Harnessing genetics to disrupt blood cancers

Tuesday, September 19, 2017
Sandeep Dave, MD

In 2016, the Duke School of Medicine selected 38 of its faculty for the new Duke Health Scholars and Duke Health Fellows Program. With funds from the Duke University Health System, the program supports the research efforts of early to mid-career clinician-scientists at Duke.

Among the faculty honored are 14 individuals from the Department of Medicine, including Sandeep Davé, MD, MBA, MS, professor of medicine (Hematologic Malignancies and Cellular Therapy).

To better understand blood cancers, Sandeep Davé hunts down variation in the DNA sequences important to those cancers. One international project he launched is deploying comparative genetics to better classify the more than 100 blood cancers.

But the research never stops there.

Guided by patterns of genetic variation his laboratory detects in human tumors, Davé’s research team also engineers new laboratory animal models intended to better mimic the physiology of human cancers.

They deploy gene-editing tools such as CRISPR to produce lab mice with several genetic variations observed in patients with blood cancers, rather than a single gene.

The work all serves an experimental mission that Davé describes with three deceptively simple verbs: Measure. Model. Disrupt.

“What interests me most is the ability to combine these very disparate lines of work and knowledge into a unified view of how tumors work and how we can disrupt them,” says Davé.

This is not the intellectual journey that Davé expected when he studied computer engineering studies as an undergraduate . In those days, the prospect of contributing to the development of artificial intelligence fired him up most.

But when Davé learned that machine intelligence did not come close to matching the adaptability of human intelligence, biology lured him instead. That led him into graduate training in biomedical engineering at Northwestern University

Too quickly, he said, he found himself engaged in mechanistic studies focused on brain receptor activation in laboratory animals that had unknown significance in people. That was too remote from the interest in human physiology that had lured him from computers. Medical school soon followed.

“I was interested in the human experience and human physiology,” says Davé. He remained at Northwestern for medical school and residency, picking up a business degree along the way.

During medical training, Davé was drawn to oncology. Treating blood cancers particularly appealed because he could remain active in patient treatment every step of the way, rather than sending people to other specialists for significant periods of care.

Also intriguing was the prospect of expanding treatments for those patients. Davé saw great promise in using insights from genetic studies to better understand the molecular basis of disease and then design new drugs to combat those diseases.

To gain research skills at that scale, Davé joined the laboratory of Louis Staudt at the National Institutes of Health, joining scientists using applied genomics to better diagnose and, possibly, treat leukemias and lymphomas.

Suddenly his computer skills were relevant.

“At that point the standard approach for biologists was to generate data and then hand off to a biostatistician and wait patiently for results. My ability to take an early look at the data enabled me to develop a better understanding of the results and, eventually, to help generate new ways of analysis,” Davé said.

Davé brought that do-it-yourself approach to Duke in 2007 as a new faculty member in the Duke Institute for Genome Sciences and Policy. He and his postdoctoral researchers initially built their own computer servers to accommodate the computing demands of the high-throughput genetic studies.

Sometimes that meant tinkering with what had been standard. Rather than relying on fresh, frozen tissue, Davé’s laboratory developed the techniques for using human tissue embedded in paraffin for sequencing studies, for instance. This allows researchers to study samples preserved with methods used around the world, rather than being restricted to samples from far fewer institutions that routinely bank frozen tissue.

“Dr. Davé has shown outstanding dedication to the development of his research program, his laboratory, and mentoring of our fellows and junior faculty while developing broad-based collaborations both at Duke and internationally,” said Mary Klotman, MD, former chair of the Department of Medicine and now dean of the School of Medicine.

Follow the Data

So far, the approach of letting genetic data guide experimental queries is yielding insights, in blood cancers and beyond.

Davé’s research team has parsed genetic variation among multiple hematologic malignancies, including Burkitt lymphoma and other tumor types. Combining clinical and sequencing data, they have recently profiled 1,000 diffuse large B cell lymphoma tumors, which allowed them to build a new blueprint of genetic networks contributing to this most common form of blood cancer. Clinical trials at Duke will explore new treatment approaches identified by that work in coming years.

“I feel that our work is on a good trajectory that allows us to span discoveries made from a basic understanding of human tumors to preclinical and clinical studies that enable translation of new therapeutic approaches,” Davé says.

That’s right: Measure. Model. Disrupt.

The series of profiles of our Duke Health Scholars were written by Catherine Clabby, freelance science journalist. Photos are by Ted Richardson.