This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Developing quantitative slide-based assays to assess target inhibition in oncology drug
discovery and development
Pathology VisionsOctober 24-27, 2010
Doug BowmanMillennium Pharmaceuticals
Outline
▐ Imaging @ Millennium▐ Technology development & integration▐ Applications in Oncology
▌ Assess in vivo potency▌ Biomarker development▌ Assess clinical activity
Target ID Validation
Assay Dev. HTS Lead
Optimization IIIPhase I II
Preclinical Development
INDDCApproval
Mechanism of Action / Pathway Inhibition / Terminal Outcome
Preclinical PD assays and Clinical Biomarkers
Cell-based imaging assays
Tissue-based imaging enables direct and indirect biomarkers of target inhibition
Adopt to variety of tissue and biopsy types
• 15 drug candidates in the following areas: protein homeostasis, angiogenesis, growth signaling inhibition, hormone regulation, cell cycle inhibition and apoptosis
• All stages of development
Hit to Lead
•Drive medicinal chemistry•Assess pharmacodynamic response in preclinical in vivo models•Assess pharmacodynamic response in variety of clinical tissues, in use in Phase 1 clinical trials
* * *
Tissue-Based Imaging @ Millennium
▐ Sample accession to LIMs system▐ Slide preparation
▐ Challenges▌ Multiple platforms for acquisition▌ Integration of image data with Aperio Spectrum▌ Integration with specimen LIMS system▌ Barcode issues ▌ Integration with existing analysis tools, (Aperio, Definiens,
Metamorph)
LIMS Database
MetaMorph
Integration with biorepository database
▐ Problem: Associate specimen metadata with images▐ Requirements:
▌ Utilize Aperio’s Integration Server (support for upgrades)▌ Barcode must be compatible with both Ventana and Aperio
instruments▌ Flexibility for future database changes
12
LIMS / Spectrum integration
SMSSBATLIMS
HistoPathology Corporate Sample Management System
SPECTRUM
DigitalPathology
Sample Accessioning
Cancer Pharmacology Molecular and Cellular Oncology
DSE Clinical
ProjectSpecimenSlide
Barcode scan:Event Trigger
XMLFiles
• Acquire slide/scan barcode• Trigger ‘new record’ event• Retrieve metadata from SMS• Generate XML file• Import metadata to Spectrum
Challenges (multi-month project)
• MPI – Event trigger, read SMS, create XML file
• Aperio – XML import
• Ventana / Aperio: barcode compatibility issues
3rd Party Access to Spectrum Images
▐ Problem: Currently there is no easy method to retrieve images from Spectrum to run analysis with third party analysis software (MetaMorph, Definiens)
▐ Requirements▌ Web-based tool▌ Access to Spectrum information (project, slide ID, or
ImageID)▌ Select networked destination for images and annotation
layers (XML)
14
15
Annotation Information
Copy of ROI info and .svs files
Aperio Image Exporter
• Web-based Pipeline Pilot tool• User selectable by project, slide
ID, or image ID• Define destination directory
• Pipeline Pilot protocol finds image location and constructs XML, then copies files to destination directory
• Images and annotation available for image analysis
Application examples
▐ Direct and indirect pathway biomarkers
▐ Preclinical biomarkers▐ Clinical biomarkers
▐ Preclinical biomarker▌ Lead optimization efforts to measure
potency of compounds▌ Hit target, affect pathway▌ Guide clinical: understand temporal
response of biomarker for optimal sampling point and to help define clinical sampling
▐ Two P1 trials in patients with advanced solid tumors▌ C14001 in US; C14002 in Spain
▐ Secondary Objectives▌ Evaluate MLN8237 PD effect on Aurora A inhibition in skin / tumor biopsies
PT 703, a case study to highlight pharmacodynamic assays used
▐ 33 year old woman with neural sheath sarcoma▐ 150 mg QD dose group (Spain)▐ Completed 4 cycles of treatment ▐ Usable tissue and high dose make this a good case study