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Stratifed medicine Interdisciplinarity Interdisciplinarity Immune microenvironment Immune microenvironment Cancer therapeutic strategies Cancer therapeutic strategies Opportunities Targeted therapies Targeted therapies Targeted therapies Modelling Signal transduction Social challenges Cancer genome Cancer New insights New insights Predictive Predictive Predictive Anti-cancer agents Anti-cancer agents International Forum (ProCaRT) (ProCaRT) nd on Prospective in Cancer on Prospective in Cancer October 9 October 9 - 10, 2012 - Institut Pasteur - Paris 10, 2012 - Institut Pasteur - Paris Research and Treatment Research and Treatment

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Stratifed medicine

InterdisciplinarityInterdisciplinarityImmune microenvironmentImmune microenvironment

Cancer therapeutic strategies

Cancer therapeutic strategies

Opportunities

Targeted therapiesTargeted therapies

Targeted therapiesM

odellingSignal

transduction

Social

challenges

Cancer

genome

Cancer

New insightsNew insightsPredictive

Predictive

Predictive

Anti-cancer agentsAnti-cancer agents

International Forum

(Pro

CaR

T)(P

roC

aRT)

nd

on Prospective in Canceron Prospective in Cancer

October 9October 9 - 10, 2012 - Institut Pasteur - Paris10, 2012 - Institut Pasteur - Paris

Research and TreatmentResearch and Treatment

SCIENTIFIC COMMITTEE

VENUEEE

2

Fabien Calvo Director of the Research and Innovation Division - French National Cancer Institute (INCa) Director of the Alliance Aviesan cancer

Tom Hudson President and Scientifi c Director of the Ontario Institute for Cancer Research

Guido Kroemer Director of Inserm U848, Villejuif, France, and Director of the Paris Alliance of Cancer Research Institutes (PACRI)

Patrick Mehlen Director of Inserm U1052 / CNRS URMS 5282, Research Cancer Center of Lyon, Léon Bérard Center

François Taddéi Director of the Doctoral school Frontiers of Life (FdV), Center for Research and Interdisciplinary

Institut Pasteur Auditorium CIS - 28 rue du Dr Roux 75015 Paris

3

R ecent years have seen the emergence of novel targeted cancer therapies

based on an increasing knowledge of the tumour cell and its interaction

with the surrounding tissues. This has resulted in the development of

small chemical compounds with the capacity to specifi cally target dysfunctional kinase activity but also in new types

of biological engineered components that mimic the function of antibodies against extra cellular targets that are vital

to tumour growth and survival. The understanding of the conditions in which tumour cell proliferate and its

implication on cellular metabolism and how tumour cells alter its micro environment has rekindled the interest in

tumour metabolic pathways and opened up new avenues for targeted treatments. There are also new emerging

concepts of stratifi ed medicine based on genomic profi les of tumour and the translation of this promising research

into novel precision medicine as well as the social and political challenges will be discussed.

There are many cancer meetings held every year where the progress and results of fundamental and clinical research

within these different fi elds are presented. However, the aim of this International forum is to give a comprehensive

overview of the current state of the art of a few selected fi elds of cancer research by some of the world leading experts

from academia and industry, followed by discussions on how ongoing research can translate into future therapies.

The forum will highlight how combined multidisciplinary efforts from basic and clinical academic research and from

the industry can stimulate new concepts of combinational approaches for the benefi t of the patients. In this second

edition of the International forum on Prospective in Cancer Research and Treatment, the INCa and Aviesan also wish

to address a multi-level observation that is needed to understand cancer and a dedicated session will discuss how

a coordinated interdisciplinary research can provide a multi-level approach simultaneously.

The conference is organised as an International Forum and the objective is to exchange experience and to discuss

around selected themes in a prospective worldwide vision towards cancer research for the benefi t of people

diagnosed with cancer in developed as well as in developing countries.

INTRODUCTIONProf Fabien CALVODirector of the Research and Innovation Division at INCaDirector of the Alliance Aviesan Cancer

PROGRAM

4

08.30 Registration and welcome coffee

09.00 - 09.10 Introduction Fabien Calvo Institut National du Cancer - Institut Cancer d’Aviesan

Session 1 Beyond cancer genomes Chair: Thomas Hudson

09.15 - 09.55 Lecture Thomas Hudson Genome variation affecting predisposition and response to therapy Ontario Institute for Cancer Research, Toronto, Canada

10.00 - 12.00 Barbara Prainsack The social challenges of genomics and personalised medicine Centre for Biomedicine & Society (CBAS), Brunel University, United Kingdom

Jean Yves Blay How molecular characterization is changing cancer clinical research? Centre de recherche en cancérologie de Lyon (CRCL) Centre Léon Bérard, Lyon, France

David Cox Precision Medicine and Cancer Genomics: An Industry Perspective Pfi zer Inc, South San Francisco, USA

12.00 - 13.00 Round table and discussion

13.00 - 14.00 Lunch

Session 2 From discovery of signalling pathways to the emergence of new cancer therapies Chair: Patrick Mehlen

14.15 - 14.55 Lecture Patrick Mehlen The dependence receptor notion: from a cell biology paradigm to alternative targeted therapies Centre de recherche en cancérologie de Lyon (CRCL) Centre Léon Bérard, Inserm U1052/CNRS UMR 5286, Lyon, France

15.00 - 17.00 Jordi Rodon Early Development of PI3K inhibitors: lessons learnt from the fi rst clinical trials, lessons missed Molecular Therapeutics Research Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

Paolo Comoglio The Met oncogene: from signal transduction to clinical trials Institute for cancer research and treatment, Turino, Italy

Frederic de Sauvage Development of a Hedgehog Pathway Inhibitor for the Treatment of Basal Cell Carcinoma Genentech Inc., South San Francisco, USA

17.00 - 18.00 Round table and discussion

October 9, 2012

PROGRAM

5

09.00 - 09.30 Welcome coffee

09.30 - 09.50 Opening Fabien Calvo Institut National du Cancer - Institut Cancer d’Aviesan

Session 3 Frontiers in sciences for cancer: addressing cancer complexities through blending of different disciplines Chair: François Taddéi

09.55 - 10.40 Lecture François Taddei Why interdisciplinary approach is a must in cancer research and how FdV brings disciplines together? Université Paris Descartes, Inserm, Paris, France

10.45 - 11.25 Dirk Drasdo Towards predictive quantitative modeling of tissue organization and tumor growth on histological scales by imaging, image analysis and modeling Institut national de recherche en informatique et en automatique (INRIA), Rocquencourt, France Interdisciplinary Center for Bioinformatics, Leipzig, Germany

Julie Livingston Ethnography as Early Warning System: Anthropology and the Intimate Complexities of Africa’s Emerging Cancer Epidemic Rutgers School of Arts and Sciences, New Brunswick, USA

11.30 - 12.30 Round table and discussion

12.30 - 13.45 Lunch

Session 4 Cancer immunity and infl ammation Chair: Guido Kroemer

13.50 - 14.30 Lecture Guido Kroemer The secrete ally: immunostimulatory effects of conventional and targeted anticancer agents Université Paris Descartes, Institut Gustave Roussy, Inserm, Assistance Publique-Hôpitaux de Paris, France

14.35 - 16.35 Robert Schreiber Cancer Immunoediting: Mechanistic and Therapeutic Insights Washington University School of Medicine, Saint-Louis, USA

Lisa M. Coussens Infl ammation and Cancer: Reprogramming the immune microenvironment as an anti-cancer therapeutic strategy Knight Cancer Institute, Oregon Health & - Science University, Portland, USA

Charles Drake Immune Checkpoint Blockade in the Clinic - Moving the Bar John Hopkins Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA

16.40 - 17.40 Round table and discussion

17.40 - 18.00 Conclusion Agnès Buzyn Institut National du Cancer

October 10, 2012

Thomas HUDSONOntario Institute for Cancer ResearchToronto, Canada

ABSTRACTThe Genetic Basis for Cancer Treatment Decisions

6

Dr. Thomas J. Hudson is President and Scientifi c Director of the Ontario Institute

for Cancer Research, a new Institute with a focus on translational research

in prevention, detection, diagnosis and treatment of cancer. Dr. Hudson is a

thought leader in making personalized medicine a reality. He is internationally

renowned for his work in genomics and human genome variation and was instrumental in the creation of

the International Cancer Genome Consortium. He was a founding member of the International Haplotype

Map Consortium and the Public Population Project in Genomics. Dr. Hudson is a fellow of the Royal

Society of Canada and editor-in-chief of the journal Human Genetics. Dr. Hudson has co-authored over

250 peer-reviewed scientifi c publications.

Genomic variation, through its effect on gene structure

and expression, plays an important role in disease

predisposition, biology, and clinical response to

therapy. Cancer mutations can be classifi ed as germline

(inherited) and somatic (tumoral). I will provide

examples of ongoing projects that emerged from

large-scale genome studies of cancer patients that are

pertinent to both classes of cancer mutations.

Genome-wide association studies (GWAS) have led to

the identifi cation of many genetic loci that contribute

to an increased predisposition to cancer. For example,

to date more than 22 loci have been associated with

colon cancer. In a study of a chromosome 11q23 locus

that is genetically associated with colorectal cancer

risk, we investigated two adjacent transcripts named

COLCA1 and COLCA2 and show that inheritance of

one or two protection-associated alleles correlates with

increased expression of both proteins as well as

lymphocyte infi ltration at the periphery of neoplastic

tissue, a histological feature that is associated with

increased survival. Our fi ndings provide evidence for

a genetically regulated host immune and tumor

response involving multiple cells that reside in the

microenvironment of colon cancer.

Personalized cancer medicine is based on a rapidly

emerging knowledge of the cancer mutation repertoire

through comprehensive studies such as the International

Cancer Genome Consortium and the increased

availability of anti-cancer agents that target altered

genes or pathways. In the second part of my

presentation, I will present concepts and experiences

gained from a pilot study involving patients with

advanced metastatic cancers from fi ve cancer centers in

Ontario who are potential candidates for early phase

clinical trials of targeted agents. The study includes

rapid mutation detection using next-generation

sequencing technologies in a set of genes deemed to

be actionable, validation in a clinical molecular

diagnostics laboratory, and reporting of actionable

mutations to clinicians and patients.

Barbara PRAINSACKCentre for Biomedicine & Society, Brunel UniversityUxbridge, United-Kingdom

ABSTRACTThe social challenges of genomics and personalised medicine

7

Barbara Prainsack is Professor of Sociology and Politics of Bioscience at the Centre

for Biomedicine & Society (CBAS), Dept of Sociology and Communications,

Brunel University. She has published widely on the societal, ethical, and regulatory

dimensions of biomedicine and bioscience (genetic and genomic science and

technologies in particular). She is a member of the Austrian National Bioethics Commission, and co-chair of the

Scientifi c Committee of the ESF’s Forward Look on Personalised Medicine (http://bit.ly/AcJzNY). From January to

July 2011, she was AHRC/ESRC Fellow for the project ‘Solidarity as a Core Value in Bioethics’ at the Nuffi eld Council

on Bioethics in London, UK.

Like the discipline of bioethics, but partly underpinned

by different conceptual and methodological concerns,

the social studies of biomedicine explore the

societal and ethical dimensions of medical research

and practice. The Human Genome Project, which

dedicated a portion of its public funding to research

into societal, ethical, and legal implications (ELSI)

of genomics, marked the turn towards a more

interdisciplinary and increasingly empirically informed

scholarship in this fi eld.

Along the lines of three important themes, identity,

justice & equity, and participation, this presentation

will discuss some of the core social challenges that

genomics poses. Especially the theme of participation

has recently led to controversial debates. Some regard

the ideal of the ‘empowered’ patient who is actively

in charge of her or his health, and also willing to

contribute data for research, as a necessity for the

arrival of Personalised Medicine; others reject the

notion of a participatory turn in medicine as

dangerous rhetoric that conceals inequalities and

potentially compromises clinical care. I will argue that

regardless of what side one stands on in this debate, an

interdisciplinary and evidence-led exploration of

the ways in which genomics both has the potential

to increase injustice, but also helps to alleviate it,

will be necessary to achieve socially and politically

robust solutions.

Jean-Yves BLAYCentre de recherche en cancérologie, Centre Léon BérardLyon, France

ABSTRACTHow molecular characterization is changing cancer clinical research?

8

Jean-Yves Blay conducts translational research in national and international

networks, in the fi eld of rare tumours in particular sarcomas, cancer immunology,

and development of innovative targeted therapies of cancer.

Jean-Yves Blay obtained his medical degree from the Claude Bernard University in

1990, specializing in oncology, and in 1994, received his PhD on the role of interleukin-6 in renal cell carcinomas.

Jean-Yves Blay is an active member of the European Society of Medical Oncology (serving as National

Representative), the Connective Tissue Oncology Society (Board member 2001-2004 American Society of Clinical

Oncology, the American Association for Cancer Research, the American Society of Hematology), the French Society

of Cancer (Board member 2005-2011), the European Association of Cancer Research. He co-chairs the French

Sarcoma Group and acts as the Network director of the French national network dedicated to sarcoma since 2009

Netsarc. (netsarc.org). He is also the Network Director of Conticanet, a network of excellence funded by the EU,

Commission and dedicated to novel treatment approaches in sarcomas (www.conticanet.eu, conticabase.org,

conticagist.org). He leads the current FP7 Eurosarc project, and serves as the director of the French NCI (INCa)

supported Lyon Integrated research site in Cancer (LYRIC), one of the 8 integrated sites created so far in France.

Jean-Yves Blay served as President of the European Organisation for Research and Treatment of Cancer (EORTC).

His main research themes are clinical and translational research in sarcoma and cancer immunology, and

development of targeted therapies.

In the last 10 years, the emergence of molecular

characterisation of tumor cells has enabled refi ne the

nosological classifi cations of neoplastic diseases and

to select targeted treatments in individual patients.

One consequence is the fragmentation of disease

groups based on tissue origin into a variety of more

homogenous molecular subtypes, distinguished by

their presumed driving molecular alterations. These

groups are always of smaller size, and it has been

predicted that all neoplastic diseases would ultimately

become rare. The identifi cation of this “initial” molecular

alteration, happening early in the transformation

process, presumably at a premalignant stage is essential

to guide the development of targeted therapies.

In frequent diseases, e.g. lung carcinoma, rare

subgroups with mutations on specifi c genes (e.g. Alk

or HER1) representing each 3 to 4% of all patients must

distinguished to select the optimal systemic treatments.

Even with each subgroup, the precise sequence of

molecular alteration (HER1) may identify patients with

distinct prognosis and optimal treatment. Importantly,

the frequencies of these mutations may vary

considerably across ethnic groups and around the

globe. In rare tumors, the same process is in place:

gastrointestinal stromal tumors, GIST, a nosological

entity identifi ed in 1998, is now recognized to gather at

least 10 different molecular subgroups, which require

distinct treatments in advanced phase (7 rev GIST)

as well as in adjuvant phase. This nosological

fragmentation is probably just at its beginnings. This

heterogeneity is even occurring at the level of a single

patient, with the recent demonstrations of a complex

branched evolution of mutations from primary

tumour to primary and secondary metastasis. Indeed

9

secondary resistance to targeted agents is occurring in

the vast majority of patients with solid tumors in

advanced phase. It is logical to hypothesize that the risk

of emergence of resistant clones is proportional to

tumour cell mass, with adjuvant. However, the

conclusions on the effi cacy of treatment in metastatic

phase may not be relevant in the adjuvant setting:

adjuvant trastuzumab treatment may benefi t patients

with HER2 non amplifi ed breast adenocarcinoma.

The need for very long- maybe life long- maintenance of

targeted therapy in advanced phase, and possibly in

adjuvant setting.

Finally, the impact of these refi ned nosological

classifi cations on local treatment is not known

yet: should the standard local treatments, surgery

and radiotherapy, of localized disease be adapted to

the molecular subtype of the disease, Molecular

characterization is changing in depth the perspective of

clinical and translational research in oncology, both in

localized and advanced disease. The development of

personalized medicine will have to face these multiple

dimensions of complexity. We will not be able to

address with the usual clinical research methodologies,

This evolution of oncology research from empirical

approaches to more rationally based approaches in the

last 20 years makes it not yet a hard, “exact” science,

but moves towards this direction. As for mathematical

research, there are now questions to be addressed

whose resolution will be essential for the future

development of research in oncology.

Here are some important questions to be answered:

1) How can we integrate the volume of molecular

information generated to the routine care of the

patient? The characterisation of genomic alterations

of each individual tumour identifi es hundreds of

alterations but it is not known how to integrate these in

the routine setting

2) Specifi cally, how to recognize the driver mutations

in individual patients to guide the treatment?

3) How to generate algorithms integrating these

molecular characteristics of the tumour, the genomic

characteristic of the patient, and the clinical characte-

ristics (age, stage, PS…) of the patient to guide

treatment decisions?

4) Does adjuvant treatment with targeted therapies

prevent or postpone relapse?

5) Can we defi ne better surrogate markers for overall

survival?

6) Is resistance to targeted treatment unavoidable

in advanced phase?

7) Considering the previous question, is it possible

to prevent secondary resistance with novel paradigms

of combination, sequential, or rotation treatment

with different classes of targeted treatments?

8) Can surgical removal of the metastatic burden

reduce the risk of emergence of clonal and clinical

resistance?

9) Can modern immunotherapy cure minimal residual

disease in man?

10) Is it possible to generate models on when to stop

specifi c treatment?

11) Is it possible to organize the health care systems

to ensure optimal local treatments, surgery and

radiotherapy, for all patients?

12) Is it possible to organize annotated multinational

tumour collection and storage to enable clinical

research on molecular subtypes?

13) In this context, the number of clinical trials will

increase, at times where their cost and administrative

complexities are increasing tremendously. How can we

reconcile these opposite needs and build simple not

costly academic clinical trials?

14) Finally, and more importantly, these achievements

have a substantial cost: can our health care systems

absorb the cost of these novel tools and targeted

treatments?

These different questions are relevant in most tumours

according to the disease classifi cations which guide our

treatment now. These, and probably many others,

will need to be addressed in order to progress towards

true personalized treatment of cancer.

DAVID COXPfi zer IncSouth San Francisco, USA

TITLEPrecision Medicine and Cancer Genomics: An Industry Perspective

10

Dr. Cox serves as Chief Scientifi c Offi cer for the Rinat/Applied Quantitative

Genotherapeutics Unit of Pfi zer’s Worldwide Research & Development. This group

integrates human biology, next- generation DNA sequencing and quantitative

mechanistic mathematical modeling to defi ne the biological basis of complex

disease and to enable patient stratifi cation in clinical trial design. Dr. Cox is a co-founder of Perlegen Sciences Inc.,

and was Chief Scientifi c Offi cer of that company from 2000 until 2008. From 1993 to 2000 Dr. Cox was Professor

of Genetics and Pediatrics at the Stanford University School of Medicine as well as the co-director of the Stanford

Genome Center. From 1980 to 1993 Dr. Cox was a faculty member at the University of California, San Francisco.

He obtained his A.B. and M.S. degrees from Brown University in Rhode Island and his M.D. and Ph.D. degrees from

the University of Washington, Seattle. He completed a Pediatric Residency at the Yale-New Haven Hospital in New

Haven, Connecticut and was a Fellow in both genetics and pediatrics at the University of California, San Francisco.

Dr. Cox is certifi ed by the American Board of Pediatrics and the American Board of Medical Genetics. He has been

an active participant in the large scale mapping and sequencing efforts of the Human Genome Project while carrying

out research involving the molecular basis of human genetic disease. He has authored over 100 peer-reviewed

scientifi c publications. Dr. Cox has been a member of numerous commissions and boards, including the National

Bioethics Advisory Commission (NBAC) and the Health Sciences Policy Board of the Institute of Medicine.

He presently serves as a member of the Council of the Human Genome Organization (HUGO). Dr. Cox’s honors

include election to the Institute of Medicine of the National Academy of Sciences.

Patrick MEHLENCentre de recherche en cancérologie, Centre Léon BérardLyon, France

ABSTRACTThe dependence receptor notion: from a cell biology paradigm to alternative targeted therapies

11

Dr. Patrick Mehlen is director of the “Laboratoire d’Excellence DEVweCAN”,

vice-director of the Research Cancer Center of Lyon and co-director of the institute

of Clinical Science in the comprehensive cancer center Centre Léon Bérard in Lyon.

Dr. Mehlen has pioneered a cell biology paradigm called dependence receptor

notion and has described the importance of this paradigm in the regulation of tumor progression. He has published

over 120 peer-reviewed scientifi c publication and has received several awards included the silver medal from CNRS,

the Pius XI Gold Medal from Pontifi cia Academia Scientiarum City of Vatican or the Prix Bettencourt-Schueller pour

les Sciences du Vivant. Dr. Mehlen has been elected EMBO member in 2006 and is adjunct professor at the Buck

Institute for Age Research, CA, USA. Dr. Mehlen is co-founder of Netris Pharma, a SME dedicated to the

development of targeted therapies against cancer based on the dependence receptor notion.

A few years ago, an original concept of cell biology was

proposed: whereas the classic dogma postulates that

transmembrane receptors are inactive unless bound

by their specifi c ligand, it was suggested that some

receptors may be active not only in the presence of their

ligand, but also in their absence. In this latter case, the

signaling downstream of these unbound receptors

leads to apoptosis. These receptors were consequently

named “dependence receptors”, as their cell expression

renders the cell’s survival dependent on the presence in

the cell environment of its respective ligand. This dual

function is hypothesized to lead these receptors to have

key roles both during embryonic development and in

the regulation of tumorigenesis.

In the context of cancer, the hypothesis is that these

receptors are tumor suppressors that would limit

tumor progression by inducing apoptosis of tumor cells

outside of settings of ligand accessibility/availability.

This was recently formally demonstrated for the proto-

typical dependence receptors that bind netrin-1 –i.e.,

DCC and UNC5H-. Because expression of DCC and

UNC5H is a constraint for tumor progression, their

expression is often lost in many aggressive cancers.

However, a loss of dependence receptors is not always

the selective advantage used by tumor cells to escape

this survival dependence on the presence of the ligand.

Indeed, it was shown that in many cancers such as me-

tastatic breast cancer, lung cancer or neuroblastoma,

tumor cells acquire the preferred autocrine expression

of netrin-1. This selective advantage for the tumor is

much more appealing in terms of therapeutic strategy.

Indeed, the titration of the ligand by a molecule that

interferes on the interaction between a dependence

receptor and its ligand should lead to tumor cell death.

Along this line, it was shown that titration of netrin-1

by a drug candidate allows tumor cell death in vitro

and triggers regression of tumors and metastases in

mice. Of interest, this gain of ligand is probably not

limited to netrin-1 but may possibly be extended to the

other ligands of other dependence receptors. Thus,

drugs based on the interference on the interaction

between dependence receptors and their ligands are

under development. The fi rst human trial (Phase I)

using an agent interfering between netrin-1 and its

receptors should begin in late 2013. Thus, from a basic

cell biology concept, our laboratory may, within the

next few years, provide new tools to fi ght against

cancer.

Jordi RODONMolecular Therapeutics Research Unit, Vall d’Hebron Institute of Oncology (VHIO) Barcelona, Spain

ABSTRACTEarly Development of PI3K inhibitors: lessons learnt from the fi rst clinical trials, lessons missed

12

Medical Oncologist (Catalan Institute of Oncology), research fellow at the

Advanced Drug Development Fellowship program at the Institute For Drug

Development in San Antonio, Texas, and Senior Research fellow at the Investigational

Cancer Therapeutics Department at MD Anderson Cancer Center in Houston,

Texas, Dr Jordi Rodon joined the Medical Oncology Department in 2008. Principal investigator or co-investigator

in more than 80 phase I trials, Dr Rodon coordinates the phase I program and the clinical research at UITM, and

focuses in complex clinical trials with drugs in early development (phase I and early phase II trials) and novel novel

targets. Main interest of his laboratory is proof-of-concept and proof-of-mechanism trials with targeted therapies,

especially target therapies focusing in cell signaling and cancer stem cells. These trials include First-in-human studies

of targeted therapies, rational combinations of targeted therapies, biomarker-driven trials and trials in molecularly

selected populations. In the last two years, collaborations were conducted with the Molecular Pathology and the

Genomics labs to perform molecular analysis of the patients tumor in order to select the best possible treatment with

the available experimental treatments, in a step towards Personalized Medicine.

PI3K pathway activation is commonly observed in

human cancer and is critical for tumor progression and

resistance to antineoplastic drugs. Several molecular

aberrations affecting key components of this pathway

have been described, including genetic mutations and

amplifi cations (PIK3CA, AKT) and loss of function

of negative regulators (PTEN). Rapalogs were the fi rst

inhibitors of downstream effectors of the PI3K pathway

to enter the clinic. As monotherapies, antitumor activity

has been demonstrated only in selected neoplasms.

Preclinical studies show that mTOR inhibition relieves

feedback activation of receptor tyrosine kinases, leading

to subsequent PI3K/AKT signaling, what could limit

the effectiveness of rapalogs as antineoplastic agents.

Multiple second-generation PI3K pathway inhibitors

are in the early phases of clinical development, some

of them already going into phase 2 trials. Toxicity

profi le has been acceptable, with no unexpected

adverse events. Partial responses and prolonged

disease stabilization have been reported in multiple

tumor types, although in a lower than expected rate.

Furthermore, pharmacodynamic studies showed

reduction of activation of key pathway readouts in the

range of 50 to 90%, both in tumor and surrogate

tissues. Signifi cant decline in proliferation markers and

reduction of glucose avidity on FDG-PET scans have

been reported, confi rming that the targets are being

hit. Nevertheless, one question leads to many others,

and several important questions remain unanswered

in the PI3K pathway translational development.

Paolo M. COMOGLIOIRCC, Institute for Cancer Research @ CandioloUniversity of Turin School of MedicineTurin, Italy

ABSTRACTThe Met oncogene: from signal transduction to clinical trials

13

Paolo Comoglio is Full Professor at the University of Turin Medical School and

Scientifi c Director of the Institute for Cancer Research @ Candiolo (Italy). He holds

a MD Degree. His post-doctoral studies in Immunology were carried out at the

Washington University in St. Louis (USA).

He was appointed Editorial Board Member of several international peer-reviewed journals as well as Scientifi c Board

Member of pre-eminent Italian and International Scientifi c institutions. He is author of approximately 300 papers

published in peer-reviewed journals.

His main area of interest is presently focused on targeting the Met oncogenic receptor by antibodies, recombinant

« decoy » proteins, ligand antagonists or small molecule kinase inhibitors. A special effort is made to unveil the

molecular mechanism(s) underlying a positive response or resistance in clinical trials.

Metastasis follows the inappropriate activation of a

genetic program termed invasive growth (or epithelial-

mesenchymal transition), which is a physio-logical

process that occurs during embryonic development

and post-natal organ regeneration. Burgeoning

evidence indicates that invasive growth is also executed

by stem and progenitor cells, and is usurped by cancer

stem cells. The MET proto-oncogene, which is expressed

in both stem and cancer cells, is a ‘master gene’ in the

control of invasive growth, acting upstream ‘squire genes’

such as RON and ROR. MET encodes the tyrosine-

kinase receptor for “Scatter Factor” -also known as

HGF- a sensor of adverse microenvironmental conditions

(such as hypoxia or ionizing radiations) and drives cell

invasion and metastasis through the transcriptional

activation of a set of genes (the invasive growth signature), that can be exploited as ‘surrogate markers’

for MET activation. In cancer cells the MET tyrosine

kinase stimulates cell scattering, invasion, protection

from apoptosis and angiogenesis, thereby acting as a

powerful expedient for dissemination. In some cancers,

MET has been genetically selected for the long-term

maintenance of the primary transformed phenotype,

and those cancers appear to be dependent on (or

‘addicted’ to) sustained MET activity for their growth

and survival. Because of its dual role as an adjuvant,

pro-metastatic gene for some tumour types and as a

necessary oncogene for others, MET is a promising

target for therapeutic intervention. Recent progress in

the development of molecules that inhibit MET function

-both small molecules and antibodies- will be discussed.

Their application in subsets of human tumours potentially

responsive will be considered.

Frederic J. DE SAUVAGEGenentech IncSouth San Francisco, USA

ABSTRACTDevelopment of a Hedgehog Pathway Inhibitor for the Treatment of Basal Cell Carcinoma

14

Frederic de Sauvage obtained his PhD summa cum lauda from the Catholic

University of Louvain in Belgium. He joined the laboratory of David Goeddel at

Genentech as a postdoctoral fellow in 1990 and was hired as a Scientist in 1992.

In 1994, Dr de Sauvage’s team at Genentech discovered Thrombopoietin (TPO),

the long sought physiological regulator of platelet production. His laboratory made many discoveries in the fi eld

of hematopoeisis before switching his focus to the Hedgehog pathway in the late 1990s. His work led to the

development of vismodegib (GDC-0449), a Hedgehog Pathway Inhibitor recently approved for the treatment of

metastatic or locally advanced basal cell carcinoma and currently tested in clinical trials for the treatment of a

number of other cancers. In 2011 he received the Achievement in Advancing Targeted Therapies for Cancer &

Melanoma Award from the American Skin Association. Dr de Sauvage is now the vice president of research-

Molecular Biology at Genentech Inc.

The Hedgehog (Hh) pathway is an ancient signalling

cascade that directs patterning in most animals and

is crucial for proper development. While Hh signalling

is very active during embryogenesis, it remains relatively

quiet in adult life. However, aberrant reactivation of the

pathway in adult tissue can lead to the development

of cancer. Hh pathway activation in tumors such as

basal cell carcinoma (BCC) and medulloblastoma is

the result of inactivating mutations in PATCHED

(PTCH) or activating SMOOTHENED (SMO) mutations.

Targeting the Hh pathway with small molecule

antagonists therefore provides a new therapeutic

opportunity for the treatment of these tumor types.

Vismodegib (GDC- 0449), an oral Hedgehog (Hh)

pathway inhibitor, was tested in a fi rst - in - human,

fi rst - in - class, phase I study BCC patients. Strong

anti-tumor activity was observed in patients with

locally advanced and metastatic BCC, thereby

highlighting the potential benefi t of inhibiting aberrant

Hh signalling in tumors where the pathway is mutated.

These results were confi rmed in a pivotal study, leading

to the approval of vismodegib by the FDA for that

indication. While most BCC tumors display Hh

pathway activity, only a subset of medulloblastoma

tumors are caused by mutations in the Hh pathway.

Early evidence of clinical benefi t of vismodegib in a

medulloblastoma patient selected for Hh pathway

activity was demonstrated. However, as is the case for

most targeted therapies used in cancer, mechanisms of

resistance to Hedgehog Pathway Inhibitors have started

to emerge in man and mouse models, highlighting

the importance of this pathway for these tumors.

In addition to its role in BCC and medulloblastoma,

Hh pathway activation in other solid tumor types is

the result of upregulation of Hh ligand expression

in epithelial tumor cells, which acts in a paracrine

manner to activate the pathway in surrounding stromal

fi broblasts. These may in turn provide growth factor(s)

and/or a microenvironment that promotes tumor growth

directly or by affecting other compartments such as

the vasculature. Inhibition of the Hh pathway may

also provide benefi t in tumors where Hh ligands

are overexpressed and is currently being explored in

the clinic.

François TADDEIUniversité Paris DescartesParis, France

ABSTRACTTraining the next generation of interdisciplinary students at the frontiers of sciences

15

Over the last eight years, François Taddei has created the CRI (Center for Research

and Interdisciplinary) in Paris, which offers 3 programs integrated in the Liliane

Bettencourt curriculum: a new undergrad program, a Master’s degree (Interdisci-

plinary Approaches to Life Sciences, AIV), a doctoral school (Frontiers of Life, FdV).

CRI‘s dedicated facilities host visiting professors, a wide choice of courses and several student discussion clubs.

CRI’s main role is to promote new pedagogies to help creative students take initiatives and develop their research

projects, with the help of mentors, research institutions, private companies, and foundations, such as the

Bettencourt Foundation, which has supported many student-created activities. These activities range from the

fi rst French synthetic biology team (for the MIT-sponsored iGEM competition) to the « Paris-Montagne » science

festival and the « Science Académie », an outreach program that allows high schools students from disfavored

neighborhoods to discover the creativity of science.

François Taddei participates in various working groups on the future of research and education (« France 2025 »,

OECD report…). He has been involved in scientifi c committees for the NIH, the INSERM and the ministry of research

and served as advisor for the French government, the European Union and the OECD that asked him to write a

report on the future of education in the 21st century. He is about to take the lead of the future Institute for Learning

Through Research that has been selected in March 2012 by the International Scientifi c Committee of the National

Innovative Training Program (IDEFI) of the French ministry of research.

François Taddei also heads the Evolutionary Systems Biology team at a unit of the French National Institute of

Health & Medical Research (INSERM) in Paris-Descartes University’s Medical School. After a generalist scientifi c

education, with majors in physics and biology at the École Polytechnique, he became a tenured higher civil servant

at the French Ministry of Agriculture, before earning a PhD in genetics, studying the evolution of the rate of evolution

with Miroslav Radman. After postdoctoral training with John Maynard-Smith, for the last 12 years, his research team

has been studying innovation and degeneracy in biological systems. This work has produced many publications in

generalist scientifi c journals, and has been recognized by several awards (European Young Investigator award,

Human Frontier Science Program award, INSERM Award for Fundamental Research, Liliane Bettencourt Life

Science Award).

Interdisciplinarity in science, and the benefi ts of sharing

expertise accross different areas, are far from being a

new concept. Mahmet Toner (Massachusetts General

Hospital, part of SU2C YT) said that treating and

curing cancer appears even more complicated than

going to the moon. Just as going to the moon wouldn’t be

possible without the joined efforts of material scientists,

physicians, engineers, physiologists etc., progressing

in the fi ght with cancer requires the cooperation of

biologists, physicists, informaticians, mathematicians,

clinical translational medicine and so on. To understand

cancer, and eventually cure cancer, a multi-level obser-

vation is needed; at the molecular, organism and societal

levels, without forgetting the cellular behaviour and

16

tissue architecture. Only a well coordinated interdisci-

plinary team can provide such a multi-level approach

simultaneously. An important step towards such

challenges is to train the next generation able to explore

new frontiers collaboratively.

The Centre for Research and Interdisciplinarity (CRI)

and its bachelor, master and PhD programs take the

proverb « None of us is as smart as all of us » even further

by adding a “and we can be even smarter if we have

diverse backgrounds”. The international interdisciplinary

PhD program « Frontiers in Life Sciences » (French

acronym: FdV, for Frontières du Vivant) provides an

environment for broad education and maximized

intellectual exchanges, necessary for the further

development of interfaces in life science research. The

school promotes students involved in research projects

centered on an understanding of Life requiring the

blending of different disciplines. This is done by

recruiting highly motivated students trained in distinct

disciplines (natural sciences, humanities, medicine,

pharmacy, biology...) and devoting the time and

resources necessary to foster their scientifi c life and

provide them advanced interdisciplinary courses and

workshops.

Dirk DRASDOInstitut national de recherche en informatique et en automatique (INRIA), Rocquencourt, FranceInterdisciplinary Center for Bioinformatics, Leipzig, Germany

ABSTRACTTowards predictive quantitative modeling of tissue organization and tumor growth on histological scales by imaging, image analysis and modeling

17

Dirk Drasdo is head of group for “Multi-cellular Systems Biology” co-localized

at INRIA Paris-Rocquencourt in France and the Interdisciplinary Center for

Bioinformatics, Univ. of Leipzig, Germany. Before his current position as Directeur

de Recherche at INRIA he has hold a faculty position at the Mathematics Dept.

and the Center for Systems Biology at Univ. of Warwick, UK, and research associate positions at the Max-Planck-

Institutes for Mathematics in the Sciences in Leipzig, and Colloid and Interface Science in Golm, as well as at the

Institute for Medical Informatics, Statistics and Epidemiology at the Medical Faculty of Leipzig University; he has

a habilitation in Computer Science (Univ. of Leipzig), a PhD in Physics (MPI for Biophys. Chemistry and Univ. of

Göttingen), and master degree in Physics from the Technical University of Aachen (RWTH). He has been or is PI in

several EU as well as national German or French projects on tissue organisation. His main research topic is modeling

of multi-cellular tissue organisation. For example, he and his group established single cell, center-based growth

models of tissues in various applications, and a process chain parameterizing single-cell-based tissue models out of

image data by which they could predict a previously unrecognized order mechanism in liver regeneration.

A major challenge is to understand how cells and

molecules act coordinately together to form complex

functional tissue architectures and which processes are

perturbed in aberrant states. While invitro systems,

frequently considered as model systems may help in

identifying candidate mechanisms that may act invivo,

the increased complexity of the invivo system of

interest - usually a patient - ultimately require invivo

validation. We propose a mathematical modeling -

guided experimental strategy to optimize and economize

the choice of experiments that address tissue organization

and growth processes. Our procedure is based on a

recently established process chain composed of confocal

laser scans, image processing and three-dimensional

tissue reconstruction, as well as on quantitative mathe-

matical modeling resolving tissue architecture (Hoehme

et. al., PNAS, 2010). We demonstrate how by iterative

application of this procedure a fi nal mathematical

model could be constructed that unambiguously

predicted a previously unrecognized order mechanism

in liver regeneration. The model prediction has subse-

quently been experimentally validated. We show that

hepatocytes that lack cell cycle entrance control form

an - experimentally observed - tumor phenotype that

refl ects the order mechanism. If the order mechanism is

compromised, another tumor phenotype forms which

is very robust against changes of other parameters such

as cell-cell adhesion, micro-motility etc. The signature

of the order mechanism gets lost once the tumor size

overcomes the size of a single liver lobule. Validation

experiments in human are particularly diffi cult to

perform. We fi nally illustrate that our model, fi rstly

calibrated with static and dynamic mouse data, and in

a second step re-calibrated with only static pig data,

provides a valid prediction for liver regeneration after

partial hepatectomy in pig. This may serve as a fi rst

proof-of-concept step to use models of tissue organiza-

tion to extrapolate from an animal model to patients.

Julie LIVINGSTONRutgers University New Brunswick, USA

ABSTRACTEthnography as Early Warning System: Anthropology and the Intimate Complexities of Africa’s Emerging Cancer Epidemic

18

Julie Livingston is Associate Professor of History at Rutgers University and affi liated

with the Rutgers Institute for Health. She was trained in public health, anthropology,

and history, and her research is mainly in southern Africa. Livingston is the author

of a new book, Improvising Medicine in an African Oncology Ward; and also of

Debility and the Moral Imagination in Botswana. Her co-edited works include A Death Retold: Jesica Santillan,

the Bungled Transplant, and the Paradoxes of Medical Citizenship; and Three Shots at Prevention: The HPV Vaccine

and the Politics of Medicine’s Simple Solutions. She has received numerous awards in support of her research, and

in 2010/2011 she was an invited fellow at the Wissenschaftskolleg zu Berlin, where she co-directed a research group

on contemporary challenges of clinical practice in Africa.

This paper provides insight into the cancer epidemic

rapidly emerging in Africa, by offering a close look at a

single clinical space - Botswana’s one and only cancer

ward, one of very few public oncology settings in Africa.

It outlines the complex combination of institutional,

clinical, intellectual, social, and moral challenges of

cancer care in a setting that by and large lies on the

periphery of the oncology industry. In the process, it

suggests what contributions humanistic (anthropological)

research has to offer to our understanding of serious

and pressing clinical, scientifi c, and public health problems.

One of the key strengths of ethnography, it is argued

here, is its ability to operate as an early warning system

of sorts – identifying emerging problems and issues for

which scientifi c research is needed.

Guido KROEMERUniversité Paris Descartes, Institut Gustave RoussyParis, France

ABSTRACTThe secrete ally: immunostimulatory effects of conventional and targeted anticancer agents

19

Guido Kroemer is best known for the discovery that the permeabilization of

mitochondrial membranes constitutes a decisive step in programmed cell death.

Guido Kroemer has explored the fi ne mechanisms of mitochondrial cell death

control, the molecular pathways that explain the inhibition of cell death in cancer

cells, upstream of or at the level of mitochondria, and the mechanisms that make cancer cell death immunogenic.

His work has had far reaching implications for the comprehension, detection and therapeutic manipulation of

cellular demise. His contributions have been recognized by the Descartes Prize of the European Union, the Carus

Medal of the German Academy of Sciences, the Grand Prix Mergier-Bourdeix of the French Academy of Sciences,

the Dautrebande Prize of the Belgian Royal Academy of Medicine, the Gallet & Breton Prize of the French Academy

of Medicine, and the Prix Coup d’Elan of the Fondation Bettencourt-Schueller. He currently serves on more than fi fty

Editorial Boards. These include EMBO Journal, Cancer Research, Oncogene and Molecular & Cellular Biology.

Kroemer is also the Editor-in-Chief of Cell Death & Disease and OncoImmunology. He is member of EMBO,

German Academy of Sciences (Leopoldina), Academia Europaea, European Academy of Sciences (EAS) and

European Academy of Sciences and Arts (EASA).

He is the President elect of the European Cell Death Organization (ECDO) and the Founding President of the

European Academy of Tumor Immunology (EATI).

The tumour microenvironment, and in particular the

immune system, has a crucial role in modulating

tumour progression and response to therapy.

Indicators of an ongoing immune response, such as the

composition of the intratumoural immune infi ltrate, as

well as polymorphisms in genes encoding immune

modulators, have been correlated with therapeutic

outcome. Moreover, several anticancer agents -

including classical chemotherapeutics and targeted

compounds - stimulate tumor-specifi c immune responses

either by engaging immune effector mechanisms

through warranted off-target effects on leukocytes or

by inducing the immunogenic death of cancer cells.

Depending on the upstream triggers, apoptosis can be

immunogenic and hence alert the innate immune

system and instruct it to stimulate a cognate response

against dead-cell antigens. Hence, even though chemo-

therapy usually only kills a fraction of cancer cells, it

can convert the tumor into a therapeutic vaccine,

thus stimulating an anticancer immune response that

assures the long-term control of residual cancer cells.

Immunogenic cell death is characterized by the

pre-apoptotic exposure of calreticulin (CRT) on the cell

surface, secretion of ATP during apoptosis, and

post-apoptotic release of the chromatin-binding

protein high mobility group B1 (HMGB1). CRT

exposure depends on an endoplasmic reticulum stress

response, ATP secretion on pre-mortem autophagy,

and HMGB1 on secondary necrosis. CRT, ATP and

HMGB1interact with three receptors (CD91 receptor,

20

the purinergic P2RX7 receptor, and toll-like receptor 4

respectively) that are present on the surface of dendritic

cells. CD91, P2RX7 and TLR4 promote engulfment of

dying cells, production of interleukin-1ß and presenta-

tion of tumor antigens, respectively. Inhibition of any

of these pathways, either within cancer cells or within

the immune system, can attenuate the chemotherapy-

induced immune response in preclinical models.

We postulate that, at least in certain cases, both classical

and targeted anticancer chemotherapies require an

active contribution of the immune system to be

optimally effi cient. We obtained clinical evidence that

this hypothesis holds true for anthracycline-treated

breast cancer, oxaliplatin-treated colorectal cancer and

imatinib-treated gastrointestinal stromal tumors.

Robert D. SCHREIBERWashington University School of MedicineSaint-Louis, USA

21

Robert D. Schreiber received his B.A. degree in Chemistry from the State University

of New York at Buffalo in 1968 and his Ph.D. in Biochemistry from that same

institution in 1973. He then moved to the Molecular Immunology Department at

The Research Institute of Scripps Clinic, LaJolla, CA, to obtain postdoctoral

training with Hans Muller-Eberhard. Three years later, Schreiber was promoted to the rank of Assistant Member

at Scripps and, after a sabbatical year with Emil Unanue in the Department of Pathology at Harvard Medical School

from 1979-80, he returned to Scripps as an Associate Member with tenure. In 1985, Robert D. Schreiber was

recruited to the Department of Pathology, Washington University School of Medicine as Professor of Pathology and

Microbiology and, since 1990, he has held the rank of Alumni Endowed Professor of Pathology and Immunology at

that institution. Robert D. Schreiber was the Director of the Washington University Immunology Graduate Program

from 1993-2003 and has been the Leader of the Tumor Immunology Program of the Washington University Siteman

Cancer Center since 1999. He is also an Affi liate of the Ludwig Institute for Cancer Research and an Associate

Director of the Scientifi c Advisory Board to the Cancer Research Institute. Schreiber is a member of the Board

of Scientifi c Advisors of the National Cancer Institute.

For more than 25 years, Schreiber’s work has focused on the biochemistry and molecular cell biology of cytokines.

Robert Schreiber was the fi rst to clearly demonstrate that IFNγ was the major murine cytokine responsible for

activating macrophages to express anti-tumor and anti-microbial activities. He was also the fi rst to produce

neutralizing monoclonal antibodies to murine IFNγ TNFα, IL-1α and IL-1β and their receptors and pioneered their

in vivo use to defi ne the physiologic roles of these cytokines in promoting host resistance to tumors and infectious

agents and in effecting immunopathologic processes. Dr. Schreiber was one of the investigators who elucidated the

structure of the IFNγ receptor, and he has been acknowledged for identifying the critical receptor sequences required

for intracellular signaling, for determining how STAT proteins associate with activated cytokine receptors, and

for defi ning the molecular basis of cytokine receptor signaling specifi city. Dr. Schreiber generated some of the fi rst

gene-targeted mice lacking specifi c JAK-STAT pathway components (STAT1 and JAK1) and validated the physiologic

relevance of JAK-STAT pathway signaling. Using IFNγ unresponsive IFNGR1-/- or STAT1-/- mice or immunodefi cient

RAG2-/- mice, R. Schreiber was the fi rst to unequivocally demonstrate that the immune system protects the host

against spontaneous and carcinogen-induced tumor development and thereby rekindled interest in the process of

cancer immunosurveillance. Dr. Schreiber has also shown that the immune system can facilitate outgrowth of

tumors with reduced immunogenicity and thus paradoxically facilitate tumor growth. These observations led

Dr. Schreiber to the reformulate the cancer immunosurveillance concept into one he has called “cancer

immunoediting”. Dr. Schreiber’s work has thus led to a generalized appreciation of the profound effect of

immunity on developing tumors and has contributed critical conceptual and practical support to the fi elds

of tumor immunology and cancer immunotherapy.

Robert Schreiber has authored more than 200 peer reviewed and invited publications and his work has been well

recognized. He has received several honors including the Milstein Award for Outstanding Achievements in Research

on Interferon and Cytokines from the International Society of Interferon and Cytokine Research (1996); Induction

as a Fellow of the American Association for the Advancement of Science, (1996); Bonazinga Award for Excellence in

Leukocyte Biology Research from the Society for Leukocyte Biology (1998); William B. Coley Award for Distinguished

22

ABSTRACTCancer Immunoediting: Mechanistic and Therapeutic Insights

Cancer Immunoediting is the process by which the

immune system controls and shapes cancer. We

originally envisaged that cancer immunoediting would

occur in three phases: Elimination (also known as

cancer immunosurveillance, the host protective phase

of the process), Equilibrium (the phase in which tumor

cells that survive immune elimination remain under

immunologic growth control resulting in a state of

functional tumor dormancy) and Escape (the phase

where clinically apparent tumors emerge because

immune sculpting of the tumor cells has produced

variants that display either reduced immunogenicity

or enhanced immunosuppressive activity). Strong

experimental data has now been obtained using mouse

models of cancer to demonstrate the existence of each

phase of the cancer immunoediting process and

compelling clinical data suggests that a similar process

may also occur during the evolution of certain types of

human cancer. Our efforts now focus on elucidating

the molecular and cellular mechanisms that underlie

each phase of cancer immunoediting and identifying

the critical checkpoints that regulate progression from

one phase of the process to the next. This approach has

helped identify the nature of antigens seen by immunity

in nascent developing cancers and has further shown

that immunoselection is a major mechanism of

immunoediting. Moreover, we have found that edited

tumors can still be controlled by the immune system

if natural mechanisms that prevent autoimmunity are

suspended. As reported by others, we have confi rmed

that inhibition of CTLA-4 induces ejection of edited

MCA sarcomas. However, we have also found that

inhibition of PD-L1 does the same, although by

perhaps different mechanisms. These differences will

be discussed.

Research in Basic and Tumor Immunology from the Cancer Research Institute (2001) and The Charles Rodolphe

Brupbacher Prize for Cancer Research (2007). Dr. Schreiber has also given a number of honorary and/or keynote

lectures including: The First Hans J. Muller-Eberhard Memorial Lecturer, University of Texas Houston (1999);

The First David S. Finbloom Lecturer in Immunobiology, FDA and NIAMS, NIH 2000; AAI Presidential Symposium

Speaker, FASEB (2002); 41st Annual J.S. and H.R. Blumenthal Memorial Lecturer, University of Minnesota (2003);

Keynote Speaker Cancer Research Institute Annual Meeting (2004); and Keynote Speaker for the Robert Baldwin

Retirement Symposium (2005). Dr. Schreiber was a co-organizer of the Keystone Symposium E2 Jaks and Stats:

Development to Disease (2004), and completed service as Chairman of the Transplantation, Tolerance and Tumor

Immunology (TTT) NIH Study Section (2006).

Lisa M. COUSSENSKnight Cancer Institute, Oregon Health & Science University Portland, USA

ABSTRACTInfl ammation and Cancer: Reprogramming the immune microenvironment as an anti-cancer therapeutic strategy

23

Dr. Lisa M. Coussens, Ph.D, is the Chair of the Department of Cell & Developmental

Biology, and Associate Director for Basic Research in the Knight Cancer Institute at

Oregon Health & Sciences University (OHSU) and holds the Hildegard Lamfrom

Chair in Basic Science. Dr. Coussens joined OHSU in Fall 2011 from the University

of California San Francisco (UCSF) where she was a Professor in the Department of Pathology, and Co-Leader of the

Program in Cancer, Immunity and Microenvironment in the UCSF Helen Diller Family Comprehensive Cancer Center.

Dr. Coussens has an international reputation for exceptional high - impact research; her pioneering studies

have fueled a paradigm shift in understanding the role of the tumor microenvironment in regulating solid tumor

development. Dr. Coussens research focus is on the role of immune cells and their mediators as critical regulators of

solid tumor development, and in understanding the molecular and cellular mechanisms that regulate leukocyte

recruitment into neoplastic tissue, and the subsequent regulation those leukocytes exert on evolving cancer cells. She

received her Ph.D. in Biological Chemistry from UCLA in 1993, and completed her postdoctoral fellowship in Cancer

Biology at UCSF in Douglas Hanahans’ laboratory. Since establishing her own laboratory in 1999, Dr. Coussens has

received the prestigious Gertrude B. Elion Award from the American Association of Cancer Research (AACR), the

Mallinckrodt Award for Medical Science and a V Foundation Scholar Award for her novel discoveries regarding the

role of matrix metalloproteinases and mast cells as critical regulators of epithelial cancer development. More

recently, Dr. Coussens was awarded two sequential Era of Hope Scholar Awards from the Department of Defense

Breast Cancer Research Program to support her novel investigations of chronic infl ammation as a regulator of breast

carcinogenesis. In 2011, she and her clinical collaborators received a Susan G. Komen Promise Grant to conduct a

multi- center trial to evaluate novel therapeutic approaches emerging from her research on the tumor microenvironment.

Dr. Coussens demonstrates a deep commitment to educating and mentoring the next generation of scientists, and

as such was awarded the 2012 AACR-Women in Cancer Research Charlotte Friend Memorial Lectureship.

The concept that leukocytes are components of

malignant tumors is not new; however, their functional

involvement as promoting forces for tumor progression

has only recently been appreciated. We are interested

in understanding the molecular mechanisms that

regulate leukocyte recruitment into neoplastic tissue

and subsequent regulation those leukocytes exert on

evolving cancer cells. By studying transgenic mouse

models of skin, lung and breast cancer development, we

have appreciated that adaptive leukocytes differentially

regulate myeloid cell recruitment, activation, and

behavior, by organ-dependent mechanisms. Thus,

whereas premalignant progression, including chronic

infl ammation, activation of angiogenic programming,

tissue remodeling and malignant conversion during

skin carcinogenesis are B cell, Ig and Fc γR–dependent,

during mammary carcinogenesis by contrast, TH

2-CD4+ T cells play a dominant role in regulating

pro-tumor and pro-metastatic properties of

macrophages and dendritic cells, that together regulate

24

metastasis of malignant mammary epithelial cells

to lung, as well as responses to cytotoxic therapies.

To be presented will be recent insights into organ and

tissue-specifi c regulation of epithelial cancer development

by adaptive and innate immune cells, and new studies

evaluating how attenuating protumor properties of

myeloid cells can be exploited to enhance therapeutic

responses to cytotoxic therapy.

LMC acknowledges generous support from the NIH / NCI,

a Department of Defense Era of Hope Scholar

Expansion Award, Susan G. Komen Foundation, and an

Investigator-Initiated Research Award in Mesothelioma

from the DoD.

Charles DRAKEJohns Hopkins Sidney Kimmel Comprehensive Cancer CenterBaltimore, USA

ABSTRACTImmune Checkpoint Blockade in the Clinic - Moving the Bar

25

Dr. Charles Drake is currently the Associate Professor of Oncology, Immunology

and Urology at Johns Hopkins University. Dr Drake obtained his PhD in immuno-

logy at the National Jewish Center for Immunology and Respiratory Medicine and

his MD at the University of Colorado Health Science Center. He completed his

postgraduate training at Osler Medical Service, Johns Hopkins Hospital for internal medicine and in the Department

of Oncology at Johns Hopkins University for medical oncology.

Dr Drake’s research goal is to understand the immune response to cancer and to use the obtained data to inform

immunotherapy studies in humans. He has won several awards, including the Damon Runyon-Lilly Clinical

Investigator Award, the V Foundation Scholar Award and the Prostate Cancer Foundation Creativity Award.

Dr Drake has published 49 peer-reviewed research articles and is currently a member of the American Society of

Clinical Oncology, The American Association of Immunology and the American Association for Cancer Research.

Medical oncology is a rapidly shifting fi eld, re-directing

its focus every few years, from combination chemothe-

rapy, to targeted therapy, and most recently to espouse

the notion of “personalized” medicine, a concept based

on the ambitious premise that understanding a

patient’s tumor at a molecular and genetic level can

inform oncologists to select a regimen with especial

effi cacy. Unfortunately, data from recent sequencing

studies are somewhat at odds such an approach, since,

within a given patient, each tumor may harbor its

own set of mutations and other genetic alterations.

In addition, tumors possess a robust ability to adapt

to even the most effi cacious of targeted therapies, so

that impressive response rates to agents like vemurafi nib

(in melanoma) are not refl ected in equally impressive

improvements in overall survival. Indeed, this adaptive

capacity of tumors is especially challenging – and only

the mammalian immune system possesses similar

adaptive properties. Evolving clinical data support the

notion that, at least in some patients, induction (or

potentiation) of an adaptive immune response can lead

to long-term disease regression, including occasional

long-term complete responses. Data in this regard are

most compelling for immune checkpoint blocking

agents, including anti-CTLA-4 and anti-PD-1. Both

agents induce objective responses; occasionally

long-term in nature Unwanted side-effects are mainly

autoimmune, and are sometimes severe in nature.

Given the multiple mechanisms by which tumors evade

the immune system, this single-agent effi cacy is

somewhat surprising. Moving beyond single-agent

checkpoint blockade will require combinatorial

regimens intended to capitalize on immunogenic cell

death; although a few innovative clinical trials are

currently in progress, it remains challenging to rapidly

translate lessons learned in the laboratory to the clinic.