The Wistar Approach to Ovarian Cancer
Sometimes, changing the world begins by breaking down the sort of borders that only exist in the mind. For researchers, it means stepping outside of the routine to embrace new ideas and new approaches to the most intractable problems. In 2012, The Wistar Institute embarked on a quiet, but potentially revolutionary attempt to resolve the murky genetic and molecular origins of ovarian cancer.
Despite many advances throughout cancer medicine, physicians still lack diagnostic tools that will allow them to diagnose ovarian cancer early or therapeutics that will specifically target the disease, based on the inherently complicated and resistant character of ovarian tumors. As a result, the National Cancer Institute (NCI) estimates that in 2013, more than 22,000 women will be diagnosed with ovarian cancer in the United States alone, and over 14,000 will die of the disease. The Institute’s approach to ovarian cancer is Wistar “team science” at its best.
On one side of the Institute are experts in the tumor microenvironment — immunologists and cancer biologists whose research has focused on how cancer cells interact with and influence their normal neighboring cells. On the other are experts in the nuts and bolts of gene expression — the structure and mechanics of the systems that control how our genes are activated and repressed.
Binding them together are experts in the art and science of coordinating and interpreting large sets of scientific data — specialists in bioinformatics and biostatistics. In this past year, these researchers coalesced into a team at Wistar called the Ovarian Cancer Affinity Group.
“The Ovarian Cancer Affinity Group is another example of how Wistar can put substance behind the rhetoric of ‘team science’,” said Dario C. Altieri, M.D., chief scientific officer and director of The Wistar Institute Cancer Center. “As we have seen with our Melanoma Research Center and our Tumor Microenvironment and Metastasis program, we excel at organizing around our scientific strengths.”
The affinity group arose from the interests of Wistar scientists. The recent recruitments of José Conejo-Garcia, M.D., Ph.D. (in 2010), and Rugang Zhang, Ph.D. (2012), brought two laboratories experienced in the behavior of ovarian cancer to the Institute. They naturally began to interact with other researchers with an interest in cancer microenvironment (Ashani Weeraratna, Ph.D.), and tumor immunology (Hui Hu, Ph.D.) and biological markers of ovarian cancer (David W. Speicher, Ph.D.). “We soon realized that we had a collective interest in the biology of ovarian cancer, and began to meet regularly, exchanging our own viewpoints on the disease,” said Conejo-Garcia, professor and leader of Wistar’s Tumor Microenvironment and Metastasis program.
Meanwhile, Altieri had asked Wistar’s Gene Expression and Regulation (GER) program leader, Ronen Marmorstein, Ph.D., to survey his GER colleagues with an eye toward identifying emerging (and thus unfunded) research projects that might be packaged into a new theme. Coincidentally, one of the themes that arose meshed nicely with the interests of the Ovarian Cancer Affinity Group.
“We wanted to explore ideas that had a good chance of maturing into interesting, fundable research projects, and it just so happened that four members of our group were studying gene regulatory systems that had clear connections to ovarian cancer,” said Marmorstein, Wistar’s Hilary Koprowski, M.D., Professor. “In addition to their ovarian cancer link, these four projects also had an underlying theme that really plays to our strengths, and that is epigenetics.”
The Four R’s of Epigenetics
Over the last decade, the GER program has collectively made tremendous advances in the field of epigenetics. The prefix “epi-” comes from the Greek, meaning “besides” or “in addition to,” so the word epigenetic refers to the changes made outside of the DNA that alter how genes are activated or “expressed.” While cancers often begin with mutations that result in physical changes to the DNA, they are frequently helped along by epigenetic changes that could, for example, squelch tumor-suppressing genes or activate genes to enable malignant growth.
The first four projects to be tackled by the Ovarian Cancer Affinity Group stem from the four R’s of epigenetics at Wistar: Ronen, Rugang, Ramin, and Rauscher. Frank Rauscher, III, Ph.D., will study how the curiously named Snail and Slug gene-control proteins influence the ability of cancer cells to metastasize. Ramin Shiekhattar, Ph.D., has teamed with Conejo-Garcia to understand how a transcription factor called BRCA1, which is mutated in many breast cancers, plays a role in ovarian cancer through its regulation of the immune system.
Concurrently, the laboratory of Rugang Zhang will tackle the biology of a protein called ARD1, a member of a group of proteins that mediates chromatin remodeling, which alters how DNA is configured in order to promote the reading of specific genes. ARD1 is mutated in more than 60 percent of ovarian cancers. Ronen Marmorstein will work with David Speicher to analyze ovarian cancer-associated acetyltransferase enzymes, which epigenetically alter gene reading by “tagging” histones, with the goal of developing new candidate drugs to negate their cancer- causing effects.
“Bringing together cell biologists, molecular biologists, biochemists, and structural biologists makes sense as ovarian cancer is a disease informed by both the inner workings of the cell — the genetics and epigenetics — and the ability of these cancer cells to relate to each other and surrounding tissue,” Conejo-Garcia said.
Team Ovarian Cancer
At the nerve center of the group are the proteomics, and biostatistics cores, comprised of Speicher, and Qin Liu, Ph.D., respectively. The Speicher lab offers expertise in proteomics, the sum total of proteins a cell will produce, which allows the study of protein activity and the hunt for new drug targets. Liu, whose formidable task is to assess and validate data generated through the four projects, provides the biostatistic component using stringent statistical data analysis.
In 2013, Wistar’s hybrid team of ovarian cancer and epigenetic scientists will apply for a P01 grant — the NCI’s programmatic funding grant — that will enable the researchers to invest in the materials and staffing necessary to conduct research in this area.
“I see great promise in this team going forward. It is the right combination of talents and perspectives,” said Altieri, Robert and Penny Fox Distinguished Professor. “We combine two pioneering fields in science — tumor microenvironment and epigenetics — and apply them to a complex and demanding disease. Only at a place like Wistar can we put together a group this well-rounded and driven in less than a year.”