Demetri's Team Approach Translates Into Success in Sarcoma Research

George D. Demetri, MD

For some cancer researchers, success means running your own laboratory independent of others, who might be viewed as competitors. Others, like George D. Demetri, MD, find success pursuing a career as a translational and clinical investigator, in which his goal is to bring other researchers together into highly functioning teams of global collaborations across academia, government, biopharma, and philanthropic enterprises.

His collaborative leadership has led to remarkable advances in the treatment of sarcoma, particularly the sarcoma subtype known as gastrointestinal stromal tumor (GIST).

“I was once told by a well-meaning mentor, ‘You are smart enough, you could run your own lab, but you are throwing your career away to be a clinical investigator.’ Traditionally, laboratory investigators are set up as the really smart guys. But that was not the role I chose to pursue,” said Demetri, recipient of the 2014 Giants of Cancer Care® award in Gastrointestinal Cancer.

Rather than spending his time in the laboratory, Demetri views himself more as a matchmaker, “making connections between faculty members, research nurses, and our various research teams in the experimental therapeutics program here at the Dana-Farber Cancer Institute, across Harvard Medical School, and extending into many other sectors of research, development, and care delivery.

I bring people together and make sure that our projects and programs are moving forward— whether they focus on GIST or other subtypes of sarcomas, whether they are in early or late clinical trial stage, or in expansion cohorts to other diseases,” said Demetri.

This approach to teamwork has been fruitful, says Demetri, who is the senior vice president for Experimental Therapeutics at the Dana-Farber Cancer Institute and a professor of Medicine at Harvard Medical School in Boston, Massachusetts.

This teamwork approach has extended to productive collaborations with start-up biotechnology companies such as Sugen and Plexxikon in the past, according to Demetri.

“Initially, this approach didn’t appear to fit the outdated standard concepts in which academicians ask basic questions. Also, biopharma companies are in the business of implementing studies to get drugs approved,” Demetri said. The lack of overlap in these separate worlds seemed inefficient and poorly designed for the modern era of mechanism-based drug discovery and more precise and predictive therapeutic development; Demetri thought if academicians could drive the science behind the trials in collaboration with top-notch companies, then nearly magical efficiencies and effectiveness could be achieved.

“The foremost example of our team’s work has been the sequential development of uniquely different tyrosine kinase inhibitors as effective therapies for patients with GIST. By targeting specific molecular structural variants of GIST, we have validated the concept that a human solid tumor can be treated by signal transduction inhibitors,” Demetri said.

He has designed and implemented a worldrenowned clinical research center focused on the treatment of sarcomas, and his team is at the cutting edge of developing personalized cancer therapeutics for several uniquely defined subtypes of sarcomas.

Evolving Sarcoma Research

Their efforts helped lead to the development and subsequent FDA approval of imatinib mesylate (Gleevec) as the first effective therapy for patients with metastatic or unresectable GIST, and serves as the basis for ongoing research into other novel agents. The development of Gleevec, one of the first examples of a rationally targeted oral cancer therapy for a solid tumor, was followed by research to overcome drug resistance through other targeted drugs, including sunitinib (Sutent) and regorafenib (Stivarga) for GIST as well as pazopanib (Votrient) for other sarcomas.Sarcomas are a paradigm of the complexity and heterogeneity of solid tumor oncology. Clinically important subsets of sarcomas are increasingly being defined by molecular signatures and biological characteristics rather than by the part of the body in which the disease arose. Demetri’s team is translating this research about the basic biology of sarcomas into new therapeutics directed at novel targets.

“The biggest change in sarcoma research is that we have discarded the notion that there is one thing called ‘sarcoma,’” said Demetri. Sarcoma has been parsed into hundreds of different diseases, Demetri continued. “If we really understand the wiring in all the tumors, we might be able to make some difference for patients.”

Looking back, he described sarcoma research before the 1990s as limited by a therapeutic nihilism: there was a sense that nothing could possibly make a big difference for patients. Clinicians met with infrequent treatment success, although advances in chemotherapy of certain sarcomas, especially the pediatric cases, such as Ewing sarcoma and osteosarcomas, could indeed lead to cures. “But adults with metastatic soft tissue sarcomas typically did not do well. That nihilism associated with sarcoma was a barrier in building a sarcoma program, even at Dana-Farber and Harvard,” he said.

Funding for diseases that affect a small population of people is often not forthcoming, making for little progress. Sarcoma is one such example, he said. “That made it frustrating, even if it was completely understandable,” Demetri said.

From Driver Mutations to New Drugs

Now, however, the picture has changed. “What has happened in sarcoma is now clearly being applied to more common cancers,” said Demetri. “We know there is no single thing called ‘lung cancer.’ Our field has parsed lung cancer into various clinically important defined subsets. There is no one disease called ‘breast cancer,’ [because] there are lots of different kinds of breast cancers. “I think that we are going to find that every form of cancer is an orphan disease, and—ultimately— that mixing and matching of these rare subsets are going to create new bins, new therapeutic categories that will allow us to study sarcomas and make a difference in subtypes of carcinomas and hematologic malignancies that match them,” Demetri predicted.“Dana-Farber has a unique culture,” said Demetri. “It’s one in which basic scientists and clinicians work shoulder to shoulder on common challenges.” He relates an anecdote about a breakthrough in understanding the KIT mutation in GIST. Approximately 80% of all GISTs contain a mutation in the KIT receptor tyrosine kinase that results in uncontrolled activation of this signaling protein. In the early 1990s, Christopher D.M. Fletcher, MD, the renowned sarcoma pathologist at Dana-Farber/Brigham and Women’s Hospital, described various immunohistochemically defined subsets of these sarcomas of the intestinal tract. This led to many discussions within the team, as they struggled to understand whether these subsets might explain mechanisms important for this cancer. Eventually, another colleague from Dana-Farber returned to Japan and was part of the team that made the first KIT mutation discovery in GIST in 1998.

“And finally we had a mechanism,” said Demetri. “In many ways it was the ‘a-ha’ moment, the idea that we had this class of tumor that we were arguing about. What is really driving it? The immunohistochemistry (without KIT at the time) wasn’t really giving us any insights, but at last we had this molecular biology insight which brought everything together,” Demetri explained. Jonathan A. Fletcher, MD, a molecular biologist and pediatric oncologist at Dana-Farber/Brigham and Women’s Hospital, had created some of the first GIST cell lines, which enabled more collaboration between his lab, Demetri, and other colleagues including David A. Tuveson, MD, PhD, to test the new drug then known as STI-571 (now called Gleevec) to shut down the mutation.

Science Is a Remix

Demetri said, “It was just a terrific and rapid movement from seeing this disease as a ‘black box’ challenge to putting the basic science on top of it, to putting the functional validation together, and then ultimately saying, ‘We have got to get this to patients to test this; it looks almost too good to be true, but it has got to be tested.’”As the first in his family to attend college, Demetri set his sights on nuclear physics, but soon found that “all the physics seemed way too mathematical for me.” Eventually, he found himself gravitating toward the molecular biology department at Harvard University.

There were giants in that molecular biology department—for example, the DNA pioneer James Watson and the noted geneticist Matthew S. Meselson. “I was fortunate to be trained by such incredible people who could see the value in this new field,” he said. “For example, in 1974, the polymerase chain reaction (PCR) hadn’t been invented, our tools were primitive by today’s standards,” he said. The PCR is a biochemical technology in molecular biology used to amplify a single copy or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence.

Throughout his academic and professional career, Demetri has brought teams together to use what has come before and improve upon it and thus advance current thinking.

There’s a lecture that Demetri is particularly fond of bringing up when he thinks about the work he has done in the GIST field. It’s a TED Talk by filmmaker Kirby Ferguson called, “Embrace the Remix.”

TED, a conference where technology, entertainment, and design converge, is a nonprofit organization devoted to spreading ideas, usually in the form of short, powerful talks (18 minutes or less). TED began in 1984.

In his talk, Ferguson explains how everything is a remix of something else, everything is sampled, everything is mixed together, postulating that there are very few, if any, truly original ideas on the planet in any field. Ferguson uses an example of how Bob Dylan used folk songs as the basis for some of his own compositions, but it could be applied to any field. “And I think that goes for science. Science is continually remixing things,” said Demetri.

So whether he’s receiving an award like the Giants of Cancer Care, or tracking how a particular kinase shuts off a crucial step in the cell cycle, Demetri is keenly aware of who and what has come before and all who have contributed along the way.

“I have mixed feelings about any kind of prizes and honors because there are so many people that need to be honored and deserve to be honored,” he said. “Even in my field, even in GIST, I feel a little guilty being honored like this because it has been such a team effort.”

In 1999, when the researchers of imatinib met at the American Society of Clinical Oncology Annual Meeting, they knew they might have something special, and they weren’t just referring to the targeted agent.

“We said if we were all still talking to each other in 5 years, we will have succeeded. And here we are, more than 15 years later and we are all good friends, we are all talking to each other, there have been no major breakups, and I think we have all treated each other fairly. “So, that to me is important, maybe not as important as having done so well by patients because that takes precedence over everything. But it is certainly second on the list. I can sleep at night feeling that it hasn’t been all about me, I have treated people fairly, and I feel in many ways I have been fairly treated, too,” he said.