introducing dktk: rationale and strategic …...precision medicine program 22 •molecularly aided...
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INTRODUCING DKTK: RATIONALE AND STRATEGIC GOALS
… of the German Centers for Health Research (including DKTK) since 2009:
Defeating common diseases more efficiently by:
• transferring knowledge from basic research into innovative diagnostics and therapeutics
• forming new alliances between research centers and university medical centers
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INTRODUCING DKTK: MISSION
• Discover, develop, validate, and apply novel strategies for personalized oncology and translate them into clinical practice
• Provide advanced training opportunities for the next generation translational and clinical scientists
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DKTK STRATEGY
Focus on five major challenges in cancer research:
Molecular profiling-based diagnosis and therapy
Tumor heterogeneity and resistance
Immunotherapy beyond checkpoint inhibition
Early diagnosis of cancer and detection of minimal residual disease
Turning big data into smart data
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DKTK PARTNER SITES
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GOVERNANCE – STEERING COMMITTEE
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STRUCTURAL ACHIEVEMENTS: SUMMARY 2012-2016
• Legal framework (statute, implementation agreements) completed
• Governance structure successfully established
• Joint Translation centers at DKTK partner sites built up
• Efficient administrative and coordinative structures implemented
• DKTK Professorships and Young Investigator Groups recruited
• „Joint Funding Program“ up
and running
• DKTK Community building
accomplished
• School of Oncology
• Cooperations with German
Centers for Health Research
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NEW DKTK PROFESSORS
Jürgen Becker, E/D Skin Cancer Research
Helmut Salih, TÜ Tumor Immunology
Mechtild Krause, DD Radiation Oncology
Benedikt Brors, HD Bioinformatics
Björn Scheffler, E/D Neurooncology
Jens Siveke, E/D Thoracic/Visceral
Oncology
Holger Sültmann, HD Cancer Genome
Research
Gerald Willimsky, B Tumor Immunology
Roland Rad, M Gastroenterological
Oncology
Sven Diederichs, FR Thoracic Oncology
Partner sites: Berlin (B), Dresden (DD), Essen/Düsseldorf (E/D), Freiburg (FR), Heidelberg (HD), München (M), Tübingen (TÜ)
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COMMUNITY BUILDING
Communication tools:
• Newsletter, Brochure
• Website, Intranet
• Video-conferencing and streaming
• Seminars
• Retreats
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SCHOOL OF ONCOLOGY
Goals
• Fill the gaps in education of physician
scientists & postdocs
• Continued education & professional
mentoring
• Translational research curricula for natural
scientists & physicians
• Become a national & international leader in
translational cancer research education
130 fellows
Actions
• Regular summer schools, conferences, workshops
• Program for physician scientists: protected research time
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MAJOR ACHIEVEMENTS OF DKTK – IMPORTANT RESEARCH INFRASTRUCTURES
• Key elements of Clinical Communication Platform (CCP)
• Illumina X-Ten Sequencing Platform
• RadPlanBio-Platform Particle Therapy Research Network
• Expansion of GMP
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KEY OBJECTIVES OF THE CLINICAL COMMUNICATION PLATFORM (CCP)
• Create hypotheses • … • Perform clinical trials • Develop Biomarkers
TRANSLATION REVERSE TRANSLATION
• Systematically note clinical response
• Reprofile samples
• …
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CCP – DATA INTEGRATION AT EACH SITE
Pseudonymization Algorithms
Clinical Scientists
Basic Scientists
Web-Based Search Algorithms Implementation of Data Access Rules
Safe Data Transfer Protocols
Bridgehead
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CCP – CENTRAL REGISTRY AND SEARCH
Tool for patient and sample
announcement:
What do we have?
• All DKTK Researchers
• Unrestricted access
• Data Sets allow for quite sophisticated search
• Response contains number only (n=X)
• Data sets do not allow for analyses and publication
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CCP – DECENTRAL SEARCH
• Feasability analyses
• Clinical analyses
• Reverse translational scientific projects
• Precision medicine
• Recruitment tools for clinical trials
• Detailed and retrospective data sets
Federated search and data/material retrieval tool
?
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OVERVIEW OF SCIENTIFIC PROGRAMS 2012-2015
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Structured programs to optimize translation efficiency:
Differently weighted focus to bridge the translational valley of death
FUTURE PROGRAMS 2016 - 2020: FOCUS ON DEVELOP AND VALIDATE
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FOCUS ON 5 MAJOR CHALLENGES
1: Molecular profiling-based diagnosis & therapy
2: Tumor heterogeneity and resistance
3: Immunotherapy beyond checkpoint inhibition
4: Early diagnosis of cancer and detection of minimal residual disease
5: Turning big data into smart data
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Aims 2016 – 2020: • Extension to PANOMICS • Extension to larger entities: GI, Lung, Breast, Head & Neck • Broadening spectrum of druggable lesions
Unique Strength: Sequencing platform Illumina Hiseq X Ten
Highlights: • INFORM (pediatric cancer) • MASTER (advanced cancer) • N2M2 (glioma) • Integrative lymphomics • HNPrädBio (radiation oncology)
FUTURE STRATEGY – 1: MOLECULAR PROFILING-BASED DIAGNOSIS AND THERAPY
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INFORM = BLUEPRINT FOR PERSONALIZED MEDICINE TRIALS
Individualized Therapy For Relapsed Malignancies in Childhood
Peter Lichter Stefan Pfister Angelika Eggert Olaf Witt
National Patient Recruitment
11 Trial Coordination Centers
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INFORM WORKFLOW
Quality Control & Nucleic Acid
Extraction
RNA Seq
Exome Seq
Low-cov. WGS
450k methylation
Gene expression
Treating Centers (n=58)
Trial Coordination Centers (n=11)
Request
Advice: INFORM
Biomaterial (FF + FFPE) +
Normal Tissue
Validation of Mutations (up to 5 targets)
Data
Data
Central Pathology Lab, DKFZ
DKFZ Sequencing Core Facility
Central Pathology Lab, DKFZ
INFORM – Registry: Documentation
Molecular Tumor Board
Target Prioritization + Potential Drugs
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INFORM2 GOES INTERNATIONAL
INFORM2 as complementary part of a European
precision medicine program
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• Molecularly Aided Stratification for Tumor Eradication Research
• Molecular and bioinformatic analysis completed, 401 patients
• Clinical evaluation through dedicated Precision Oncology Tumor Board, 375 patients
• Integration of DKTK partner sites and internationalization ongoing
MASTER – CENTRAL DIAGNOSTICS USING THE GENOME AND PROTEOME PLATFORM
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CANCER IMMUNOTHERAPY – CHALLENGES
Chen DS & Mellman I., Immunity 2013
Advanced Tumor Vaccines
New Therapeutic Antibodies
Advanced Cellular Therapeutics
Combinatorial Immunomodulation
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CANCER IMMUNOTHERAPY – HIGHLIGHT ACHIEVEMENTS
Neoantigen roulette.
From: Gubin and Schreiber; Science 2015
Ipilimumab-response mutation
Nonresponders Cancer patients with fewer mutations have a lower chance of responding to therapy
Responders Cancer patients with more mutations have a higher chance of responding to therapy
Immune checkpoint inhibition:
• demonstrated that response to ipilimumab depends on mutation number in metastatic melanoma
Van Allen et al., and Schadendorf; Science 2015
• demonstrated that clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
McGranahan ... Schadendorf et al.; Science 2016
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CANCER IMMUNOTHERAPY – HIGHLIGHT ACHIEVEMENTS
Therapeutic peptide and RNA vaccination:
• Prostate: HLA ligandomics-defined multi-peptide cocktail (MultiPro; Joint Funding)
• Breast: 5-peptide Her2neu cocktail
• IDH1 glioma “trunk” mutation* in low grade gliomas (NOA-16 peptide vaccination study)
• Individualized peptide cocktail for GBM (GAPVAC EU-funded study)
• New appraoches for RNA-based vaccines
• GMP manufacturing in Tübingen
* Schumacher et al., and Platten; Nature 2014
Immune checkpoint inhibition (response prediction**) ** van Allen et al. and Schadendorf et al.; Science 2015
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Radiation Oncology
• High-precision technologies, including particle therapy
• Biology-driven individualization of treatment
• Furthering the RadPlanBio IT-platform
Imaging
• Multiparametric imaging
• Novel imaging biomarkers, including theranostics
• IT strategies / platforms for “Big Imaging Data”
RADIATION ONCOLOGY AND IMAGING – AIMS AND TOPICS
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RADIATION ONCOLOGY (INCL. JOINT FUNDING PROGRAM)
• DKTK Radiation Oncology Group
(DKTK-ROG, all partner sites)
• Unique expertise in particle therapies
• RadPlanBio IT-platform
• Retrospective and prospective trials
(381 pts retrosp., 260 pts prospective)
• Biomarkers for outcome of radio-
chemotherapy in HNSCC
• Interventional trials ongoing
Berlin
Dresden
München
Tübingen Freiburg
Frankfurt
Essen
Heidelberg
Lohaus et al., Radiother Oncol, 2014
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Afshar-Oromieh A et al. Eur J Nucl Med Mol Imaging 2014, 41, 11-20.
68GA-PSMA-11
vs. 18F-CHOLINE
MOLECULAR IMAGING
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MOLECULARLY TARGETED THERAPY – PROGRAM AIMS
• Prepare preclinical data packages using clinically relevant cancer models
• Reverse translation of clinical findings from molecularly annotated patients
• Clinical proof-of-concept
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MOLECULARLY TARGETED THERAPY – FUTURE PROJECT: TARGETING DRUG RESISTANCE IN PDAC
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MOLECULARLY TARGETED THERAPY – TARGETING DRUG RESISTANCE IN PDAC
1. Validation of three PDAC subtypes in patient cohorts +/- therapy
• Retrospective validation cohorts (clinical outcome, therapy response) • Generation of a prospective patient cohort (resectable, neoadjuvant, palliative) to validate
therapy response
2. Targeting of 1o and 2o resistance to first line PDAC therapy • Identify, validate and target acquired resistance mechanisms for all three subtypes against
first line therapies using multi-omics approaches epigenomics and plasticity • Generate preclinical data packages for phase I trials: efficacy studies with the goal to
overcome resistance using GEMMs & PDX models
3. Epigenetic Targeting: development and characterization of dual BET/HDAC inhibitors
• Characterize HDAC subclasses and BET proteins as context-specific targets in PDAC • Develop, characterize & optimize dual BET/HDAC inhibitors (potency, selectivity,
pharmacokineetics, toxicity studies) • Preclinical validation in relevant PDAC models
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Scientific and Strategic Aims
• Discovery of novel diagnostic, prognostic & predictive molecular markers
• Translation into robust biomarkers
• Development / Validation of new techniques for molecular diagnostics
• Development of approaches for early detection & secondary prevention
Improvement of the clinical management of cancer patients
Key Strengths
• Build on a wealth of molecular data generated within DKTK
• Well established collaborative network infrastructure of the previous Programs Molecular Diagnostics, Cancer Prevention & all DKTK partners
MOLECULAR DIAGNOSTICS, EARLY DETECTION AND BIOMARKER DEVELOPMENT
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MOLECULAR DIAGNOSTICS, EARLY DETECTION AND BIOMARKER DEVELOPMENT – ACHIEVEMENTS
• Refinement of tumor classification schemes
• Discovery of novel entity-specific molecular signatures and pathways leading to redefinition of tumor entities
• Program in secondary cancer prevention of colorectal ca. and transfer into public health and clinical practice
• High-end Next-Generation-Sequencing platform (DKTK Illumina HiSeq X-Ten)
• Triggering clinical trials: INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood)
There are 9 subgroups of ependymoma
Some of these subgroups show no recurrent mutations but
response to epigenetic drugs
Pajtler et al., Cancer Cell 2015 Mack et al., Nature 2014
Sturm et al., Cell 2016
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Detection of four novel brain tumor entities
…………………………………………………………………………………………………………………………………………………………………………
Cell. 2016;164(5):1060-72
MOLECULAR DIAGNOSTICS, EARLY DETECTION AND BIOMARKER DEVELOPMENT – ACHIEVEMENTS
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FUTURE DKTK PERSONALIZED MEDICINE CYCLE
Network Analysis/ Key Targets/Stratification
Clinical Trial
Monitoring: Response
Biomarkers Imaging
Tumor Biology PanOMICS Clinical Data
CCP
Validate
in silico in vitro in vivo