Gary Stein, PhD (left) and Janet Stein, PhD (right)
Project to Identify New Targets for Drug Treatment That Could Prevent or Halt Disease
A team of University of Vermont scientists and physician investigators at the UVM Cancer Center and the Northern New England Clinical and Translational Research Network has been awarded a $9 million, five-year grant from the National Cancer Institute (NCI) to investigate the underlying causes of breast cancer with the goal of identifying new cellular-level targets that could be treated with drugs to prevent the disease or halt its progression.
The principal investigators for the project are Gary Stein, Ph.D., Perelman Professor and chair of the UVM Larner College of Medicine Department of Biochemistry and professor of surgery, and Janet Stein, Ph.D., a professor of biochemistry at the Larner College of Medicine. They lead a large, collaborative team representing scientific expertise across three colleges at the University of Vermont.
The competitive grant—about 5 percent of similar NCI grant proposals are funded—came to UVM, in part, because of the research team’s track record.
“The NCI is investing in research groups that have made major, proven contributions,” said Gary Stein. “There is a high expectation that the progress won’t be incremental but will represent a paradigm shift.”
Stein and his collaborators have published their earlier findings on the underlying mechanisms of breast cancer in publications ranging from Nature to Cancer Research. The new work will build on the previous research contributions to expand both general understanding of breast cancer dynamics and how that molecular-level knowledge could reveal new potential drug targets leading to novel, more effective treatments.
The research will focus on three interrelated projects to determine what goes awry when cell division in healthy breast tissue becomes defective and produces cancer cells. Its focus will be on epigenetics, the instructions that proteins and nucleic acids within a cell’s nucleus give to its genetic code—its DNA—that tell genes to turn on or off. When a cell reproduces, these epigenetic instructions are passed on to newly formed cells, along with the parental cell DNA, its genetic blueprint. If the epigenetic instructions don’t function precisely, cells can become cancerous.
“The goal is understanding cancer-compromised epigenetic control of genes in breast tumors,” Janet Stein said.
The first project will examine in detail how instructions for the epigenetic regulation of genes—whether they are turned on or off, or poised to turn on—are passed on from a parent cell to its two offspring cells accurately, so “there are no defects in the control of its specialized function or its ability to go through cell division in a normal way,” Janet Stein said. “We’re trying to understand, precisely, what are the components, what are the epigenetic factors that remain with the gene during cell division, in order to ensure that you are not going to compromise normal function in the progeny cells.”
The second project focuses on the proteins, called histones, that organize the two-and-a-half yards of DNA within a cell’s nucleus into intricate folds inside a chromosome. If these proteins bind a section of the folded DNA tightly, genes won’t be expressed; if the bond is loose, the genes will be expressed or poised to express. In cancer cells, the ability to modify these proteins is undermined. The project will seek both to chart how the DNA organizing process works and identify drug targets that will restore function of cancer-compromised proteins.
In the third project, researchers will examine the functioning of a type of long non-coding RNA found in a cell’s nucleus that the research team discovered in an earlier project. It is present only when cells divide, the team found, and is associated with breast cancer, especially in its most aggressive forms, and is not responsive to conventional cancer treatments. The earlier work showed that, if the activity of this particular type of RNA is blocked, the cancer cell is unable to reproduce and dies. It is a prime drug target, Gary Stein said.
Technology and Team-based Approach Helped Win the Day
UVM has two other capabilities that helped the Cancer Center team win the grant—access to advanced technology and the strength of its collaborative scientific team. The Larner College of Medicine’s advanced genome sequencing, microscopy and bioinformatics core facilities allow researchers to peer into cells and chromosomes and view genes and proteins visually in three dimensions.
“We have a saying: ‘Seeing is believing,’” Gary Stein said. “The work would be impossible without this highly advanced instrumentation and the world-class expertise behind that technology, which allow us to identify and visualize modified genes and gene expression in cancer cells. It was definitely a credential that the NCI looked favorably on.”
In addition, the NCI places priority on what it calls collaborative team science, an interdisciplinary research approach that is the fabric of the UVM Cancer Center.
“Collaboration is the guiding principle for the UVM Cancer Center,” Gary Stein said. “We engage the complementary perspectives, expertise and experience of clinicians, oncologists, molecular biologists, biochemists, bioinformaticists, pathologists and others. “UVM’s breadth and culture incentivize partnerships that synergize to accelerate the translation of laboratory discovery to advances in cancer prevention, early detection, treatment and survivorship,” he said.
Members of the research team come from the University of Vermont’s Larner College of Medicine, College of Nursing and Health Sciences, and College of Engineering and Mathematical Sciences and cover both basic science and clinical departments. Members of the team, in addition to Gary and Janet Stein, are Mark Evans, Seth Frietze, Karen Glass, Jonathan Gordon, Peter Kaufman, Jane Lian, Jason Stumpff, Coralee Tye, Pamela Vacek, Jos Van der Velden, Donald Weaver and Marie Wood. Andrew Fritz and Kirsten Tracy are NCI postdoctoral fellows participating in the project.