Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Tumor gene expression analysis - PI3K Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma

ABSTRACT: Of the 142 patients enrolled in Study CHRONOS-1, an open-label, single-arm, Phase II study evaluating the efficacy and safety of single-agent copanlisib in patients with relapsed or refractory, indolent B-cell lymphoma (NCT01660451; Part B), 96 archival formalin-fixed paraffin-embedded tumor tissues were collected under relevant consent and available for tumor macro-dissection, mRNA extraction and gene expression profiling using Affymetrix GeneChip Gene ST 1.0 Arrays (AltheaDx, Inc., San Diego, CA, USA). Of these, only 78 samples were with high quality and passed Affymetrix positive versus negative controls AUC ≥ 0.62. Affymetrix CEL files were processed with RMA (R package affy) using a custom CDF from Brainarray (version 20.0.0). 71 patients with indolent non-Hodgkin lymphoma (iNHL), including 54 with follicular lymphoma (FL), had both response data and evaluable gene expression data with high quality array data sets (array positive versus negative controls AUC ≥ 0.62) and were included in this biomarker analysis. In this study, with the exception of subject # 16349B-53, for which expression values were averaged from three equal aliquots that were amplified and scanned on 3 separate days in order to control for day-to-day batch effect, there was only one sample per subject. Affymetrix raw data (CEL files) and the gene expression matrix generated with RMA for the 78 high quality tumor samples are submitted.

ORGANISM(S): Homo sapiens

SUBMITTER: Henrik Seidel

PROVIDER: E-MTAB-6088 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma.

Dreyling Martin M Santoro Armando A Mollica Luigina L Leppä Sirpa S Follows George A GA Lenz Georg G Kim Won Seog WS Nagler Arnon A Panayiotidis Panayiotis P Demeter Judit J Özcan Muhit M Kosinova Marina M Bouabdallah Krimo K Morschhauser Franck F Stevens Don A DA Trevarthen David D Giurescu Marius M Cupit Lisa L Liu Li L Köchert Karl K Seidel Henrik H Peña Carol C Yin Shuxin S Hiemeyer Florian F Garcia-Vargas Jose J Childs Barrett H BH Zinzani Pier Luigi PL

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20171004 35

Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg in ...[more]

PMID: 28976790

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Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer. Gene expression data from 58 stage III-IV ovarian cancer patients treated with Carboplatin and Taxol agents

Project description:This study was performed to evaluated RNA extraction and gene expression analysis of FFPE specimen stored for more than 20 years. Using long time stored FFPE material; large retrospective studies correlating molecular features with therapeutic response and clinical outcome, can be performed. Quantitative PCR (qPCR) was used to evaluate RNA extraction methods and to compare gene expression profiles of FFPE and fresh frozen (FF) tissue. Extracted RNA was subsequently subjected to microarray analysis and compared to qPCR data. The Ambion RecoverAll kit appears to be particularly suited for RNA extraction of long time stored FFPE tissues. Gene expression analysis using Affymetrix platform displayed a high degree of correlation for endogenous control genes comparing FF and FFPE tissues. We conclude that high quality gene expression signatures can be recognized using Affymetrix gene expression platform on FFPE tissue stored for more than 20 years. However, a general interpretation must be done with caution as different FFPE procedures have varying effects on RNA quality. Three RNA extraction methods from Roche (Basel, Switzerland), Ambion (Austin, TX, USA) and Qiagen (Hilden, Germany), designed for FFPE material was used. The methods were compared using qPCR. For the qPCR analysis, two different concentrations of input cDNA were used (20ng and 100ng) and 32 human endogenous control genes were examined. RNA from the Ambion FFPE kit was further analyzed by using microarray. Amplification of RNA prior to microarray analysis was performed using Nugen technologies (San Carlos, CA, USA). Nugen has developed amplification kits both for FFPE and FF materials: WT- ovation FFPE RNA amplification System V2 (Nugen FFPE), Ovation FF RNA Amplification System V2 (Nugen V2 FF) and Ovation FF Pico RNA Amplification System (Nugen PICO FF). The Nugen FFPE kit, designed for FFPE material was only used for FFPE tissue. The Nugen Pico FF kit, designed to target small amounts of FF RNA (>500 pg) and the Nugen V2 FF kit designed to target total FF RNA, were only used for FF tissue. Affymetrix standard amplification protocol (Affy FF) designed for FF RNA was also included as the standard method for amplification.

Dataset Information

Tumor gene expression analysis - PI3K Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma

Publications

Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma.

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