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Melanoma: HELP
Articles by Jonathan A. Fletcher
Based on 6 articles published since 2009
(Why 6 articles?)
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Between 2009 and 2019, J. Fletcher wrote the following 6 articles about Melanoma.
 
+ Citations + Abstracts
1 Clinical Trial Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. 2015

Carvajal, Richard D / Lawrence, Donald P / Weber, Jeffrey S / Gajewski, Thomas F / Gonzalez, Rene / Lutzky, Jose / O'Day, Steven J / Hamid, Omid / Wolchok, Jedd D / Chapman, Paul B / Sullivan, Ryan J / Teitcher, Jerrold B / Ramaiya, Nikhil / Giobbie-Hurder, Anita / Antonescu, Cristina R / Heinrich, Michael C / Bastian, Boris C / Corless, Christopher L / Fletcher, Jonathan A / Hodi, F Stephen. ·Memorial Sloan Kettering Cancer Center, New York, New York. Weill Medical College of Cornell University, New York, New York. · Massachusetts General Hospital, Boston, Massachusetts. · H. Lee Moffitt Cancer Center, Tampa, Florida. · The University of Chicago, Chicago, Illinois. · The University of Colorado Cancer Center, Aurora, Colorado. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Beverly Hills Cancer Center, Beverly Hills, California. · Angeles Clinic and Research Institute, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Dana Farber Cancer Institute, Boston, Massachusetts. · Oregon Health and Science University, Portland, Oregon. · The University of California San Francisco, San Francisco, California. · Dana Farber Cancer Institute, Boston, Massachusetts. Stephen_hodi@dfci.harvard.edu. ·Clin Cancer Res · Pubmed #25695690.

ABSTRACT: PURPOSE: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. RESULTS: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. CONCLUSIONS: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

2 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute · Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital · Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA · Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR · Philip Friedlander, Mount Sinai Medical Center, New York, NY · Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO · Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Thomas F. Gajewski, University of Chicago, Chicago, IL · Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA · Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX · Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: PURPOSE: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. RESULTS: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

3 Article LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma. 2019

Klug, Lillian R / Bannon, Amber E / Javidi-Sharifi, Nathalie / Town, Ajia / Fleming, William H / VanSlyke, Judy K / Musil, Linda S / Fletcher, Jonathan A / Tyner, Jeffrey W / Heinrich, Michael C. ·Portland VA Health Care System, Portland, OR, USA. klugl@ohsu.edu. · Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. klugl@ohsu.edu. · Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA. klugl@ohsu.edu. · Portland VA Health Care System, Portland, OR, USA. · Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. · Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA. · Department of Pediatrics, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA. · Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR, USA. · Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. · Department of Pediatrics, Brigham and Women's Hospital, Boston, MA, USA. ·Oncogene · Pubmed #30242244.

ABSTRACT: Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.

4 Article Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-κB pathways. 2012

Wu, Xinqi / Li, Jingjing / Zhu, Meijun / Fletcher, Jonathan A / Hodi, F Stephen. ·Department of Medical Oncology, Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA. ·Mol Cancer Ther · Pubmed #22653968.

ABSTRACT: Somatic GNAQ mutations at codon 209 have been identified in approximately 50% of uveal melanomas and have been reported to be oncogenic through activating PLCβ/PKC/Erk1/2 pathways. We hypothesized that protein kinase C (PKC) may provide new opportunities for therapeutic targeting of uveal melanoma carrying GNAQ mutations. To test this hypothesis, uveal melanoma cells harboring wild-type or mutant GNAQ were treated with the PKC inhibitor AEB071 (sotrastaurin) or infected with lentivirus-expressing short hairpin RNAs (shRNA) targeting PKC isoforms. Notably, AEB071 at low micromolar concentrations significantly inhibited the growth of uveal melanoma cells harboring GNAQ mutations through induction of G(1) arrest and apoptosis. However, AEB071 had little effect on uveal melanoma cells carrying wild-type GNAQ. AEB071-mediated cell inhibition in the GNAQ-mutated uveal melanoma was accompanied by inhibition of extracellular signal-regulated kinase (Erk)1/2 phosphorylation, NF-κB, decreased expression of cyclin D1, survivin, Bcl-xL, and XIAP, and increased expression of cyclin-dependent kinase inhibitor p27(Kip1). AEB071 suppressed the expression of PKC α, β, δ, ε, and θ in GNAQ-mutated uveal melanoma cells. Our findings from shRNA-mediated knockdown studies revealed that these PKC isoforms are functionally important for uveal melanoma cells harboring GNAQ mutations. Furthermore, inhibitors of Erk1/2 and NF-κB pathways reduced viability of uveal melanoma cells. Together, our findings show that AEB071 exerts antitumor action on uveal melanoma cells carrying GNAQ mutations via targeting PKC/Erk1/2 and PKC/NF-κB pathways. Targeted PKC inhibition with drugs such as AEB071 offers novel therapeutic potential for uveal melanoma harboring GNAQ mutations.

5 Article The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. 2012

Wu, Xinqi / Zhu, Meijun / Fletcher, Jonathan A / Giobbie-Hurder, Anita / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #22253748.

ABSTRACT: GNAQ mutations at codon 209 have been recently identified in approximately 50% of uveal melanomas (UM) and are reported to be oncogenic through activating the MAPK/Erk1/2 pathway. Protein kinase C (PKC) is a component of signaling from GNAQ to Erk1/2. Inhibition of PKC might regulate GNAQ mutation-induced Erk1/2 activation, resulting in growth inhibition of UM cells carrying GNAQ mutations. UM cells carrying wild type or mutant GNAQ were treated with the PKC inhibitor enzastaurin. Effects on proliferation, apoptosis, and signaling events were evaluated. Enzastaurin downregulated the expression of several PKC isoforms including PKCβII PKCθ, PKCε and/or their phosphorylation in GNAQ mutated cells. Downregulation of these PKC isoforms in GNAQ mutated cells by shRNA resulted in reduced viability. Enzastaurin exhibited greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis. Enzastaurin-induced G1 arrest was associated with inhibition of Erk1/2 phosphorylation, downregulation of cyclin D1, and accumulation of cyclin dependent kinase inhibitor p27(Kip1). Furthermore, enzastaurin reduced the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells. Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27(Kip1) accumulation and/or inhibition of enzastaurin-induced survivin and Bcl-2 upregulation. PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis. Inhibition of the PKC pathway provides a basis for clinical investigation in patients with UM.

6 Article Impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial. 2009

Menzies, S W / Emery, J / Staples, M / Davies, S / McAvoy, B / Fletcher, J / Shahid, K R / Reid, G / Avramidis, M / Ward, A M / Burton, R C / Elwood, J M. ·Sydney Melanoma Diagnostic Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. scott.menzies@sswahs.nsw.gov.au ·Br J Dermatol · Pubmed #19747359.

ABSTRACT: BACKGROUND: Studies have shown the benign to malignant ratio of excised pigmented skin lesions is suboptimal in primary care. OBJECTIVES: To assess the impact of dermoscopy and short-term sequential digital dermoscopy imaging (SDDI) on the management of suspicious pigmented skin lesions by primary care physicians. METHODS: A total of 63 primary care physicians were trained in the use of dermoscopy and SDDI (interventions) and then recruited pigmented lesions requiring biopsy or referral in routine care by naked eye examination. They were then given a dermatoscope and the option of a SDDI instrument, and change of diagnosis and management was assessed. RESULTS: Following the use of the interventions on 374 lesions a total of 163 lesions (43.6%) were excised or referred, representing a reduction of 56.4%. Of the 323 lesions confirmed to be benign, 118 (36.5%) were excised or referred, leading to a reduction of 63.5% (P < 0.0005) in those requiring excision or referral. The baseline naked eye examination benign to melanoma ratio was 9.5 : 1 which decreased to 3.5 : 1 after the diagnostic interventions (P < 0.0005). Of the 42 malignant lesions included in the study (34 melanoma, six pigmented basal cell carcinoma and two Bowen disease) only one in situ melanoma was incorrectly managed (patient to return if changes occur) resulting in the correct management of 97.6% and 97.1% of malignant pigmented lesions and melanoma, respectively. CONCLUSIONS: In a primary care setting the combination of dermoscopy and short-term SDDI reduces the excision or referral of benign pigmented lesions by more than half while nearly doubling the sensitivity for the diagnosis of melanoma.