Third in a series of four profiles on the 2017 winners of the BWH Health & Technology Innovation Grants. Each winning team competed in a “Shark Tank”-style event and was selected for a $50,000 grant for basic/clinical/translational science-focused as well as commercialization-oriented research projects. These grants are supported by the Brigham Research Institute and the BWH Health & Technology Sub-Committee, which comprises friends of the Brigham from the philanthropic world.
Christopher French, MD, of the Department of Pathology, frequently finds himself on the phone with oncologists, patients or their family members who have searched the internet for guidance and found his research. French is one of very few primary investigators studying NUT midline carcinoma, a rare and aggressive form of cancer. With less than 100 cases diagnosed annually and an average patient survival rate of 9.5 months, lots of questions remain about the best way to treat and manage this disease.
French started at Brigham and Women’s Hospital during his pathology residency in the late 1990s. At the time, he wanted to participate in research but didn’t have a strong research background coming out of medical school. An Institutional Training Grant offered at BWH allowed French to gain the research experience he desired under the mentorship of Jonathan Fletcher, MD, of the Department of Pathology, who was studying thyroid cancer. When French asked his mentor for a new project to work on, Fletcher offered up a side project—mapping a carcinoma cancer gene detected in a patient recently seen at Boston Children’s Hospital. That side project would flourish, leading to the discovery of a new form of cancer, insights into other forms of the disease and the focus of French’s research going forward.
Sitting in his office surrounded by reading materials and files, French reflected candidly on both the challenges of working on a rare disease like NUT midline carcinoma, as well as why he has dedicated his research career to tackling it.
“I’m one of the only people who studies this cancer, so on the tough days, when I think about dropping this, I think to myself, ‘What would happen to these patients if I quit?’ And that question keeps me going. It’s not that I think I am going to be the person to cure this disease, but I am going to be the person who keeps working on it, with the hope of eventually helping these patients,” said French.
The NUTs and Bolts
Most cancers have very complex karyotypes—meaning there can be many genetic mutations and rearrangements that shuffle some of the pieces of the genome, turning on molecular machinery that shouldn’t be active. In the case of NUT midline carcinoma, there is only one chromosomal abnormality: the NUTM1 gene breaks off and fuses with a partner gene. In 2003, when French mapped the location of the genetic rearrangement found in the patient seen at Boston Children’s Hospital, he put NUTM1 and its frequent partner gene, BRD4, on the map. Since then, researchers have been able to identify other cancer cases that share this genetic rearrangement.
In about three-quarters of cases, NUTM1 fuses to BRD4 or BRD3. This results in a BRD-NUT fusion protein. BRD4 has also been implicated in more common forms of cancer, including multiple myeloma and acute lymphocytic leukemia.
For NUT midline carcinoma, French is interested in the interaction between NUT and P300, an interaction that leads to cancer growth. The team has developed several tests to try to flush out drugs or compounds that can disrupt this interaction to stop cancer growth. The most recent assay is fluorescence-based and lights up green if BRD4-NUT interacts with P300. Between 100, 000 and 200,000 compounds from the Institute of Chemistry and Cell Biology Longwood Screening Facility (ICCBL) will be screened using this assay.
“I get really excited about any new discovery that reveals something about the pathogenesis of this cancer. I am a very translational thinker—I don’t think of just the science irrespective of the overall context. I am inherently more interested in things with health relevance. I get excited about things that might lead to therapeutics,” said French.
Making a Splash in the Shark Tank
Though much of French’s research is NIH funded, other grants and funding opportunities help him to conduct the exploratory research necessary to try out new experiments and make big leaps forward. This made the 2017 BWH Health & Technology Innovation Grant a perfect fit. French was nervous to present at the Shark Tank-style event, especially after receiving particularly harsh criticism from Kevin O’Leary, from ABC’s “Shark Tank,” during the 2014 competition. The second time around, French was ready for the hard-hitting questions and was pleased with the insightful audience response. This year’s review committee and audience included BWH faculty (clinicians/researchers) as well as non-BWH reviewers including donors, venture capitalists, representatives of the biopharma/device industry and other friends of the Brigham.
One of the potential criticisms that French had prepared for, and was asked about, surrounded a question that often delivers criticism to rare disease research—why should someone invest? French responded, “Because rare diseases tell you a lot more about the common diseases.”
French cites that studying this rare cancer has led to therapeutics in other cancers and that if the team truly finds a compound that interferes with NUT, it could also be used as a reversible contraceptive in males—a potential benefit of the research he thought would be of interest to the audience. (In people who do not have NUT midline carcinoma, NUT, which stands for Nuclear protein of the Testis, is only present in the testes.)
At the end of the Shark Tank, members of the audience presented awards to the winning investigators. The individual who presented French with his award had an emotional reaction upon finding out he was one of the winners. It turned out that a close friend of the presenter had died from NUT midline carcinoma, the very disease French has committed his career to.
“It was a touching moment,” said French.