title: Predicting Response to Histone Deacetylase Inhibitors Using High-Throughput Genomics.
abstract: BACKGROUND
  Many disparate biomarkers have been proposed as predictors of response to histone deacetylase inhibitors (HDI); however, all have failed when applied clinically. Rather than this being entirely an issue of reproducibility, response to the HDI vorinostat may be determined by the additive effect of multiple molecular factors, many of which have previously been demonstrated.
  
  
  METHODS
  We conducted a large-scale gene expression analysis using the Cancer Genome Project for discovery and generated another large independent cancer cell line dataset across different cancers for validation. We compared different approaches in terms of how accurately vorinostat response can be predicted on an independent out-of-batch set of samples and applied the polygenic marker prediction principles in a clinical trial.
  
  
  RESULTS
  Using machine learning, the small effects that aggregate, resulting in sensitivity or resistance, can be recovered from gene expression data in a large panel of cancer cell lines.This approach can predict vorinostat response accurately, whereas single gene or pathway markers cannot. Our analyses recapitulated and contextualized many previous findings and suggest an important role for processes such as chromatin remodeling, autophagy, and apoptosis. As a proof of concept, we also discovered a novel causative role for CHD4, a helicase involved in the histone deacetylase complex that is associated with poor clinical outcome. As a clinical validation, we demonstrated that a common dose-limiting toxicity of vorinostat, thrombocytopenia, can be predicted (r = 0.55, P = .004) several days before it is detected clinically.
  
  
  CONCLUSIONS
  Our work suggests a paradigm shift from single-gene/pathway evaluation to simultaneously evaluating multiple independent high-throughput gene expression datasets, which can be easily extended to other investigational compounds where similar issues are hampering clinical adoption.
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Paul
authors: P
authors: Geeleher
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Andrey
authors: A
authors: Loboda
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Divya
authors: D
authors: Lenkala
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Fan
authors: F
authors: Wang
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Bonnie
authors: B
authors: LaCroix
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Sanja
authors: S
authors: Karovic
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Jacqueline
authors: J
authors: Wang
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Michael
authors: M
authors: Nebozhyn
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Michael
authors: M
authors: Chisamore
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: James
authors: J
authors: Hardwick
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH).
authors: Michael L
authors: ML
authors: Maitland
authors: Department of Medicine (PG, DL, FW, BL, SK, JW, MLM, RSH), Committee on Clinical Pharmacology and Pharmacogenomics (MLM, RSH), and the Comprehensive Cancer Center (MLM, RSH), University of Chicago, Chicago, IL; Oncology Clinical Research, Merck Research Laboratories, North Wales, PA (AL, MN, MC, JH). rhuang@medicine.bsd.uchicago.edu.
authors: R Stephanie
authors: RS
authors: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001324:Autoantigens / Q000009:adverse effects*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000009:adverse effects*; D011237:Predictive Value of Tests; D013921:Thrombocytopenia / Q000139:chemically induced / Q000175:diagnosis*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; C115323:CHD4 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex