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Melanoma: HELP
Articles by Jean-Richard Saint-Martin
Based on 2 articles published since 2010
(Why 2 articles?)

Between 2010 and 2020, Jean-Richard Saint-Martin wrote the following 2 articles about Melanoma.
+ Citations + Abstracts
1 Article Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells. 2014

Yang, Jennifer / Bill, Matthew A / Young, Gregory S / La Perle, Krista / Landesman, Yosef / Shacham, Sharon / Kauffman, Michael / Senapedis, William / Kashyap, Trinayan / Saint-Martin, Jean-Richard / Kendra, Kari / Lesinski, Gregory B. ·Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America. · Center for Biostatistics, The Ohio State University, Columbus, Ohio, United States of America. · Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America. · Karyopharm Therapeutics, Natick, Massachusetts, United States of America. ·PLoS One · Pubmed #25057921.

ABSTRACT: XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.

2 Article CRM1 and BRAF inhibition synergize and induce tumor regression in BRAF-mutant melanoma. 2013

Salas Fragomeni, Roberto A / Chung, Hye Won / Landesman, Yosef / Senapedis, William / Saint-Martin, Jean-Richard / Tsao, Hensin / Flaherty, Keith T / Shacham, Sharon / Kauffman, Michael / Cusack, James C. ·Harvard Medical School, Boston, MA, USA. ·Mol Cancer Ther · Pubmed #23615632.

ABSTRACT: Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival, and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor antitumoral effects. To test our hypothesis, selective inhibitors of nuclear export (SINE) analogs KPT-185, KPT-251, KPT-276, and KPT-330 were used to induce CRM1 inhibition. Analogs PLX-4720 and PLX-4032 were used as BRAF inhibitors. Compounds were tested in xenograft and in vitro melanoma models. In vitro, we found CRM1 inhibition decreases melanoma cell proliferation independent of BRAF mutation status and synergistically enhances the effects of BRAF inhibition on BRAF-mutant melanoma by promoting cell-cycle arrest and apoptosis. In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition. Mechanistic studies show that CRM1 inhibition was associated with p53 stabilization and retinoblastoma protein (pRb) and survivin modulation. Furthermore, we found that BRAF inhibition abrogates extracellular signal-regulated kinase phosphorylation associated with CRM1 inhibition, which may contribute to the synergy of the combination. In conclusion, CRM1 inhibition impairs melanoma survival in both BRAF-mutant and wild-type melanoma. The combination of CRM1 and BRAF inhibition synergizes and induces melanoma regression in BRAF-mutant melanoma.