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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

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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.


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. Heinrich MC, Patterson J, Beadling C, Wang Y, Debiec-Rychter M, Dewaele B, Corless CL, Duensing A, Raut CP, Rubin B, Ordog T, van de Rijn M, Call J, Mühlenberg T, Fletcher JA, Bauer S. Genomic aberrations in cell cycle genes predict progression of KIT-mutant gastrointestinal stromal tumors (GISTs). Clin Sarcoma Res. 2019; 9:3.

2. Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu M, Yu C, Mannan AM, Rubin BP, Demetri GD, Raut CP, Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019 Mar; 120(6):612-620.

3. Hmeljak J, Sanchez-Vega F, Hoadley KA, Shih J, Stewart C, Heiman D, Tarpey P, Danilova L, Drill E, Gibb EA, Bowlby R, Kanchi R, Osmanbeyoglu HU, Sekido Y, Takeshita J, Newton Y, Graim K, Gupta M, Gay CM, Diao L, Gibbs DL, Thorsson V, Iype L, Kantheti H, Severson DT, Ravegnini G, Desmeules P, Jungbluth AA, Travis WD, Dacic S, Chirieac LR, Galateau-Sallé F, Fujimoto J, Husain AN, Silveira HC, Rusch VW, Rintoul RC, Pass H, Kindler H, Zauderer MG, Kwiatkowski DJ, Bueno R, Tsao AS, Creaney J, Lichtenberg T, Leraas K, Bowen J, Felau I, Zenklusen JC, Akbani R, Cherniack AD, Byers LA, Noble MS, Fletcher JA, Robertson AG, Shen R, Aburatani H, Robinson BW, Campbell P, Ladanyi M. Integrative Molecular Characterization of Malignant Pleural Mesothelioma. Cancer Discov. 2018 12; 8(12):1548-1565.

4. Tsai HJ, Jiaang WT, Shih NY, Fletcher JA, Lin MJ, Yang MY, Chen CT, Hsu TJ, Wu CC, Lin HY, Chen LT. BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor. Cancer Sci. 2018 Nov; 109(11):3591-3601.

5. Klug LR, Bannon AE, Javidi-Sharifi N, Town A, Fleming WH, VanSlyke JK, Musil LS, Fletcher JA, Tyner JW, Heinrich MC. LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma. Oncogene. 2019 02; 38(8):1200-1210.

6. Cao M, Carrasco RD, Dubuc AM, Dal Cin P, Fletcher JA, Xiao S. ZMYM2-FGFR1 fusion as secondary change in acute myeloid leukemia. Leuk Lymphoma. 2018 Aug 30; 1-3.

7. Hemming ML, Lawlor MA, Zeid R, Lesluyes T, Fletcher JA, Raut CP, Sicinska ET, Chibon F, Armstrong SA, Demetri GD, Bradner JE. Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome. Proc Natl Acad Sci U S A. 2018 06 19; 115(25):E5746-E5755.

8. Schaefer IM, Fletcher JA, Nielsen GP, Shih AR, Ferrone ML, Hornick JL, Qian X. Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy. Cancer Cytopathol. 2018 Aug; 126(8):552-566.

9. Mariño-Enriquez A, Lauria A, Przybyl J, Ng TL, Kowalewska M, Debiec-Rychter M, Ganesan R, Sumathi V, George S, McCluggage WG, Nucci MR, Lee CH, Fletcher JA. BCOR Internal Tandem Duplication in High-grade Uterine Sarcomas. Am J Surg Pathol. 2018 03; 42(3):335-341.

10. Schaefer IM, Mariño-Enríquez A, Fletcher JA. What is New in Gastrointestinal Stromal Tumor? Adv Anat Pathol. 2017 Sep; 24(5):259-267.