of these factors shares associations with both sex and body mass index.

“Obesity is the central theme of my esophageal adenocarcinoma research,” Dr. Cook said. “Obesity is strongly associated with this malignancy, and adipose tissue is a major site of sex steroid hormone metabolism.”

Accurate risk prediction for esophageal adenocarcinoma is also needed. Most individuals are diagnosed with a late-stage malignancy, resulting in a five-year survival rate of less than 20 percent. Dr. Cook is currently assessing whether circulating microRNAs and inflammatory markers in blood can be used to differentiate between esophageal adenocarcinoma and Barrett esophagus, with the eventual goal of enhancing carcinogenic risk prediction in those with Barrett esophagus, as well as detection in those with early-stage malignancy.

Prostate Cancer: Hormonal and Genetic Mechanisms

Dr. Cook’s interest in prostate cancer includes the interplay of hormones and genetics, with continued aims of elucidating pathogenesis and increasing our ability to predict risk.

“Although most analyses of hormones and prostate cancer have not provided evidence for an association, most of these have focused on ‘parent’ hormones alone,” he said. Dr. Cook, Amanda Black, Ph.D., M.P.H., and colleagues are currently analyzing the role of estrogen metabolites, as well as the estrogen-androgen balance, in relation to aggressive prostate cancer within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

One problem with current approaches to hormonal exposure and prostate cancer is that hormones are typically quantified at only a single point. “Because of the barriers to assessing at multiple time points, we are also looking at phenotypic markers that are proxies of long-term hormone status, including male pattern baldness and adolescent and adult height,” Dr. Cook said.

In addition, Dr. Cook is investigating germline and somatic genetics of prostate cancer, and he is assessing how this may overlap with hormonal factors that may be associated with carcinogenic risk. “We are currently establishing a pilot study of somatic genetics within the Ghana Prostate Cancer Study,” said Dr. Cook. “This work is in line with my background in genetics, and the study provides a unique population in which we can conduct cutting-edge research.”

Mentoring for Success

Michael Cook receives the DCEG Outstanding Mentor Award from Stephen Chanock.

When discussing his various research pursuits, Dr. Cook often highlights the pivotal role that certain individuals, mentors, and collaborators have played each step of the way.

“The mentorship I have received at DCEG has been outstanding,” Dr. Cook said. “Especially from Katherine; she understands when to advise and when to let you spread your wings, paving the path for independence.”

Dr. Cook is now a mentor himself and credits Dr. McGlynn with teaching him mentoring skills and giving him opportunities to practice. “After a couple of years in DCEG, Katherine enabled me to co-mentor three successive summer students,” he said. “That was a great learning experience, and I’m really proud that each of my students ended up with a first-author manuscript.”

When asked about his most significant achievement to date, Dr. Cook immediately pointed to the DCEG Outstanding Mentor Award hanging on the wall of his office. Each year, the award is bestowed by DCEG fellows. Dr. Cook was nominated by HREB postdoctoral fellow Jennifer Drahos, Ph.D., M.P.H., and was subsequently selected for the honor in early 2014.

“Without a doubt, the mentoring award means a great deal to me,” he said. “Every day I’m motivated to help my fellows find success and achieve their goals.”

Back to the summer 2014 issue of Linkage newsletter