Beruflich Dokumente
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Introduction
Division of Cancer
Treatment and
Diagnosis (J.H.D., S.K.),
Developmental
Therapeutics Branch of
the Center for Cancer
Research (J.H.D.),
Room 3A44,
Building31,
31CenterDrive,
National Cancer
Institute, NIH,
Bethesda, MD 20892,
USA.
Correspondence to:
J.H.D.
doroshoj@mail.nih.gov
Competing interests
The authors declare no competing interests.
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Translational cancer biology
Key points
2004
Sensitivity of BRCA
mutant tumours
to poly (ADP-ribose)
polymerase inhibitors
2006
Oncotype Dx
TCGA begins
2008
Glioblastoma multiforme
genome completed
Molecularly targeted
melanoma therapy
2010
Immunotherapy:
checkpoint
inhibitors; genetically
engineered T cells
2012
2014
Development of individually
derived tumour models from
circulating tumour cells for
prospective drug testing
2016
TCGA completed
>10,000 tumours
Figure 1 | Timeline of 10-year translational research for oncology and prospects for the future. Over the past decade,
translational cancer research has undergone an extraordinary transformation, spanning the time from the first
demonstration of a single, functional driver mutation in a human solid tumour (NSCLC) with clear therapeutic
consequences (enhanced response to EGFR inhibitors) to the application of next-generation whole-exome sequencing for
therapeutic decision making in a growing population of cancer patients. Future prospects (shown in pink) include the
expected completion date for TCGA project and the rapid development of personal human tumour models that may begin
tobe used for testing of cancer therapeutic agents on an individualized basis. Abbreviations: ALK, anaplastic lymphoma
kinase; NSCLC, non-small-cell lung cancer; TCGA, The Cancer Genome Atlas.
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a GEM
Treat with
most appropriate
targeted drugs
Tumorigenesis
b GDA
Transplantation
into syngeneic
immunocompetent
mice
Tumorigenesis
Transplantation
into NSG mice
Tumour/patient
heterogeneity
Figure 2 | Improving tumour models for cancer biology and drug development. a | GEMs of human cancer developed through
the organ-specific expression of driver mutations in immunocompetent mice, are used to evaluate the signal transduction
pathways associated with all stages of carcinogenesis as well as to examine the effects of molecularly targeted agents in
proof-of-mechanism studies. b | GDAs facilitate the use of larger numbers of animals carrying tumours that have been
biologically defined and derived for pre-clinical clinical trials in mice with intact immune systems. c | PDXs are developed
directly from implantation of surgical, biopsy, or circulating tumour cell specimens into immune-incompetent mice;
compared with older xenograft models derived from established human tumour cell lines, PDX tumours usually carry with
them some degree of human stroma during initial tumour passages invivo, facilitating a more accurate environment for
molecular characterization and drug testing. New invitro techniques to develop early passage conditionally reprogrammed
cell lines or tumour cell organoid cultures are also under active investigation as preclinical models that might more
accurately predict the efficacy of targeted therapeutic agents. We acknowledge the important role of TerryvanDyke,
National Cancer Institute, NIH, in the development of this figure. Abbreviations: GDA, GEM-derived allografts; GEM,
genetically-engineered mouse model; NGS, NOD scid gamma; PDX, patient-derived tumour xenograft model.
Model organisms
Among the most important developments in trans
lational cancer biology during the past 10years has
been the use of genetic approaches to produce moresophisticated models of human cancer.33,34 For example,
the elucidation of critical signalling pathways essen
tial for understanding the development of pancreatic
ductal adenocarcinoma has been facilitated greatly by
genetically-engineered mouse models(GEMs) of this
disease that recapitulate the carcinogenic process in mice
with an intact immune system.35 The genetic program
ming of organ-specific expression of driver mutations
not only underlies the development of premalignant
lesions and primary tumours in these mice, but allows
for proof-of-mechanism studies of targeted therapeu
tic agents active against the genetic lesions produced
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with human clinical trial results of the same agents and
combinations.34 Additional progress will expand the
diversity of GEM models to characterize more fully
the wide range of molecular aberrations observed in
clinical tumour specimens; there is also little question
that greater use of GEM technology could assist efforts
focusing on biomarker development for early stage
disease as well as the evolution of therapeutic resistance.
There has also been a dramatic resurgence of interest
in mouse tumour models generated directly from patient
surgical or biopsy samples, denoted as patient-derived
tumour xenografts (PDXs). 36 Although such model
systems had been investigated for decades, the availabil
ity of NOD/SCID and NOD/SCID/IL2Rnull (NSG) mice
over the past 10years, which enhances murine immunoincompetence by blocking natural killer cell maturation
and facilitates tumour engraftment, has led to a renais
sance in the use of this technique for generating tumour
models. Furthermore, for certain solid tumours, such
as colorectal, pancreatic, lung, and breast cancers, early
tumour passages (probably through the third or fourth
generation in most cases) retain a degree of human
stroma, facilitating studies of gene expression, drug effi
cacy, and tumour heterogeneity.36 In the case of endo
crine sensitive and resistant breast cancer, PDX models
have been used to demonstrate the stability of genomewide allele frequencies, and response to endocrine
therapy, between the initial human tumour specimens
and PDXs established from these tissues.37 Therefore,
the development of large panels of clinically-annotated
tumours could help evaluate the diversity of responses
expected in the clinical arena, or could be used for
molecularly-characterized preclinical trials to assess the
validity of target selection strategies in advance of clini
cal testing (Figure2c). These models avoid the problems
associated with invitro tumour cell selection; however,
the absence of an intact immune system negates their
value for testing immunotherapeutic strategies. Most
PDX models have been developed from surgical speci
mens rather than from biopsies of metastatic sites; thus,
these models might not be representative of the tumours
that occur in patients with recurrent malignancies who
require systemic therapy.38 Further development of PDX
models for both biological studies and drug selection
might have an important role in improving the precision
with which cancer treatments are selected in the future.
While there has been considerable focus on improv
ing invivo models of human cancer, recent studies have
suggested better ways to study human tumours invitro.
The immortalization of epithelial cells, including human
tumour cells, by inhibiting terminal differentiation
through the use of an inhibitor of Rho kinase and con
ditioned media, has excited investigational interest; if
widely applicable, this conditional reprogramming tech
nique might facilitate the long-term culture of tumour
cells that heretofore have been difficult to propagate, such
as tumours of the prostate (Figure2c).39,40 It is not known
whether tumour cells cultured in this fashion undergo
genetic adaptation to growth on plastic, which would
diminish their predictive potential. The development of
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to use a variety of energy sources besides glucose (such
as glutamine) to increase the production of fatty acids
and other macromolecules needed for the production of
cell membranes as well as a diverse portfolio of anabolic
processes, in addition to ATP production. The metabolic
programmes of tumour cells are diverse, tissue context
dependent, highly influenced by the surrounding micro
environment as well as the tumour host, and hetero
geneous even within a single tumour.52 Recent evidence
suggests that metabolic reprogramming of tumour cells
might have a critical role in the epigenetic modification
of tumour cell DNA and histones.53 For these reasons,
substantial investigational effort is now being directed
toward the development of small-molecule inhibitors of
specific metabolic enzymes that contribute to tumour cell
proliferation (such as isocitrate dehydrogenase 1 [IDH1]
and IDH2) for low-grade gliomas and acute myelogenous
leukaemia, respectively.54,55
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beginning to demonstrate that in some instances gene
expression at the mRNA level may not provide a faithful
rendering of protein abundance in tumours,67 indicating
that integrated proteomic and genomic analyses are likely
to provide the most useful data for the development of
targeted therapeutics. Furthermore, the extent of the
data collected in these and ongoing studies of human
tumours will require collaborative efforts both in the
USA and internationally (such as the Global Alliance
for Genomics & Health) to share clinically annotated
genetic information in a way that optimizes harmonized
investigation of tumour genomics.68
Cancer genome sequencing efforts have demonstrated
the heterogeneity of the mutational spectra that exist in
primary and metastatic sites in the same patient.18,69,70
The clonal evolution of individual tumours that may or
may not retain specific driver mutations across multiple
sites of disease, or that might express resistance muta
tions in some but not other metastases, may compli
cate the application of therapies matched to specific
actionable mutations selected on the basis of sequence
data from a single biopsy.71,72 New technologies for the
molecular analysis of circulating tumour cells (CTCs)
and circulating tumour DNA offer the possibility of
repeating mutational profiles over time from small
samples of blood. 73,74 Thus, the confounding effects
of intratumoural heterogeneity might be minimized.
Furthermore, improvements in CTC collection metho
dologies have facilitated the use of these cells for repeated
pharmacodynamic, as well as mutational, analyses.75
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Non-clinical models for targets
IHC
Expression array
UM U M U MU M
Drug
concentration
Clinical observations
Clinical response
PK
Functional imaging
phase
phase
phase
Patient
monitoring
Patient monitoring:
post-treatment
molecular
re-analysis
CTCs, CECs
Tumour and normal
tissue PD markers
Tumour-initiating cells
Time
Figure 3 | Human tumour tissue-based experimental therapeutics for cancer. The evolving clinical trials paradigm for the
development of molecularly-targeted therapeutic agents focuses on careful use of pre-clinical cancer models to validate
assays that can be used with tissues obtained directly from patients for tumour characterization, proof-of-mechanism
pharmacodynamic studies, molecular monitoring of therapeutic response or the development of resistance, and correlation
with clinical observations based on imaging studies, pharmacokinetic evaluations, and assessments of toxicity.
Weacknowledge the important role of Percy Ivy, National Cancer Institute, NIH, in the development of this figure.
Abbreviations:CECs, circulating endothelial cells; CTCs, circulating tumour cells; FISH, fluorescence in situ hybridization;
IHC, immunohistochemistry; PD, pharmacodynamic; PK, pharmacokinetic.
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a
DAPI
Topotecan
Rad51
pNbs1
ERCC1
H2AX
Topotecan
Vehicle
Vehicle
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Immune checkpoints are molecules on the surface
of cells that can send inhibitory stimuli to attenuate
immune responses.21 Ongoing or endogenous responses
to tumour antigens can be suppressed either by block
ing the clonal expansion of high avidity clones (cyto
toxic Tlymphocyte antigen 4 [CTLA4]) or inducing
inhibition or exhaustion of antitumour responses (pro
grammed death1 [PD1]programmed death ligand1
[PDL1] axis). Antibodies directed against these immune
checkpoints have recently been shown to result in Tcell
activation and antitumour responses.21 The antiCTLA4
antibody, ipilimumab, is a fully humanized immuno
globulin monoclonal antibody approved by the US FDA
for the treatment of metastatic melanoma, on the basis
of results from randomized phaseIII trials that showed
improved overall survival following treatment with ipili
mumab versus cytotoxic chemot herapy.117 Although
important antitumour effects have been observed, treat
ment with antiCTLA4 antibodies can result in severe
immune-mediated adverse reactions caused by Tcell
inflammatory infiltration of solid organs, including
enterocolitis, hepatitis, dermatitis, cranial neuropathy,
and endocrinopathy that usually occur during treatment,
but can infrequently occur weeks after stopping treat
ment.118 Whether and how toxicities associated with cir
cumventing immunological checkpoints in normal tissue
can be ameliorated is an area of active investigation.
PD1 is a transmembrane molecule on immune cells
that upon stimulation results in the inhibition of the
immune response mediated by these cells. PDL1 and
PDL2 are the two chief ligands for PD1; engagement
with these molecules allows PD1 to exert its inhibi
tory effects. PDL1 is expressed widely on a variety of
immune cells as well as non-immune cells, and PDL1
upregulation can occur in normal tissues in the setting
of inflammatory pressure. PDL2 is mainly expressed on
antigen-presenting cells and dendritic cells. Antibodies
against PD1 and PDL1 that negate immune inhibi
tion are therapeutically active against a variety of solid
tumours.22 The antiPD1 antibody nivolumab produced
an overall response rate of 31% (primarily in patients
with NSCLC, melanoma, and renal cancer) during a
phaseI trial.119 The antitumour activity of antiPD1
antibodies has been confirmed in these same tumour
types, as well as ovarian cancer.120 Drug-related adverse
events in trials with antiPD1 or antiPDL1 antibodies
have also included immunologically-mediated rash,
thyroiditis, pneumonitis, andhepatitis.119
Over the past decade, there has been renewed interest
in vaccine-based cancer prevention and treatment strat
egies. Better understanding of human papillomavirus
(HPV) biology in the early 1990s121,122 was translated into
the development of a highly effective vaccine against the
major types of HPV associated with cervical neoplasia
(HPV16/18); the remarkable success of first-generation
HPV vaccines in preventing infection will undoubtedly
lead to the prevention of several HPV-related cancers,
including those of the cervix and head and neck. 123
The success of vaccine-based strategies has also been
seen in the development of early therapeutic vaccines
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18F-Oestradiol
PET-CT scan
SUV 8.6
SUV 1.5
Baseline
Day 6
Future prospects
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Clinically-annotated tumour/normal tissues
The standardization of tissue acquisition techniques,
from documentation of anoxic clamp times for surgi
cal specimens to the use of specific, uniform freezing
and fixation methodologies, is now an acknowledged
priority in pathology laboratories. The ease with
which human tumours can be perpetuated as PDXs,
with closely associated clinical histories, suggests that
many more human tumour specimens, including those
from patients enrolled on clinical trials, could become
more widely available to assist in studies of genomic
heterogeneity, the tumour microenvironment, and
cancer metabolismareas of investigation that would
benefit greatly from a proliferation of clinicallyannotated specimens that reflect the intact tumour
in its tissue context. As we understand how best to
collect human tumour specimens, we will also begin
to understand which specimens need to be obtained
under invasive (biopsy) or noninvasive (circulating
tumour cells/DNA) conditions to optimize individual
therapeuticprogrammes.
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that have been detected by sequencing of tumour DNA.
Over the coming decade, randomized trials (such as the
NCI MPACT and Lung-MAP studies), rather than nonrandomized (N of 1) efforts conducted without locked
down therapeutic algorithms, will address the usefulness
of broad panels of genomic predictors in a definitive
fashion. This is now becoming possible as regulatory
agencies in the US and Europe develop a greater degree
of comfort with the risks inherent in such trials and the
feasibility of using carefully validated multiplex genetic
testing to determine therapeutic choice. This approach,
which is just now being initiated for patients with
advanced-stage cancers, will likely become common
place in early stage disease, as the cost of genomic pro
filing continues to drop, especially when employed in
the context of rigorously-validated treatment algorithms.
The challenge of choosing which molecular targets to
investigate in the context of evolving genomic hetero
geneity will expand, rather than abate, until our ability to
interrogate large, aggregated data sets from mutationallyannotated clinical trials is dramatically improved. When
molecular characterization efforts from multiple tumour
sources in each patient are routine, it will be possible to
optimize combination approaches to driver pathways on
a patient-by-patient basis.
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