The art, and science, of collaboration

In the field of cancer research, one of the most significant discoveries in the last two decades is the finding that most cancers are caused by overactive cell division due to genetic mutations. The concept of “precision medicine” now uses a patient’s specific mutations to help treat his or her cancer. For a subset of patients, this approach—matching patients with appropriate targeted drugs—works exceedingly well. But unfortunately, many patients develop treatment resistance over time, after which the cancer can make an aggressive return. “For people like me in the signaling field, it was a pretty major disappointment that resistance can readily develop,” says David F. Stern, Ph.D., professor of pathology and associate director of shared resources at Yale Cancer Center (YCC). “And it’s been a real practical problem for the clinicians.”

Cancer cells, just like healthy cells, try to maintain internal stability, or homeostasis. When single drugs are introduced that interfere with the cells’ division pathways, many eventually switch to parallel pathways that cause the cells to continue dividing.

For Stern, who was researching melanoma, it eventually became clear that these single-agent therapies weren’t going to work well enough. He needed to find a cocktail of drugs that could hit enough targets in the cell to shut down the cancer for good. Six years ago, he and collaborator Marcus W. Bosenberg, M.D., Ph.D., associate professor of dermatology and pathology, turned to the Yale Center for Molecular Discovery (YCMD) for help. “We brought the project to them and they said, ‘Yes, we can do this,’ even though no one had done this kind of combination screening here, or really anywhere,” Stern recalls.

The YCMD, one of the core resource facilities on Yale’s West Campus in West Haven, Conn., specializes in drug screening and development. “We help faculty access and correctly implement a suite of technologies for early-stage drug design,” explains Janie Merkel, Ph.D., director of biology at the YCMD.

The YCMD’s staff includes both biologists and chemists with industry experience. The Center has a range of technologies to screen small molecules for particular effects and to quantify the results in almost any small study system, from plant seeds to nematode eggs to cell lines. Its library contains 150,000 compounds, covering a wide swath of chemical structures that can pass through the cell membrane. Once useful compounds are identified in a screen, the chemists take over, tinkering with their molecular structures to maximize their effectiveness.

When Stern and Bosenberg brought their project to the YCMD, they started with a small single-agent screen on a melanoma cell line, then worked up to a much larger assay using 41 different agents in combination with each other.

“The advantage of having the screening center here is that we developed this whole system,” he says. “Nobody showed us how to do it. Five or six years ago, there was little published literature in combination work.” It took his team nearly a year to analyze their data: they have since published their work in the journal Cancer Discovery and are hoping to move into clinical trials, while also coordinating similar projects using lung and pancreatic cancer cell lines.

Early-career researchers at the School of Medicine have also benefited substantially from collaborations with the YCMD. Ranjit Bindra, M.D., Ph.D., assistant professor of therapeutic radiology and of pathology, met with Merkel before joining the faculty three years ago. He received a YCMD pilot grant and began investigating drugs that would block DNA repair in tumors. Standard therapies—chemotherapy and radiation—largely tackle cancer by damaging cellular DNA, but cancer cells have DNA repair mechanisms that can diminish the therapies’ effectiveness. Bindra’s team is seeking a class of compounds that inhibit these repair mechanisms, making the cancer more susceptible to treatment.

“It’s easy to think you could do it all yourself,” Bindra says, “but you really need a screening, like these folks, who are going to keep you on track and make sure you design a screen which will get you meaningful hits.” Bindra’s lab has worked on four different projects with the YCMD, two of which are currently running. His work has generated two manuscripts, and Bindra plans to use the preliminary data in an application for federal grant funding.

An initial project with the YCMD often leads to funding from larger institutions, as Qin Yan, Ph.D., associate professor of pathology, discovered when he began research at Yale. Like Bindra, Yan was awarded a YCMD pilot grant shortly after he joined the medical school’s faculty in 2008. He had discovered a category of enzymes that act as major epigenetic regulators, altering gene expression globally—and realized that inhibiting these enzymes might lead to a potential cancer treatment. Searching for a compound to do so, he first screened 15,000 compounds at the YCMD, then increased that number to 106,000 in a second screen, looking for samples where the enzymes had failed to react. His lab discovered a handful of candidates, which later led to a patent and the promise of related research projects. He has successfully applied for two Department of Defense grants as an extension of the work he did at the YCMD and has developed a partnership with the National Cancer Institute.

The YCMD not only provides assay development and drug screening technologies, but also consults on projects and provides grant-writing assistance. The Center is subsidized to provide the best possible costs to School of Medicine faculty. For many researchers, it adds translational potential to their basic science research. And its highly trained staff pride themselves on creating long-term relationships and offering a custom approach to help develop any research project brought to their doorstep. “We’ll be emailing Saturday at seven a.m. going back and forth,” Bindra says. “They’re almost on-call, [as if] we’re in the hospital.”

Says Denton Hoyer, Ph.D., director of chemistry at the YCMD, “It starts with a conversation. Just call us.”