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Download BIOMARKERS!!! - Hollings Cancer Center
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Expanding Cancer and Therapeutic Biomarker Research Opportunities at MUSC Richard R. Drake, Ph.D. Professor and Director, MUSC Proteomics Center SmartState Endowed Chair in Proteomics Benign PCa stroma 100 0 Biomarker Research – The Past 7 Years Translational Human Biomarker Discovery Using Mass Spectrometry-based Proteomic and Glycomic Methods Cancers Studied: Prostate* Kidney* Breast** Colon* Head and Neck Specimens Tissue Esophageal** Serum Liver** Urine Bladder EPS *Current Funding and **Previous EDRN funding Prostate Cancer Challenges Normal HGPIN Epithelium Localized PCa Indolent VS Aggressive Over Under Risk stratification Metastatic PCa PSA Biochemical recurrence ??? Prognosis Hormone Refractory PCa Inefficient monitoring of therapy control Limited therapeutics Prediction New therapeutic targets BIOMARKERS!!! FDA-Approved Cancer Biomarkers Biomarker α-Fetoprotein α-Fetoprotein-L3 DCP Human chorionic gonadotropin-β CA19-9 CA125 Pap smear CEA EGF receptor Type Glycoprotein Glycoprotein Protein Source Serum Serum Serum Cancer Type Liver Liver Liver Clinical Use Monitoring Risk Risk Glycoprotein Carbohydrate Glycoprotein Cervical smear Glycoprotein Glycoprotein Serum Serum Serum Cervix Serum Colon KIT Thyroglobulin PSA CA15-3 CA27-29 Cytokeratins Estrogen & progesterone receptors Protein (IHC) Glycoprotein Glycoprotein Glycoprotein Glycoprotein Protein (IHC) GI tumor Serum Serum Serum Serum Breast tumor Testicular Pancreatic Ovarian Cervical Colon Colon GI stromal tumors Thyroid Prostate Breast Breast Breast Staging Monitoring Monitoring Screening Monitoring Selection of therapy Diagnosis & selection of therapy Monitoring Monitoring Monitoring Monitoring Prognosis Protein (IHC) Breast tumor Breast HER2/NEU HER2/NEU Glycoprotein (IHC)Breast tumor Glycoprotein Serum Breast Breast HER2/NEU Chromosomes 3, 7, 9, and 17 DNA (FISH) Breast tumor Breast DNA (FISH) Urine Bladder NMP22 Fibrin/FDP BTA CEA and mucin Protein Protein Protein Glycoprotein Urine Urine Urine Urine Bladder Bladder Bladder Bladder Selection of therapy Prognosis & selection of therapy Monitoring Prognosis & selection of therapy Screening & monitoring Screening & monitoring Monitoring Monitoring Monitoring HCC Supported Shared Resources Lipidomics Flow Cytometry & Cell Sorting Cell & Molecular Imaging Biostatistics Clinical Trials Tissue Biorepository Small Animal Imaging Cellular Therapy Gene Knockout Drug Discovery/Screening Translational Research Lab Drug Metabolism/Clinical Pharmacology HCC’s Research Programs (Membership = 150) BIOMARKERS BIOMARKERS Proteomics and Glycomics BIOMARKERS Integrated Biomarker Discovery Approach Tissue Proteomics: MALDI MS Imaging Prostatic Secretions: EPS Urine/Direct EPS Metabolic Labeling: Cell Lines & Click Chemistry Capture Bruker Solarix 7T Dual Source FT-MS Bruker Instrument Demo In Bremen - August Delivery and Installation at MUSC First week of December 2011 * 1000 500 400 300 200 100 843.50 843.55 843.60 843.65 843.70 843.75 8 CASI Continuous Accumulation of Selected Ions CASI Example – Olanzapine Imaging in Kidney The Cancer Tissue Proteome Anderson and Quaranta, Nature Reviews Cancer 8, 227-234 (2008) Tissue Preparation and Analysis Workflow for MALDI-MSI Slice frozen embedded tissue on cryostat at 10 μm Adjacent section H & E stained Serial sections acquired conductive slide for MALDI-MSI ImagePrep Pathologist defines areas of interest Spray with matrix Compare molecular image to stained serial section Acquire mass spectra Intens. [a.u.] UltraFlex III TOF/TOF w/ Smartbeam x104 TestWCXreflectronQC\0_C4\1\1SRef 2.0 1.5 1.0 0.5 0.0 Molecular profile 500 1000 1500 2000 2500 3000 3500 m/z Molecular image MALDI-IMS Utilizing m/z 4355 can Identify PCa Specific Regions of Prostate Histology MALDI imaging of m/z 4355 2mm Benign Benign PCa PCa stroma 100 stroma 0 Relative Intensity m/z 4355 Tumor Benign 4000 6000 8000 10000 12000 Mass to charge (m/z) 14000 16000 18000 Cazares, L.H., Troyer, D.A., et al. (2009)Clin. Cancer Res., 15, 5541-5551. Biomarker Performance Across Validation Set A. 80 n = 23 B. 1.0 0.9 0.8 0.7 Sensitivity Averaged Normalized Intensity m/z 4355 60 40 n = 31** n = 14* 0.6 0.5 0.4 0.3 0.2 0.1 20 0.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1-Specificity 0 PCa benign benign adjacent distal Currently being assessed in TMA’s Cell Line Based Metabolic Labeling with Azide-Modified Sugar Tags AC4ManNAz – Sialic Acid Labeling Biotin-alkyne N3 N3 SAv beads Cu2+ N3 1 2 3 4 5 6 10 9 8 7 Expression of CDCP1 in prostate patient tissues B CDCP1+PI CDCP1 CDCP1+PI b c d e f Tumor Normal a Currently being assessed in TMA’s CA19-9 Boronolectins to Sialyl Lewis Carbohydrate Antigens + Magnetic Bead Carbohydrate Antigen Affinity Capture System Glycoprotein Biomarker Identification Non Cancer - + Blnk NonAggressive Aggressive PCa + + SLeX-Boronolectin-biotin 976249- ? PAP? ? 3828- PSA Streptavidin Cell Lines, Clinical Tissues and Fluids Glycoprotein Biomarkers Human Subjects and Animal Models Imaging Biomarkers HCC Supported Shared Resources Lipidomics Flow Cytometry & Cell Sorting Cell & Molecular Imaging Biostatistics Clinical Trials Tissue Biorepository Small Animal Imaging Cellular Therapy Gene Knockout Drug Discovery/Screening Translational Research Lab Drug Metabolism/Clinical Pharmacology *Proteomics and Glycomics Conclusions and Challenges The core resources are present at the HCC; coordination of these resources to develop therapeutic biomarkers is needed Challenge: establishing an IT infrastructure to coordinate the data analysis and linkage of sample information to individual patients Opportunity: coordinating with the cancer genetics emphasis and new hires
