Jonathan A. Fletcher, MD: View From the Lab Bench

  

Nancy Berezin of GSI interviewed Jonathan Fletcher, MD about his GIST research and how much his lab depends on contributions.

Dr. Fletcher is an associate professor in the departments of Pathology and Pediatrics at Harvard Medical School and is an Associate Pathologist at Massachusetts General Hospital and at Brigham and Women’s Hospital.  He is also an oncologist at The Children’s Hospital in Boston.  Dr. Fletcher has been pursuing GIST research for many years and has published widely.  He has helped to train numerous GIST researchers as they have completed postdoctoral study in his lab, including Katherine Janeway, MD, Brian Rubin, MD, Anette Duensing, MD, and Sebastian Bauer, MD.  Dr. Fletcher’s lab has developed many of the GIST cell lines being used in preclinical research today.

GSI: You are a laboratory scientist, yet you have developed close ties with many Dana Farber patients. Can you tell us a little about that?

Dr. Fletcher: My background is in medical and pediatric oncology, and I would have foreseen myself becoming one of those physician-scientists who sees patients in the clinic and the wards part time while working in the laboratory. But after we started a laboratory aimed at defining the vulnerabilities of certain pediatric cancers and sarcomas, I realized that the need was so vast that if I wanted to accomplish as much as possible, I would have to be in the laboratory essentially full time. That meant stepping back from clinical care, which I did with great regret. But I felt then, as I do now, that it is crucial for everyone involved in cancer research to keep the patients forefront in our minds. They are what this work is about. So in our laboratory we always work with the faces of individual cancer patients in our minds and in our hearts.

GSI: Maura and Mike Cesarini have elected to donate all of the proceeds of Mike’s Pan Mass Challenge bike ride to your laboratory. That’s quite a testament to your efforts on behalf of GIST patients.

Dr. Fletcher: All of us have an unbridled commitment to finding a cure for GIST – or at least a drug regimen that will allow GIST patients to live long and full lives. We are doubly inspired in the case of individuals like Maura, who have unusual wild-type subtypes that are poorly understood and not sensitive to standard therapeutic management. A major focus of our laboratory is to identify compounds that could provide lasting tumor control in these individuals. We are privileged to work with Dr. Katie Janeway at Harvard, who is an international expert and research leader in the biology and treatment of wild-type and pediatric GIST. The wild-type GISTs are a bit like those oddly shaped pieces that turn out to hold the key to the entire jigsaw puzzle. If we can understand the mechanisms that drive them, we will have made a huge leap forward in our understanding of GIST as a whole.

For the majority of GIST patients who have KIT or PDGRFA activating mutations, our laboratory is working on ways to reduce that activation and stall the progression of any tumors that cannot be surgically removed. One thing that has given us a lot of encouragement is the discovery that you don’t have to knock the level of KIT or PDGRFA activation in the cells down to zero, as was the goal with imatinib; you just have to reduce it to a level that no longer supports cell growth and dysregulation. A drug like regorafenib seems to do that quite well. And there are a number of other upcoming agents that are sufficiently novel in their approach that they may bypass most imatinib (and other TKI) resistance mutations.

We are also gaining a better understanding of KIT and PDGRFA signaling pathways in GIST cells, which differ from those in normal cells or even other cancer cells. We have a general understanding of how those pathways function, but we need a more nuanced understanding in order to design narrowly targeted therapies that will inhibit tumor growth over the long term without destroying the patient’s quality of life. If patients with metastatic GIST are going to need a second agent to overcome TKI resistance – and increasingly it appears that they will — then the second agent has to be very selective in order to minimize toxicity. So ferreting out the points of vulnerability along those pathways is a huge part of what we do.

Our laboratory is also foremost in the world in the creation of GIST cell lines – credible biological models that are used both to screen new drug candidates and for studying the impact of minute genetic alternations on cell behavior. As one example, Dr. Marino-Enriquez in our lab group is asking the question: If you knock out each of the 11,000 different genes in a GIST cell individually -– or, conversely, if you re-express thousands of genes that have been downregulated in GIST cells — which genes are going to make a real functional difference? Which are the real deal breakers? It is tremendously labor-intensive work, but potentially very rewarding, because once we have mapped all those aberrant genes, we will know precisely where the next generation of chemotherapy agents can be targeted.

GSI: When it comes to cancer research, individual donors often feel that the need is too great — their check for $50 or $100 can’t possibly make a difference. How do you respond to that?

Dr. Fletcher: With any rare disease, individual contributions are absolutely essential. The NIH is generous to grantees when it comes to funding certain types of laboratory supplies, such as kits for molecular assays. Other basic equipment, however, is often excluded even when the grant is for a common cancer such as breast, lung, or prostate. With an uncommon entity like GIST, funding becomes even tighter, because the NIH is trying to address a broad range of health goals using limited resources. No matter how good the science, the question always arises: How many people are going to benefit from this research? 

The Cesarinis’ offer to donate the money from Mike’s PMC ride to buy a Veritas luminometer for our laboratory was therefore a godsend. The luminometer, which measures cellular ATP content, is a phenomenal tool for GIST research because it allows you to judge the impact of candidate drugs on cell viability with speed and accuracy. Yet it is precisely the sort of equipment that the NIH doesn’t typically fund. This year, we are hoping that Mike’s ride will generate enough interest to purchase an upgraded version of the same machine, along with a machine that enables us to more efficiently determine drug inhibition of KIT and PDGFRA in GIST cells. And that donation, like its predecessor, will actually be made up of multiple smaller contributions from their family and friends, colleagues, and fellow GIST patients. So individual contributions aren’t just the icing on the cake – they are absolutely crucial in moving GIST research forward to the next level.