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Jonathan Alfred Fletcher, MD
Cytogeneticist, Brigham and Women's Hospital
Associate Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115




Research Narrative:

My diagnostic responsibilities in tumor cytogenetics provide part of the infrastructure for my ongoing research, which is focused on solid tumors.  The research involves genetic/biological characterizations of novel oncogenes and tumor suppressor genes, particularly in sarcomas and pediatric cancers.  My present laboratory priorities are to identify and validate novel targeted therapies in cancer.  We aim for rapid translation from bench to clinic and our laboratory studies from the past five years have culminated in FDA approval of new targeted therapeutics for five cancer applications.  Current priorities include maximizing the therapeutic impact of kinase inhibitor drugs, by characterizing resistance mechanisms to these drugs, and identifying novel therapies which are not stymied by these resistance mechanisms.  Such studies, in the past two years, have particularly led us to develop preclinical models (and to initiate clinical trials) for novel therapeutics in gastrointestinal stromal tumor (GIST).  These biologically rational therapeutics include inhibitors of HSP90, HDAC (histone deactelyase), proteasome pathways,   and PI3-K.  Because GIST is a rare disease, our studies are more effectively accomplished by multi-institutional consortia approaches, and I lead several highly-collaborative group efforts that combine clinical and laboratory resources across many international centers of sarcoma research excellence:

1. For the past four years, I have led international research efforts, supported by $1.5M/year, for the LifeRaft Group, which is a patient advocate group for GIST in children and adults.  The goals of these highly-coordinated efforts are to characterize resistance mechanisms to imatinib (Gleevec), which is the first-line KIT/PDFRA-inhibitor therapy for GIST.

2. I am leading a national grant application for a SPORE (specialized program in research excellence) in sarcoma.  There are 60 SPORE awards now funded in the USA, and not one of these contains a pediatric project.  I have assembled a sarcoma SPORE with two pediatric projects, involving multiple institutions and a cooperative trials group, rather than (as in the case with all previous SPOREs) being based at a single academic center.  Hence, the sarcoma SPORE represents my interest in finding solutions to research challenges in rare forms of cancer. 

3. I have developed career development funding mechanisms, administered by the SARC sarcoma clinical trials group, to provide career development support for junior physician-scientists engaged in translational sarcoma research.
 


Education:
MD

Lab Members:
Cheng-Han Lee, MD, PhD, Postdoctoral Research Fellow
Adrian Marino-Enriquez, MD, Postdoctoral Research Fellow
Cher-wei Liang, MD, Postdoctoral Research Fellow
Yuexiang Wang, PhD, Postdoctoral Research Fellow
Meijun Zhu, MD, Postdoctoral Research Fellow
Wen-bin Ou, PhD, Postdoctoral Research Fellow
Anneliene Jonkers, Predoctoral Student
Sena Ugur, Medical Student
David Josephy, PhD, Visiting Scientist

Publications (Pulled from Harvard Catalyst Profiles):

1. Schaefer IM, Wang Y, Liang CW, Bahri N, Quattrone A, Doyle L, Mariño-Enríquez A, Lauria A, Zhu M, Debiec-Rychter M, Grunewald S, Hechtman JF, Dufresne A, Antonescu CR, Beadling C, Sicinska ET, van de Rijn M, Demetri GD, Ladanyi M, Corless CL, Heinrich MC, Raut CP, Bauer S, Fletcher JA. MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun. 2017 Mar 08; 8:14674.

2. Obata Y, Horikawa K, Takahashi T, Akieda Y, Tsujimoto M, Fletcher JA, Esumi H, Nishida T, Abe R. Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors. Oncogene. 2017 Feb 13.

3. Heinrich M, Rankin C, Blanke CD, Demetri GD, Borden EC, Ryan CW, von Mehren M, Blackstein ME, Priebat DA, Tap WD, Maki RG, Corless CL, Fletcher JA, Owzar K, Crowley JJ, Benjamin RS, Baker LH. Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol. 2017 Feb 09.

4. Lee JC, Li CF, Huang HY, Zhu MJ, Mariño-Enríquez A, Lee CT, Ou WB, Hornick JL, Fletcher JA. ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol. 2017 Feb; 241(3):316-323.

5. Yong KJ, Li A, Ou WB, Hong CK, Zhao W, Wang F, Tatetsu H, Yan B, Qi L, Fletcher JA, Yang H, Soo R, Tenen DG, Chai L. Targeting SALL4 by entinostat in lung cancer. Oncotarget. 2016 Nov 15; 7(46):75425-75440.

6. Fletcher JA. KIT Oncogenic Mutations: Biologic Insights, Therapeutic Advances, and Future Directions. Cancer Res. 2016 Nov 01; 76(21):6140-6142.

7. Ou WB, Lu M, Eilers G, Li H, Ding J, Meng X, Wu Y, He Q, Sheng Q, Zhou HM, Fletcher JA. Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53. Br J Cancer. 2016 Nov 08; 115(10):1253-1263.

8. de Jong Y, van Maldegem AM, Marino-Enriquez A, de Jong D, Suijker J, Briaire-de Bruijn IH, Kruisselbrink AB, Cleton-Jansen AM, Szuhai K, Gelderblom H, Fletcher JA, Bovée JV. Inhibition of Bcl-2 family members sensitizes mesenchymal chondrosarcoma to conventional chemotherapy: report on a novel mesenchymal chondrosarcoma cell line. Lab Invest. 2016 Oct; 96(10):1128-37.

9. Peterse EF, Cleven AH, De Jong Y, Briaire-de Bruijn I, Fletcher JA, Danen EH, Cleton-Jansen AM, Bovée JV. No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone. BMC Cancer. 2016 Jul 14; 16:475.

10. Falkenhorst J, Grunewald S, Mühlenberg T, Marino-Enriquez A, Reis AC, Corless C, Heinrich M, Treckmann J, Podleska LE, Schuler M, Fletcher JA, Bauer S. Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib. Oncotarget. 2016 Jul 05; 7(27):41390-41403.