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