Tumor plasticity in the translational space

Pierre Saintigny

Centre Léon Bérard

Centre de Recherche en Cancérologie de Lyon

Université de Lyon

Forum de la Recherche en CancérologieVendredi 5 Avril 2019

LYon Recherche Innovation

contre le CANcer

INCa-DGOS-Inserm_12563

LYriCAN : OBJECTIVES AND AMBITION

Address a next set of questions in molecular medicine

Pursue our strategy of identification of novel nosological entities

Describe the multidimensional complexity of cancer

Develop first-in-human, combination Phase 1 studies, randomized Phase II trials, basket & umbrella studies, and Phase III trials within national/international networks

Develop innovative physical and mathematical methods to analyze and treattumor plasticity at the macroscopic level

Integrate Social Sciences and Humanities

Develop innovative training programs

Build multidisciplinary partnerships to promote intellectual property protection, spin off creation and transfer of innovation to patient care

Characterize and treat cancer and immune cell plasticity through coordinated approaches

Development of paradigm changing for local and systemic cancer therapies

Innovative diagnostic tools

FROM LYric TO LYriCAN

Cancer cellsand immune

targets

Combining treatments to

prevent resistance

Physical Agents

Overcomingcell

plasticity

Tumorcell

Macro-scopictumor

Immunotherapy

New targetsand

treatments

Personalised medicinebased on genomic

context

DevWeCan, PlasCan

TumAdoR, Hermione2Man

Personalized medicine based on genomic context and

tumoral heterogeneity

AURAGEN, EURACAN, SSH Chair

ProfiLERMOST

BASIC RESEARCH

LYriCAN AND PARTNERS

GCS-LCU

New Partner

PARTNERS

• SCIENTIFIC DIRECTION

Jean-Yves BLAY• COORDINATION

Marina Rousseau-Tsangaris

STRONG BASIC RESEARCH

MULTIDISCIPLINARITY

RESEARCH ENTITIES

CRCL - LABTAU

CREATIS

UNIVERSITY HOSPITALS

HUMAN AND SOCIAL SCIENCES

TRIANGLE

BIOINFORMATICS

APPLIED MATHEMATICS

ALGORITHMS

DIGITAL HEALTH

EPIDEMIOLOGY

PREVENTION

COHORTS

CLINICAL RESEARCH

TRAINING

EDUCATION

MASTERS

TECHNOLOGICAL PLATFORMS

MANIPULATING CELL PLASTICITY FOR INNOVATIVE CANCER TREATMENT

BASIC RESEARCH

CLINICAL RESEARCH

Mechanism

IdentifyDrug/Tool

Tumor characterization

Patients stratification

Innovativeclinical trials

IRP1

IRP3IRP2PLASTICITY

1

2

34

5

TUMOR MODELS

OVERCOMINGCANCER CELL PLASTICITY

INTRA-TUMORAL HETEROGENEITY

Genetic alteration

Epigenetic modification

Micro-environment Cancer cellCancer Stem cell

PrimaryResistance

SecondaryResistance

Targeted therapyImmunotherapy

Conventional TherapyTreatment combination

Targeted therapyImmunotherapy

Conventional TherapyTreatment combination

Normal cell

Improve treatments – Response prediction

UNDERSTANDING CELL PLASTICITY TO IDENTIFY INNOVATIVE CANCER CELL AND IMMUNE TARGETSIRP1

COMBINING TREATMENTS TO PREVENT PRIMARY AND SECONDARY RESISTANCE THROUGH CANCER CELL PLASTICITY

IRP2

PHYSICAL AND MATHEMATICAL METHODS TO ANALYZE AND OVERCOME TUMOR PLASTICITY AT THE MACROSCOPIC LEVEL FOR PERSONALIZED TREATMENTSIRP3

Lung tumors MelanomaPancreatic tumors

Rare tumorsGIST Sarcoma Neuroendocrine tumors Ovarian tumors Head and Neck tumors

Breast tumorsLymphoma

Prevention - Prediction

Pediatric tumors

UNDERSTANDING CELL PLASTICITY TO IDENTIFY INNOVATIVE CANCER CELL AND IMMUNE TARGETS

INTEGRATED RESEARCH PROGRAM 1

Leaders : A Traverse-Glehen - C Caux – Young Faculty : N Bendriss-Vermare

v

Cancer and immune cell

plasticity

Genetic drivers and epigeneticreprogramming

EMT targeting

Axis 1

Axis 3 Axis 4

Axis 2

Cell plasticityand Immune

responses

Patient trajectories,

networks, accessto treatments

INTEGRATED RESEARCH PROGRAM 1UNDERSTANDING CELL PLASTICITY TO IDENTIFY INNOVATIVE CANCER CELL AND IMMUNE TARGETS

COMBINING TREATMENTS TO PREVENT PRIMARY AND SECONDARY RESISTANCE THROUGH CANCER CELL PLASTICITY

INTEGRATED RESEARCH PROGRAM 2

Leaders: P Saintigny - S Dalle – Young Faculty : A Dufresne

v

Resistance to targetedtherapy

Resistance to immune therapy

Innovative combination treatment

Hospitalorganization

Self reportingtools

Big data visualization

Axis 1

Axis 3

Axis 4

Axis 2

Cancer cell

plasticity

INTEGRATED RESEARCH PROGRAM 2COMBINING TREATMENTS

PHYSICAL AND MATHEMATICAL METHODS TO ANALYZE AND OVERCOME TUMOR PLASTICITY AT THE MACROSCOPIC LEVEL FOR PERSONALIZED TREATMENTS

INTEGRATED RESEARCH PROGRAM 3

Leaders: AL Giraudet - D Sarrut – Young Faculty : A Dupré

2. Imaging tumorplasticity

Tools:Conventional imaging and Radiomic (Axis 3)Immunoscintigraphy (Axis 2 and 3)Dosimetry (Axis 2)

Focal tumor destruction :• HIFU (Axis 1)• External beam Rx (Axis 1 and 2)• Radionuclide therapy (Axis 2)

1. Personalized local treatment

Systemic tumor destruction :• Vectorised Targeted

Radionuclide Therapy (Axis 2)

LYric: Development of physical agents

Use of Physical agents to analyze and overcome tumor plasticity at the macroscopic level:

a theranostic approach

INTEGRATED RESEARCH PROGRAM 3PHYSICAL AND MATHEMATICAL TOOLS TO OVERCOME TUMOR PLASTICITY AT THE MICROSCOPIC LEVEL

« SUPPORT » WORKPACKAGES

LYriCAN: PLATFORMS

INNOVATION AND DISCOVERY

BIOLOGICAL COLLECTIONS MOLECULAR CHARACTERIZATION

Small and medium animal

models

Experimentalsurgery

Imaging

C3D

Immunomonitoring

BiologicalRessources

Tissue characterization

NGS CGHMicroarrays

Ex Vivo

BIOINFORMATICSHigh throuput data analysis, database development, pipelines …

HOSPITAL INFORMATICS SERVICE DIRECTION (DSI)Electronic Patient Record (DPI)

NanostringDigital Spatial

Profiling

HTG

New technologies

Leaders: C Dumontet – S Lantuejou; Junior: S Tabone-Eglinger

CORE DATA MANAGEMENT

CORE DATA MANAGEMENT Good Clinical Practise

ProfilER expertise

EXISTING DATABASES

ProfiLER (LYric)Cleanomics (LYric)

MOST & MOST+Liquid biopsy (LIBIL NCT02511288)

Lynch synd, Breast cancer

LYriCAN PROJECTS

Sequencing (IPR1 &2)Flow Cytometry (IPR1,2)Clinical data (IPR1&2&3)Imaging (IPR3)

Dataspace repository

Basic scientistsClinicians

Computer scientistsBioinformaticians

Fill the gapCommunicateAdviseAssistance

Working group Local Researchers

Clinicians

DAT

AM

ININ

G

Sharing and InteroperabilityPrevious Inter-SIRIC working group OSIRIS - Proof of Concept

PUBLIC DATA REPOSITORIES

ICGC, TCGA, GENIE

EMT

SURROGATE MARKERS AND TARGET

Phenotypicscreening of

chemicallibraries

Externalizedproteins in EMT-

committed cancer cells

Ribosome modifications in EMT-committed

cancer cells

EMT-Transcription factors expression, pancancer EMT signature as a biomarkers of

EMT-driven cancer cell plasticity

Longitudinal dynamics of EMT-driven cancer cell plasticity in NSCLC

EMT, Immune checkpoints and immune

escape

Combine physical Tt & immunotherapy; imaging tumor

immune response

PLASCAN PREVENT CANCER PLASTICITY AND ADAPTABILITY:

TOWARDS DECODING THE CANCER CELL PLASTICITY

Institut François Rabelais pour la recherche multidisciplinaire sur le cancer

ERiCAN EPIGENETIC REPROGRAMMING OF CANCER CELL PLASTICITY

AND RESILIENCE – Setting the basis of the next generation of personalized medicine

TEAM MEMBERSNathalie Borel

IR or senior post-docsMarie Alexandra Albaret

Sandra Ortiz-Cuaran

Vincent Lavergne

Jean-Philippe Foy

Involved cliniciansVincent Grégoire

Jérôme Fayette

Philippe Zrounba

Maurice Pérol

Aurélie Swalduz

Chloé Bertolus

Ingénieurs d’étudeGeneviève De Souza

Solène Marteau

PhD studentsLucie Mallet

Camille Léonce

(Jebrane Bouaoud)

M2 studentsDelphine Avril

Nour El Houda Mourksi

Maud Guy

Dorsaffe Fekiri

COLLABORATORSLocal (CRCL)

Platform of Bioinformatics-Gilles Thomas

Equipe Caux

Equipe Puisieux

Equipe Diaz

Equipe Dumontet

Equipe Ichim

National

IHNPACTInvestigators

LIBIL et Acsé Vémurafenib investigators

C. Chomienne (St Louis, UMR 1131)

Yohann Couté (CEA Grenoble)

D. Planchard and B. Besse (Gustave Roussy)

J. Mazières (CHU Toulouse)

T. Dubois (Institut Curie)

F. Penault-Llorca (UMR 1240 IMoST)

International

SM Lippman (MCC, San Diego, USA)

M. Lingen (U. Chicago, USA)

M. Rosin (CCCA,Vancouver, Canada)

CM Lovly (U. Vanderbilt, USA)

R Thomas (Cologne, Germany)

Integrated analysis of the dynamics of cancer