Abstract C12: Identification of biomarkers and pathways associated with response to the DOT1L inhibitor Pinometostat (EPZ-5676) in MLL-r leukemia
| العنوان: | Abstract C12: Identification of biomarkers and pathways associated with response to the DOT1L inhibitor Pinometostat (EPZ-5676) in MLL-r leukemia |
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| المؤلفون: | Brad Patay, Andrew Carson, Ty M. Thomson, Christine Klaus, Jeff Keats, Alejandra Raimondi, Stephen J. Blakemore, David A. Drubin, Guillermo Garcia-Manero, Alice McDonald, Scott R. Daigle, David A. Rizzieri, Jesus G. Berdeja, Blythe Thomson, Raoul Tibes, Michael J. Maria, Eytan M. Stein |
| المصدر: | Molecular Cancer Therapeutics. 14:C12-C12 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Genetics, Cancer Research, Messenger RNA, Cell growth, Cancer, RNA, Biology, medicine.disease, Peripheral blood mononuclear cell, Molecular biology, In vitro, Leukemia, chemistry.chemical_compound, Oncology, chemistry, medicine, DNA |
| الوصف: | Pinometostat is a highly selective first in class DOT1L inhibitor currently in Phase 1 clinical trials in adult and pediatric leukemia patients (pts) with MLL rearrangements (MLL-r or MLL-PTD). Preliminary results of the adult trial have demonstrated clinical activity including complete remissions in a subset of patients (Stein, 2014). Investigation and identification of candidate molecular correlates of pinometostat response in both pt samples and cell lines are reported. RNA and DNA were isolated from PBMCs and/or bone marrow collected prior to treatment from 18 pts enrolled in the adult pinometostat Phase 1 study (CT.gov: NCT01684150), at the following doses 24 (n = 2), 36 (n = 3), 54 (n = 6), 80 (n = 3) and 90 mg/m2/day doses (n = 4). mRNA transcript abundance was assessed using whole genome RNASeq and DNA variants were determined using a 194 gene panel, MyAML (Genection Inc.). Correlations of transcript abundance and DNA variants detected with categorical (responder = CR or PR [n = 3], or no response [n = 16]) and continuous response parameters (time on study [TOS], mean = 59 days: range = 8-196 days) were performed. For cell lines, whole genome RNASeq data was generated from 14 cell lines (MLL-r or MLL-PTD) with a range of in vitro sensitivity to pinometostat (cell proliferation IC50 2 nM to > 10 μM) and RNA transcripts identified as correlated with IC50 were submitted for pathway analysis. Univariate analyses revealed no DNA variants to be associated with either response category (FDR adjusted P < 0.05), however, a statistical association (unadjusted P = 0.05) was identified between increased TOS and those pts harboring t(11:19). Indicating that specific MLL fusion partners may elicit differential sensitivity to pinometostat therapy (2/2 CR pts had t(11:19)). Analysis of the baseline PBMC RNASeq data revealed 201 genes as significantly correlated with TOS (FDR adjusted P MLL-r fusion partner (e.g. t(11:19)) may influence clinical response to pinometostat. In addition RNASeq based characterization of patient samples and cell lines revealed candidate pathways that may cooperate with or antagonize pinometostat activity that warrant further investigation. Citation Format: Scott Daigle, Alice McDonald, Ty M. Thomson, David A. Drubin, Michael Maria, A. Carson, Brad Patay, Jeff Keats, Christine Klaus, Alejandra Raimondi, G. Garcia-Manero, D. A. Rizzieri, Raoul Tibes, Jesus Berdeja, Eytan M. Stein, Blythe Thomson, Stephen J. Blakemore. Identification of biomarkers and pathways associated with response to the DOT1L inhibitor Pinometostat (EPZ-5676) in MLL-r leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C12. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::21f67bbb3a78ed9afaeb069fed211a31 https://doi.org/10.1158/1535-7163.targ-15-c12 |
| رقم الأكسشن: | edsair.doi...........21f67bbb3a78ed9afaeb069fed211a31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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