signal predictive stratifed medicine opportunities targeted … · prof fabien calvo director of...
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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
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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.