Multigene Expression–Based Predictors for Sensitivity to Vorinostat and Velcade in Non–Small Cell Lung Cancer

Abstract

The ability to predict the efficacy of molecularly targeted therapies for non-small cell lung cancer (NSCLC) for an individual patient remains problematic. The purpose of this study was to identify, using a refined "coexpression extrapolation (COXEN)" algorithm with a continuous spectrum of drug activity, tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat, a histone deacetylase inhibitor, and Velcade, a proteasome inhibitor. Using our refined COXEN algorithm, biomarker prediction models were discovered and trained for Vorinostat and Velcade based on the in vitro drug activity profiles of nine NSCLC cell lines (NCI-9). Independently, a panel of 40 NSCLC cell lines (UVA-40) were treated with Vorinostat or Velcade to obtain 50% growth inhibition values. Genome-wide expression profiles for both the NCI-9 and UVA-40 cell lines were determined using the Affymetrix HG-U133A platform. Modeling generated multigene expression signatures for Vorinostat (45-gene; P = 0.002) and Velcade (15-gene; P = 0.0002), with one overlapping gene (CFLAR). Examination of Vorinostat gene ontogeny revealed a predilection for cellular replication and death, whereas that of Velcade suggested involvement in cellular development and carcinogenesis. Multivariate regression modeling of the refined COXEN scores significantly predicted the activity of combination therapy in NSCLC cells (P = 0.007). Through the refinement of the COXEN algorithm, we provide an in silico method to generate biomarkers that predict tumor sensitivity to molecularly targeted therapies. Use of this refined COXEN method has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost. Mol Cancer Ther; 9(10); 2834-43. ©2010 AACR.

Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma

“…Cell-cell interactions and cancer-initiating cells further complicate the biology of MM [24]. A previous study, in accordance with our present results, examined gene ontogeny related to bortezomib and suggested involvement in cellular development and carcinogenesis [25]. …”

Drug Selection in the Genomic Age: Application of the Coexpression Extrapolation Principle for Drug Repositioning in Cancer Therapy

“…Shown in Figure 1 is a basic schematic of the COXEN approach with regard to the data utilized for the identification of differentially expressed genes, coexpression analysis, model building, model learning, and model testing and validation. The COXEN approach has been used to accurately predict the sensitivity and resistance of cancer cell lines 7 as well as patient outcomes of several histological types, including breast, [14][15][16] bladder, 15,17 ovarian, 18,19 and lung 20 with regard to predicted drug response. Methods have also been established using the COXEN approach for the prediction of drug combination chemosensitivity 21 that is critically important considering that patients are rarely treated with single drugs but are generally treated with drug combinations consisting of multiple agents with differing but presumably complimentary mechanisms of action.…”

“…While there is significant retrospective data showing the ability of COXEN-derived biomarkers to predict outcome in patients, 7,[14][15][16][17][18][19][20] specific predictions for selecting first-line therapy using the COXEN approach require prospective validation if it is to replace standard-of-care systemic therapy assignment principles. For locally advanced bladder cancer, a national clinical trial has been recently approved in Southwest Oncology Group (S1314: ''A Randomized Phase II Study of CO-eXpression ExtrapolatioN [COXEN] with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer'') that is prospectively evaluating the value of COXEN prediction for response to MVAC and GC in patients randomly selected for either regimen.…”

Novel neoadjuvant therapy paradigms for bladder cancer: Results from the National Cancer Center Institute Forum

“…In retrospective studies, multigene biomarker panels developed using COXEN have been shown to effectively stratify clinical response in patients with a variety of tumor types including breast [36], ovarian [37], lung [38] and head and neck [39] treated with chemotherapy and/or radiation. In the case of BC, GEMs panels developed using COXEN have been shown to predict clinical responses of patients treated with GC and M-VAC [34] in several clinical settings including neoadjuvant use.…”