PrograMME and abstracts

Transcription

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PrograMME And AbstractS
Symposium
April 22 – 23, 2013
Hotel Bristol, Bonn, Germany
Organising Committee:
Jürgen Debus, Heidelberg
Markus Hohenfellner, Heidelberg
Roland Schüle, Freiburg
Günter Feick, Gehrden
Jens-Peter Zacharias, Gehrden
Franz Kohlhuber, Bonn
Deutsche Krebshilfe e.V.
Buschstr. 32
53113 Bonn
Tel: 02 28 / 7 29 90-0
E-Mail: [email protected]
Internet: www.krebshilfe.de
Symposium 'Challenges and Chances in Prostate Cancer Research' 1
Prostate Cancer
Research
Symposium
Symposium
April 22 – 23, 2013
Assisted by:
Stephanie Combs, Heidelberg
Boris Hadaschik, Heidelberg
Thomas Höfner, Heidelberg
Malte Schwardt, Freiburg
www.dkh-symposium-prostatakarzinom.de
2 Symposium 'Challenges and Chances in Prostate Cancer Research' Symposium 'Challenges and Chances in Prostate Cancer Research' 3
Deutsche Krebshilfe e. V.
German Cancer Aid
Introduction
German Cancer Aid is Germany’s leading non-governmental funding and non-profit-making organization of oncology-related activities. Based in Bonn, our core objectives are
to improve care for cancer patients, promote research and to heighten cancer awareness through information, education and public campaigns.
German Cancer Aid has decided to implement an international symposium focussing on
prostate cancer research. With this meeting, German Cancer Aid would like to provide
an impetus to current aspects of translational prostate cancer research as well as to
support multidisciplinary co-operations in the field, in order to strengthen prostate
cancer research in Germany.
German Cancer Aid was founded in 1974 and follows the motto „Helping. Researching.
Informing.“. We support research projects to improve prevention, diagnosis, therapy,
after-care and self-help. Fundamentally, all the projects supported are driven by high
levels of scientific quality and the potential for significant clinical impact, so that cancer patients rapidly benefit from new knowledge. We also invest in the training of future
generations of scientists and medical doctors.
But that is not our only task. We launch campaigns, organise information events and
offer brochures to inform the public about the various types of cancer. Awareness,
prevention and early detection are very important to us. Cancer patients get advice and
help. We support self-help associations and provide advanced training for those who
deal on a daily basis with cancer patients and their needs.
For almost 40 years, German Cancer Aid has been an important contact for health and
research politics. Because of its sustained work and the involvement of leading experts, it has enormous influence. It has made a major contribution to the improvement
in the care of cancer patients throughout Germany and has helped to ensure that the
voices of cancer patients are heard.
Please find further information about our numerous activities on www.krebshilfe.de or
contact us via e-mail: [email protected]
The major aims of the meeting are:
1. Survey of recent prostate cancer research in Germany
2. Identification of areas requiring further research
3. Discussion about possibilities of coordinated prostate cancer research
Recent results and developments of prostate cancer research will be presented by
national and international experts in the field. German Cancer Aid attaches special
importance to the participation of young scientists in this meeting. The Organisation
gratefully acknowledges the time and effort every participant dedicates to this meeting
and is looking forward to a high-level series of lectures and discussions.
Jürgen DebusMarkus Hohenfellner
Universitätsklinikum Heidelberg
German Cancer Aid Advisory Board
Roland SchüleFranz Kohlhuber
Universitätsklinikum Freiburg
German Cancer Aid, Bonn
Managing Director
4 Symposium 'Challenges and Chances in Prostate Cancer Research' Face the Challenges and changes
A Message of Caring
Dear participants,
Dear participants of the “Challenges and Chances in Prostate Cancer Research
Symposium”,
Prostate cancer continues to be a major public health problem in both industrialized and
developing countries worldwide. It is the most common cancer among men. In 2012 nearly 67.600 men were diagnosed with the disease in Germany – with upward tendency.
While significant progress has been made in understanding the genetics, behavioural
and environmental risk factors for prostate cancer, there still is a need for improved diagnostic tools and treatment options. Therefore it is as important today, as it has ever been,
for researchers and clinicians to come together to advance diagnosis and care for prostate
cancer.
The aim of this conference is to support networking among individuals involved in all
aspects of prostate cancer research and to facilitate the development of a scientific
community to address common challenges in prostate cancer. These challenges include
prevention, early detection, diagnosis, treatment and survivorship.
During the next two days, nationally and internationally recognized experts will share the latest results and developments in
state-of-the-art prostate cancer research. Focusing on opportunities and challenges in prostate cancer research, the symposium
is a chance for prostate cancer clinicians, scientists and other
professionals to meet, share their experience and ideas, and most
importantly combine their efforts in a friendly and collaborative
environment.
I hope that we will have a successful and enjoyable conference.
Yours,
Dr. h. c. Fritz Pleitgen
President of the German Cancer Aid
Your attendance as scientific and medical experts confirms your strong interest in the
research and treatment of prostate cancer. Your contributions to the symposium will
be regarded as a message of caring for the fate of all prostate cancer patients and their
families.
The German Self-Help Organization for Prostate Cancer (Bundesverband Prostatakrebs
Selbsthilfe e.V. BPS) attests to the need of coordinated research. Together with reputed
individuals and organizations we want to inspire scientists and physicians to organize
a structure so that qualified experts can work together. As patient representatives we
would like you to determine the unanswered questions, define the goals, and design
projects for collaboration.
All member organizations from 22 European countries organized in the European Prostate Cancer Patient Coalition Europe (UOMO) are united in asking you to please support
building a coordinated prostate cancer research program that will accelerate expansion
of knowledge and improvement of treatments.
The BPS thanks you for joining in this symposium.
Günter Feick Jens-Peter Zacharias
Chairman of the executive board BPS
Member of the executive board BPS
www.prostatakrebs-bps.de
6 Symposium 'Challenges and Chances in Prostate Cancer Research' ProgramME
03:40 pm
Imaging
Page 16
Nuclear medicine imaging in prostate cancer
Holger Palmedo, Germany
Monday, April 22
noon
Arrival of Participants, Refreshments
01:15 pmOpening remarks
Fritz Pleitgen, Bonn, Germany
The patient comes first
Louis Denis, Belgium
Page 10
01:30 – 04:10 pmSession 1
(chair: Thomas Wiegel, Ulm; Boris Hadaschik, Heidelberg)
01:30 pm
Epidemiology
Prostate cancer risk assessment model
Mahdi Fallah, Germany
02:00 pm
Tumor Banking
Biobanking
Markus Hohenfellner, Germany
02:30 pm
Tumor Banking
Translational prostate cancer research
in a high-volume center
Guido Sauter, Germany
03:00 pm
Imaging
Multi-parametric MRI in detection and
characterization of prostate cancer and
nano-fluid MR-lymph node imaging
Jelle O. Barentsz, Netherlands
Page 11
Page 12
Page 14
Page 15
04:10 pm
Coffee break
04:30 – 07:00 pm
Session 2 (chair: Sven Perner, Bonn; Thorsten Schlomm, Hamburg)
04:30 pm
Current clinical trials
German prostate screening trial
Peter Albers, Germany
Page 17
05:00 pm
Current Clinical trials
Ongoing prospective clinical phase III-trials
for non metastatic disease:
PREFERE and ART 2
Thomas Wiegel, Germany
05:30 pmBioinformatics
Computational analysis of prostate carcinoma sequencing data
Benedikt Brors, Germany
Page 18
06:00 pm
Bioinformatics
Generation and analysis of epigenomes
Thomas Manke, Germany
Page 19
06:30 pm
07:00 pm
International Cancer Genome Consortium – Page 20
Prostate cancer early onset
Genome research for the molecular
stratification of cancer
Holger Sültmann, Germany
Buffet
8 Symposium 'Challenges and Chances in Prostate Cancer Research' Tuesday, April 23
09:00 – 11:00 amSession 3
(chair: Bernd Wullich, Erlangen; Ulrich Wetterauer, Freiburg)
09:00 am
Translational research
Bridging the mind-to-market
gap: the Vancouver Prostate Centre
approach
Martin Gleave, Canada
Page 21
09:30 am
Translational research
Page 22
LSD1 coordinates migration and invasion
Roland Schüle, Germany
10:00 am
Biomarker
Adding the value of epigenetic biomarkers
Reinhard Büttner, Germany
Page 23
10:30 pm
Biomarker
Novel biomarkers for high-risk
prostate cancer – focus on
genomic instability
Stefan Duensing, Germany
Page 24
11:00 am
Coffee break
11:30 am – 02:00 pmSession 4 (chair: Louis Denis, Antwerp; Stefan Müller, Bonn)
11:30 am
Developments in radiotherapy
Jürgen Debus, Germany
noon
Active surveillance
Punctuated evolution of prostate cancer
genomes
Mark A. Rubin, USA
Page 25
00:30 pm
Active surveillance
A review of current evidence
Fritz Schröder, Netherlands
Page 26
01:00 pm
Complementary oncology
Physical activity and sports in prostate
cancer patients
Elke Jäger, Germany
01:30 pm
Complementary oncology
Integrative oncology – from patients‘
perspective to translational research
Jutta Hübner, Germany
Page 28
02:00 pmRefreshments
03:00 pmFinal discussion
03:30 pmConcluding remarks
Progress through cooperation: chances
and challenges in low-risk prostate cancer
research – the PREFERE study
Michael Stöckle, Germany
04:00 pmEnd of meeting
10 Symposium 'Challenges and Chances in Prostate Cancer Research' The Patient comes First
Louis J. Denis 1
The ever increasing incidence and prevalence of prostate cancer (PCa) remains a constant
threat to the male European population and a burden to social health care.
Despite improved diagnostic and management advances too many questions remain
unanswered leaving the patient unguarded with doubts and fears on his survival, quality
of life and cost-efficacy of new drug treatments, health technology and specific health
policies.
We face a triple challenge. How to provide the aging patient with personalized quality
care, controlled performance results and optimal management outcomes. Maybe the best
for the patient should be replaced by what is good for the patient.
How to reduce the burden for society by utilizing clear guidelines where possible and care
paths for long-term survivorship and prostate cancer clinical units. Treatment of the man
should precede over treatment of the cancer.
Last but not least, we do need a revision of our social health care to adapt to the ever
increasing lifespan, the constant advances in medical science and technology and a decreasing budget. Never will so few have to provide for so many. This will take an intergenerational debate and a concerted action of all stakeholders towards collaborative basic,
clinical and social research.
We, the messengers of the next generation of patients, are eager to participate in meeting
these challenges to secure their rights and defining our and their obligations.
The patients expect optimal medical treatment based on scientific evidence leading
to personalized treatment by a multiprofessional team. As important they expect
patient-centered holistic care. This includes psychological, social, financial and cultural
well-being for all citizens with possible preservation of health and participation in the
active society. An integrated health policy, related to the economical status, can lead to
improved quality of life for all citizens with respect to their individual lifestyle decisions
including the right for a dignified death.
1
Oncology Center Antwerp
Prostate Cancer Risk
assessment model
Mahdi Fallah 1
Many prostate cancer (PC) risk assessment models have been developed, however almost
none include familial history. It is also of clinical and public health interest to know who
would need the PC screening earlier than others and how many years earlier. The aim is to
produce a risk assessment model for PC based on familial background of related cancers.
976 859 independent index men aged ≥ 30 in year 1998 and their family members in the
Swedish Family-Cancer Database (FCD2010) were randomly divided into development
(60 %) and validation (40 %) datasets (follow-up = 10 years). The HR from Cox model was
used to extrapolate risk scores.
Specified scores were: for PC in situ at age < 60 years in index man, 5; for PC at age < 60
years in each first-degree relative (FDR), 15; for PC at age ≥ 60 years in each FDR, 10; for
PC at age < 60 years in each second-degree relative, 5; for breast cancer in each FDR, 2;
for oesophageal carcinoma in situ in index man, 2; and for oesophagus cancer in each
FDR, 2. Based on the findings, if the milestone age for a PC screening programme was
60 years or more, the recommended starting age for the men with the score-group 6-10
would be 54 years; score-group 11-15, 52 years; score-group 16-20, 50 years; scoregroup 21-25, 44 years; and for the score-group 26+ it should start before age 40. The concordance index in development and validation sets was 0.885 (95 % CI 0.883 to 0.888).
No significant difference was found between curves from development and validation
datasets (internally validated using twofold validation and bootstrapping).
The conclusion: Familial history of relevant malignancies can be used as risk factors to
estimate a man‘s prior risk of developing PC. The prostate cancer risk assessment model
could satisfactorily assess risk of developing prostate cancer.
1
German Cancer Research Center (DKFZ), Heidelberg
12 Symposium 'Challenges and Chances in Prostate Cancer Research' Biobanking
Markus Hohenfellner 1
„Biobanking“ describes the collection and storage of biomaterials such as tissues, blood,
plasma, cells, DNA, and urine for later use. Except for forensic biobanks, most biobanks
aim at improving our knowledge concerning the understanding, diagnostics and treatment options of diseases.
The research about widespread diseases is often conducted with so-called population
based biobanks. They store e.g. plasma samples from an epidemiologically defined yet
otherwise indiscriminate portion of the population. A current example of such a biobank
is described on http://www.nationale-kohorte.de. Disease-specific biobanks focus on the
research of e.g. different types of cancer by storing cancer tissue specimens along with
other biomaterials.
In any case requires the reasonable future use of stored biomaterials the diligent, systematic and prospective registering of general and clinical data of the subjects, who donated their biomaterials. The use of retrospective unstructured data does hardly justify the
enormous efforts of banking biomaterials. In the same way, as associated data have to be
of a standardized high quality, the quality of the stored biomaterials have to be defined
and controlled as well. This comprises the whole pathway from harvesting e.g. tissues,
confirming its histology, surveying the storage conditions and ensuring the retrieving
algorithms. Ideally, all of these methodological steps are organized through standard
operating procedures (SOP‘s).
As biobanks in general are considered as one of the „10 ideas changing the world right
now“ (quote: Time Magazine), an abundant number of them exist in developed countries.
In Europe, the largest project, the Biobanking and Biomolecular Resources Research
Infrastructure (BBMRI - http://www.bbmri.eu) is supported by the European Research
Infrastructure Consortium (ERIC) and forms a kind of logistic and scientific umbrella for
the participating nationally distributed individual biobanks. In Germany, numerous different institutions maintain different biobanks, which themselves form different networks,
which again may overlap each other. The same variant perspectives are true for the funding of these initiatives.
In summary, many or even most biobanks are an investment in the future. The hope is,
that in a distant day the combination of refined analytical tools as well as a critical mass
of soundly stored biomaterials and associated high-quality data allow to comprehend
the nature of diseases such as cancer, infections, neurodegenerative and cardiovascular
disorders among others. In fact, based on longer existing biobanking projects, there is
sufficient proof already today that this type of research bears the most rewarding scientific and clinical insights.
1
14 Symposium 'Challenges and Chances in Prostate Cancer Research' Translational Prostate Cancer
Research in a high-volume
Center
Guido Sauter 1, Thorsten Schlomm 2
The Martini Clinics in Hamburg performs more than 2200 prostatectomies per year.
Standard procedures include extensive frozen section analysis of surgical margins and an
extensive quality control system with annual questionnaires for all patients. These procedures together with high-volume surgeons result in the highest possible quality of clinical
care and make the clinics an optimal nucleus for translational prostate cancer research.
Our current prostate cancer tissue microarray (TMA) contains samples from 11,152
patients with detailed follow up-data including all PSA values and complete treatment
information. The associated molecular database includes more than 60 features including
gene copy number changes and protein expression data. Several molecular parameters
provide strong prognostic information, which is independent of pathologic parameters. The best prognostic information can be obtained by combining multiple molecular
features. For example, a classifier built from 27 biomarkers enabled a strong distinction
of prognostic groups even within Gleason 3+4 and 4+3 cancers. This demonstrates, that
relevant multiparametric prostate cancer prognosticators – as currently launched by several companies – are feasible. Cancer heterogeneity may represent a major obstacle for
routine molecular testing, and thus represents another research focus of our group. For
this purpose, entire prostates are frozen down in in 50-100 frozen tissue blocks per patient to enable heterogeneity studies using next generation sequencing and other „omics“
tools. To enable large-scale screening for heterogeneity of specific features, a novel TMA
platform was manufactured from hundreds of cancers. These heterogeneity TMAs contain
at least 10 different samples per tumor, each taken from a different cancer containing
tissue block. This novel tool enabled us to show that TMPRSS2-ERG fusions, earlier considered a tumor-initiating event, is almost always heterogeneous in prostate cancer.
1
2
Institute for Pathology, University Medical Center Hamburg-Eppendorf
Martini Clinics, University Medical Center Hamburg-Eppendorf
Multi-paramatric MRI in detection and characterization of
prostate cancer and nan0-fluid
MR-lymph node imaging
Jelle O. Barentsz 1
In selected populations multi-parametric (mp) MRI has shown to decrease detection of
insignificant PCa, increase the number of significant PCa, reduce the number of biopsy
needles, and improve the determination of the aggression. However, in the population
of men with elevated PSA prior to TRUS biopsy mp-MRI has not been investigated to full
extent yet. Therefore, the role of mp-MRI and future studies will be discussed.
MRI with using a nano-fluid (Combidex/Sinerem) has shown to be superior to detect small
(3 mm) lymph node (LN) metastases. By the end of this year this agent will become available again. Clinical efficacy studies investigating the combined role of the improved visualization and localization of these small LN metastases with focused –dose-painting- IMRT
are needed. Both the potential role of this nano-fluid and its guided localized therapies
will be presented and discussed.
1
University Medical Center Nijmegen
16 Symposium 'Challenges and Chances in Prostate Cancer Research' Nuclear medicine imaging in prostate cancer
German Prostate Screening Trial
Holger Palmedo 1
P. Albers 1, N. Becker 2, J. Gschwend 3, K. Herkommer 1,
M. Hohenfellner 4, B. Hadaschik 4, M. Kuczyk 5, F. Imkamp 5,
G. Antoch 4, G. Kristiansen 7, C. Arsov 1
To overcome the limitations of bone scintigraphy, new hybrid camera systems like SPECTCT and PET-CT are being investigated.
We have conducted a prospective study including 451 oncological patients with bone
scintigraphy to evaluate the diagnostic and clinical effects of the new technique SPECT-CT
on patients with suspected bone metastases due to prostate cancer.
Whole body SPECT-CT was performed in 81 % of patients. In the group of 406 evaluable
patients, clinical follow-up was used as the gold standard. Bone metastases were confirmed and excluded in 102 and 304 cases, respectively. In the total patient group (prostate
cancer and other cancer types), sensitivities, specificities, and negative and positive
predictive values on a per-patient basis for whole body scintigraphy, SPECT and SPECT-CT
were respectively 94 %, 78 %, 97 %, 59 %; 94 %, 71 %, 97 %, 53 %; and 96 %, 95 %,
99 %, 87 %. In all subgroups, specificity and positive predictive value were significantly
(p < 0.01) better with the use of SPECT-CT. Down staging of metastatic disease in prostate
cancer patients using SPECT-CT was possible in 29.5 % of cases. Further diagnostic imaging procedures for unclear scintigraphic findings were necessary in only 2 % of patients.
SPECT-CT improved diagnostic accuracy for defining the extent of multifocal metastatic
disease in 32 % of these cases.
We conclude that SPECT-CT has a significant effect on clinical management of prostate
cancer patients because of correct down-staging, better definition of the extent of metastases and reduction of further diagnostic procedures.
SPECT-CT might also be helpful in performing dosimetry studies in prostate cancer
patients receiving radionuclide therapy to treat bone metastases. For this purpose, new
radiopharmaceuticals like Rhenium-188 HEDP or Radium-223 chloride are currently under
investigation. For the diagnosis and therapy monitoring of vital prostate cancer tissue (not
only in bone but also in other organ systems), PET-CT with F-18 cholin plays an increasing
role. Additional radiopharmaceuticals (F-18 cholin, C-11 cholin, F-18 acetat, F-18 FACBC)
are studied.
Prostate cancer is the most commonly diagnosed cancer accounting for approximately
60,000 new cases every year in Germany. However, it is only the third common cause of
death from cancer. The widespread use of PSA as screening method for prostate cancer
has led to an increased incidence of prostate cancer which is accompanied by a shift
towards earlier stages of detected cancers. Despite encouraging data from large international PSA screening trials, general population based PSA screening cannot be recommended due to concomitant risk of overdiagnosis and overtreatment. Risk-adapted PSA
based screening strategies are potential tools to overcome this dilemma. The probability
to develop prostate cancer and more important to experience life-threatening disease
during lifetime is markedly decreased if the “baseline” PSA value is very low (< 1.6 ng/
ml) at age 44-50. For young men with a baseline PSA value below median (0.6 ng/ml),
two further PSA tests every 5 years would probably be sufficient to rule out the risk of
death from prostate cancer. The optimal age to begin a risk-adapted PSA screening with
screening intervals according to the level of the individual baseline PSA value has never
been evaluated in a prospective randomized trial. The present trial is the first randomized
trial to prospectively evaluate the concept of a baseline PSA. Furthermore, it is the first
trial to define the beginning of a risk-adapted screening either at age 45 or 50. In addition,
this trial will evaluate subsequent risk-adapted screening intervals according to the level
of the individual baseline PSA value. The main goal of the present trial is to demonstrate
the superiority of a delayed risk-adapted PSA screening beginning at age 50 (study arm
B) as compared to a risk-adapted PSA screening beginning at age 45 with respect to
the specificity of the screening. The detection of metastatic prostate cancer is the main
endpoint in a non-inferiority design (combined primary endpoint). The hypothesis is that
young men undergoing a risk-adapted PSA screening at age 50 do not more frequently
develop metastatic disease up to the age of 60 as compared to those men beginning a
risk-adapted PSA screening at age 45. The screening will end at age 60 with both groups
finishing 15 years of screening.
1
1 Clinic for Radiology and Nuclear Medicine, Bonn
Department of Urology, Düsseldorf University 2 German Cancer Research Center (DKFZ), Epidemiology, Heidelberg 3 Department of
Urology, Technical University Munich 4 Department of Urology, Heidelberg University 5 Department of Urology, Hannover University Department of Diagnostic and Interventional Radiology, Düsseldorf University 7 Department of Pathology, Bonn University
6 Symposium 'Challenges and Chances in Prostate Cancer Research' 19
18 Symposium 'Challenges and Chances in Prostate Cancer Research' Computational Analysis of Prostate Carcinoma Sequencing Data
Generation and Analysis of
Epigenomes
Benedikt Brors 1
Thomas Manke 1
Cancer genome sequencing has provided unique insight into genetic alterations that drive
cancer initiation and progression. In the German Early-Onset Prostate Carcinoma Consortium, which is part of the International Cancer Genome Consortium, we are focusing on
tumors from patients under the age of 50, which make up a rare population of prostate
cancer patients. The underlying hypothesis is that these cancers harbor only few mutations which are indicative of the tumor initiating processes. In line with this hypothesis,
we find a strong correlation between a patient‘s age and the number of somatic non-synonymous coding mutations in the tumor genome, and between tumor size and the number
of muations. Contrary to many other solid tumor types, structural aberrations seem to
play a major role in prostate cancer. In young patients, aberrations driven by dysregulated
androgen signaling are more prevalent than in patients of advanced age. In my talk, I will
provide an overview on compuational methods to infer genetic aberrations from tumor
sequencing data and present recent data on somatic alterations in prostate cancer.
Both genetic and epigenetic mechanisms play an important role for gene regulation and
chromatin architecture. Molecular alterations of the genome or the epigenome may provide important biomarkers for disease progression, prognosis and possible treatments.
As part of the German Epigenome Programme (DEEP) and the CRC „Medical Epigenetics“
(MEDEP), our group generates genome-wide reference maps for histone modifications
in various cell types and different conditions. In this talk I will describe challenges and
opportunities of deep-sequencing data generation, computational analysis and interpretation.
In particular I will present algorithms to identify functional elements in the genome, and
investigate their regulatory potential with a biophysical model of transcription factor
binding. In combination with a statistical approach, our framework also allows us to predict the mechanistic consequences of sequence variations and their effect on regulatory
networks.
References:
Bulut-Karslioglu A. et al.
A transcription factor-based mechanism for mouse heterochromatin formation. Nat Struct
Mol Biol. 2012 Oct;19(10):1023-30.
Thomas-Chollier M. et al.
Transcription factor binding predictions using TRAP for the analysis of ChIP-seq data and
regulatory SNPs. Nat Protoc. 2011 Nov 3;6(12):1860-9.
1
Division Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg
1
Max Plank Institute of Immunobiology and Epigenetics, Freiburg
20 Symposium 'Challenges and Chances in Prostate Cancer Research' Genome Research for the Molecular Stratification of Cancer
Holger Sültmann 1
In recent years, national and international high throughput projects, in particular the ICGC
and TCGA, have led to a substantial catalogue of genomic and epigenomic alterations in
cancer. However, it has also become clear that the molecular diversity of tumors is much
higher than previously anticipated, and that recurrent mutations associated with tumor
development or progression are rare. The challenge is to understand the basic principles
of this diversity, to identify the causal mutations (“drivers”) and to map these onto the
cellular processes promoting tumor progression in patient subgroups or even individuals.
The presentation will focus on recent results based on integrated genomic and epigenomic approaches for the molecular characterization of prostate tumors.
1
German Cancer Research Center (DKFZ) und National Center for Tumor Diseases (NCT), Heidelberg
Bridging the Mind-To-Market
Gap: the Vancouver Prostate
Centre Approach
Martin Gleave 1
The Vancouver Prostate Centre (VPC) is a translational cancer research facility that
integrates key components of translational research under one organization, facilitating seamless management of the complex processes involved in discovery, preclinical
development, and clinical research in close partnership with national clinical trials and
research networks as well as industry. Our mission is to serve as an academic-industry
hybrid research centre that fosters the paradigm of team-driven translational health
research. We aim to discover molecular mechanisms of cancer progression and therapeutic resistance, to use this information to discover new patent-protected drug products
and biomarkers, and develop new services and products to improve cancer outcomes and
promote regional growth of biotechnology.
The VPC is supported by 5 integrated core research platforms: Laboratory for Advanced
Genome Analysis, Molecular Pathology, Functional Genomics, Therapeutics Development, and Clinical Trials. Integrated management of our Core Platforms identify and functionalize genes associated with treatment resistance which are converted into targets and
products that, in turn, are out-licensed as value-added IP to biotech spin-offs. Contract
research agreements (CRAs) are then established for value-added pre-clinical and clinical
development of new therapies. This approach has led to discovery and patenting of
targeted inhibitors against 10 gene targets linked to treatment resistance. For example, 5
drug products were licensed to OncoGenex, which partners with VPC to leverage existing
resources, conduct proof-of-concept studies to expand use- and composition- patent
position, and add value to its early stage products. OGX-011, an inhibitor of clusterin, has
been tested in > 1000 patients with prostate, breast and lung with positive indicators of
anticancer activity in Phase II trials; 3 Phase III trials in prostate and lung cancer are now
underway. The Hsp27 inhibitor, OGX-427, is a 2nd drug licensed to OncoGenex leveraged
by VPC now in Phase II trials in bladder and prostate cancer, with exciting signals of anticancer activity. The VPC generates revenue through licensing fees and royalties, as well
as sales of its services, both of which support sustainable operations.
1
Vancouver Prostate Centre at the Vancouver General Hospital
22 Symposium 'Challenges and Chances in Prostate Cancer Research' LSD1 coordinates migration and
invasion
Adding the Value of Epigenetic
Biomarkers
Roland Schüle 1
Reinhard Büttner 1
Lysine specific demethylase 1 (LSD1) is linked to prostate cancer as it controls gene
expression and cell proliferation in an androgen-dependent manner. In contrast, only
little is known about the role of LSD1 in androgen independent metastatic prostate
cancer. Here, we show that RNAi-mediated knock down of LSD1 leads to increased
migration and invasion in androgen-independent prostate cancer cells. Genome-wide
cistrome and transcriptome analysis revealed LSD1 as a transcriptional regulator of
several genes associated with focal adhesions, including the adaptor protein paxillin
(PXN). Furthermore lysophosphatidic acid receptor 6 (LPAR6) is upregulated in LSD1
knock down cells. Subsequently, enhanced LPAR6-signalling leads to an increased
phosphorylation of PXN which is critical for focal adhesion turnover. By the use of two
different in vivo assays we demonstrate that overexpression of LPAR6 leads to an increase of metastasis, whereas knock down of LPAR6 remarkably abolishes the metastatic
potential of prostate cancer cells. Taken together, we uncovered a novel mechanism
how LSD1 controls metastasis and we identified LPAR6 which might serve as a promising therapeutical target for treating metastatic prostate cancer.
Histone methylating and demethylating enzymes have been characterized as important
regulators of gene expression programs and oncogenic signaling. In collaboration with
Professor Roland Schüle (University of Freiburg) we previously showed that the H3K4 and
H3K9 tri-Demethylase LSD1 acts as a context-dependent transcriptional coregulator both
in androgen-dependent and –independent prostate cancer. Our data provide clear evidence that LSD1 expression levels predict aggressive biology and poor clinical outcome
of prostate cancer.
More recently, collaborative research identified selective inhibitors for LSD1 monaminooxidase activity. These compounds provide novel therapeutic options for selective therapies of advanced prostate cancer. The value of measuring LSD1 expression levels will be
discussed.
1
1
University Medical Center Freiburg
Institute of Pathology, University of Cologne Medical Center
24 Symposium 'Challenges and Chances in Prostate Cancer Research' Novel biomarkers for high-risk
prostate cancer – focus on
genomic instability
Punctuated Evolution of
Prostate Cancer Genomes
Nina Korzeniewski 1, Yanis Tolstov 1, Maria Tapia-Laliena 1,
Sascha Pahernik 2, Boris Hadaschik 2, Markus Hohenfellner 2,
Stefan Duensing 1, 2
Mark A. Rubin 1
Prostate cancer genomes are unstable and harbor numerous numerical and structural
chromosomal aberrations. These include somatic mutations, copy number alterations,
gene fusions, complex chromosomal rearrangements and whole chromosome copy
number imbalances (aneuploidy). Some of these alterations have been shown to have
prognostic relevance and there is compelling evidence that genomic instability increases
with malignant progression. The development of this perplexingly broad spectrum of
genomic alterations can be reduced to two main cellular events: cell division and DNA
double strand break repair. Approaches to identify high-risk patients should hence
encompass not only genomic alterations detectable by next generation sequencing
and other methods but also include signaling pathways that are causatively involved in
their origin. Our laboratory has identified a number of signaling alterations that can fuel
genomic instability in prostate cancer. We found that the para-/autocrine growth factor
FGF-2 can rapidly disrupt mitotic fidelity of prostate cancer cells through CEP57, a centrosomal protein involved in intracellular trafficking and microtubule stabilization. We also
identified a number of mitotic regulators that are aberrantly expressed in prostate cancer
including Polo-like kinase 4 (PLK4), which is one of the most potent inducers of mitotic
defects reported. Overexpression of PLK4 was associated with an impaired biochemical
recurrence-free survival. While these aberrations mainly promote aneuploidy, we also
identified alterations that can contribute to structural chromosomal instability by interfering with accurate DNA break repair. For example, we detected a loss of BRCA1 protein
and mRNA expression in a proportion of prostate cancers that was significantly higher
than the reported frequency of BRCA1 germline mutations. In conclusion, characterization of the molecular defects underlying genomic instability in prostate cancer is likely to
yield numerous novel prognostic markers and potential therapeutic targets.
1
2
Molecular Urooncology, University of Heidelberg School of Medicine, Heidelberg
Department of Urology, University of Heidelberg School of Medicine, Heidelberg
The analysis of exonic DNA from prostate cancers has identified recurrently mutated
genes, but the spectrum of genome-wide alterations has not been profiled extensively
in this disease. We sequenced the genomes of 57 prostate tumors and matched normal
tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By implementing an algorithm to identify genomic alterations
that arise together, we found abundant sets of DNA rearrangements and deletions that
arise in a highly inter-dependent manner. This phenomenon, which we term “chromoplexy”, frequently accounts for the dysregulation of prostate cancer genes and can disrupt
multiple cancer genes coordinately or simultaneously. In prostate cancer and other
neoplasms, chromoplexy induces considerable genomic derangement over relatively few
events, supporting a model of punctuated cancer evolution. By characterizing the clonal
hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events
along which chromoplexy drives prostate carcinogenesis.
1
Weill Cornell Medical College, New York
26 Symposium 'Challenges and Chances in Prostate Cancer Research' Active surveillance –
a review of current evidence
Fritz Schröder 1
Active surveillance has become a common strategy in managing apparently low risk
prostate cancer. This strategy is based on recent evidence from epidemiological studies
showing how many more men diagnosed with prostate cancer die ‘with the disease’ than
‘of the disease’.
Why active surveillance?
Based on data from the European Randomized study of Screening for Prostate Cancer
(ERSPC) overdiagnosis was quantified according to age and screening procedures and
was estimated to amount to about 50 % in cancers diagnosed in men age 55-74 who have
undergone PSA testing. Obviously, if such men could be accurately identified they should
not be treated to avoid side effects and expenses of management.
Trigger points for treatment
Demonstration of clinical progression or progression on biopsy to either a higher Gleason
score or a larger tumor are uniformly agreed parameters. A short PSA doubling time is
(almost) generally accepted.
Outcomes
The main outcome parameters under study are PSA progression, clinical progression and
death from prostate cancer. Our understanding of the outcomes of active surveillance is
limited by follow-up periods which must be considered too short.
Conclusions
Active surveillance is a timely form of management which is used in men with prostate
cancer judged to be low risk. Available follow-up is too short to evaluate the most important outcomes, clinical progression and death from prostate cancer. The identification
of relatively high rates of upgrading and upstaging in radical prostatectomy cases who
choose treatment or progressed under active surveillance indicates that the present procedures used in active surveillance cannot be considered to be entirely safe.
Ongoing studies and inclusion criteria
A systematic review of active surveillance has identified six large ongoing studies which
all together have included more than 3,000 patients (Dall’Era MA et al 2012). Inclusion
criteria consider clinical stage (usually ≤ T2a), PSA values < 10-15, Gleason ≤ 3+4 (3+3 in
most studies) and less than two positive biopsy cores with small tumor volumes.
Follow-up criteria
Also criteria for follow-up are variable in the available large active surveillance studies.
Major points of discussion and controversy are the use of PSA kinetics, the frequency
of repeat biopsies, the number of necessary repeat biopsies, the role of age and the
frequency of follow-up in general The inclusion of MRI imaging is an option for future
improvement of the inclusion criteria, follow-up criteria and trigger points for treatment.
Information on the issue so far is very limited.
1
Erasmus University Medical Center Rotterdam
28 Symposium 'Challenges and Chances in Prostate Cancer Research' Integrative Oncology:
From patients‘ perspective to
translational research
Jutta Hübner
1
Complementary and alternative medicine is extensively used by cancer patients. Reviews
conclude that about 50 % of patients use CAM during course of disease. A recent German study reports up to 90 % of patients using CAM during radiotherapy. Our group has
confirmed these data in different settings. Also 70 % of patients in comprehensive cancer
centers as well as those taking part in a study use CAM, mostly substance bound and
mostly without talking about it to their oncologist.
The American Cancer Society defines alternative medicine as methods applied instead
of and complementary methods along with conventional therapies. The working group
Prevention and Integrative Oncology (PRIO) of the German Cancer Society underlines the
scientific evidence based approach of complementary medicine. In contrast, alternative
medicine denies the applicability of scientific research on CAM. CAM may have benefit for
patients but as well may result in side effects and interactions putting the patient at risk
of worse outcome and even death. Some proponents of conventional medicine therefore
advise to avoid CAM at all. We do not agree with this because of three reasons:
• First of all, CAM is a patient-centered approach which offers the opportunity of better coping.
• Second, patients advised or being afraid to be advised against CAM will avoid discussion but not refrain from using CAM
• Third, maybe some complementary methods offer benefits besides psychological effects.
CAM is perfect for translational research, as many substances have been characterized
molecularly. Mostly, preliminary preclinical data are available. Furthermore, for many
substances we have substantial data regarding clinical application and safety in noncancer patients. Yet, we urgently need additional data on cancer cells and cancer patients
and we have to assess safety issues very carefully.
1
German Cancer Society, Berlin
participants
Albers
Peter
Universitätsklinikum Düsseldorf
Germany
Al-Janabi
Omar
Universitätsklinikum Erlangen
Germany
Arencibia
Jose M.
Universitätsklinikum Frankfurt a. M.
Germany
Baniahmad
Aria
Universitätsklinikum Jena
Germany
Barentsz
Jelle O.
University Medical Center Nijmegen
Netherlands
Bartsch
Georg
Germany
Baur
Alexander
Charité - Universitätsmedizin Berlin
Germany
Beine
Birte
Ruhr-Universität Bochum
Germany
Biondi
Ricardo M.
Germany
Blettner
Gabriele
Klinikum der Landeshauptstadt Wiesbaden
Germany
Bochen
Florian
Universitätsklinikum des Saarlandes, Homburg/Saar
Germany
Braun
Martin
Universitätsklinikum Bonn
Germany
Breitbart
Eckhard W.
Elbe Klinikum Buxtehude
Germany
Brennan
Gwydion
Deutsche Krebshilfe e. V., Bonn
Germany
Brors
Benedikt
Deutsches Krebsforschungszentrum Heidelberg
Germany
Bruhn
Robin
Universitätsklinikum Aachen
Germany
Büttner
Reinhard
Klinikum der Universität zu Köln
Germany
Cato
Andrew
Karlsruher Institut für Technologie
Germany
Combs
Stephanie
Germany
Debus
Jürgen
Germany
Denis
Louis
Oncology Center Antwerp
Belgium
Drendel
Vanessa
Germany
Duensing
Stefan
Germany
Eckstein
Niels
Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn
Germany
Enderer
Klaus
Praxis für Dermatologie/Allergologie, Köln
Germany
Engelmann
David
Universitätsmedizin Rostock
Germany
Engenhart-Cabillic Rita
Universitätsklinikum Gießen und Marburg (Standort Marburg)
Germany
Erben
Philipp
Universitätsklinikum Mannheim der Universität Heidelberg
Germany
Fallah
Mahdi Deutsches Krebsforschungszentrum Heidelberg
Germany
Feick
Günter
Bundesverband Prostatakrebs Selbsthilfe e. V., Gehrden
Germany
Giersiepen
Klaus
Universität Bremen
Germany
Gleave
Martin
Vancouver Prostate Centre at the Vancouver General Hospital
Canada
Gottberg
Antje
GKV-Spitzenverband, Berlin
Germany
Greiner
Markus
Germany
Hadaschik
Boris
Germany
Haferkamp
Axel
Germany
Hammon
Matthias
Germany
30 Symposium 'Challenges and Chances in Prostate Cancer Research' participants
participants
Henkel
Corinna
Ruhr-Universität Bochum
Germany
Persigehl
Thorsten
Klinikum der Universität zu Köln
Germany
Herkommer
Kathleen
Technische Universität München
Germany
Planko
Laura
Germany
Höfner
Thomas
Germany
Pleitgen
Fritz
Germany
Hohenfellner
Markus
Germany
Queisser
Angela
Germany
Holleczek
Bernd
Ministerium für Justiz, Gesundheit und Soziales, Saarbrücken
Germany
Regier
Marc-Ulrich
Universitätsklinikum Hamburg-Eppendorf
Germany
Holmes
Emily Eva
Germany
Roobol
Monique J.
Erasmus University Medical Centre, Rotterdam
Netherlands
Hübner
Jutta
Deutsche Krebsgesellschaft, Berlin
Germany
Rubin
Mark
Weill Cornell Medical College, New York
USA
Jäger
Elke
Krankenhaus Nordwest, Frankfurt a. M.
Germany
Rüenauver
Kerstin
Germany
Jung
Maria
Germany
Santourlidis
Simeon
Germany
Kaulfuß
Silke
Universitätsmedizin Göttingen
Germany
Sauter
Guido
Germany
Kharazmi
Elham
Germany
Schilling
David
Germany
Kohlhuber
Franz
Germany
Schlomm
Thorsten
Germany
Kortmann
Rolf-Dieter
Universitätsmedizin Leipzig
Germany
Schoth
Felix
Universitätsklinikum Aachen
Germany
Korzeniewski
Nina
Germany
Schröder
Fritz
Erasmus University Medical Centre, Rotterdam
Netherlands
Kübler
Hubert
Technische Universität München
Germany
Schüle
Roland
Germany
Küffer
Stefan
Universitätsmedizin Göttingen
Germany
Schultze
Martin
Charité - Universitätsmedizin Berlin
Germany
Ladilov
Yury
Ruhruniversität Bochum
Germany
Schulz
Wolfgang
Germany
Lange
Tobias
Germany
Schwardt
Malte
Germany
Leuschner
Roland
BKK-Bundesverband, Berlin
Germany
Schwentner
Christian
Universitätsklinikum Tübingen
Germany
Lippuner
Max
Europa Uomo Switzerland, Lausanne
Switzerland
Stöckle
Michael
Germany
Ludwig
Svenja
Germany
Sültmann
Holger
Germany
Maier
Christiane
Universitätsklinikum Ulm
Germany
Taubert
Helge
Germany
Manke
Thomas
Max-Planck-Institut für Immunobiologie und Epigenetik, Freiburg Germany
Thiel
Stefan
Germany
Marienfeld
Ralf
Universität Ulm
Germany
Tolstov
Yanis
Germany
Meller
Sebastian
Germany
Tonak
Julia
Germany
Menon
Roopika
Germany
Turner
Jan
Germany
Merz
Constanze
Bonn
Germany
Uhl
Barbara
Universitätsklinikum Bonn Germany
Muders
Michael Helmut Universitätsklinikum Carl Gustav Carus der
von Hardenberg
Jost
Universitätsklinikum Mannheim der Universität Heidelberg
Germany
Technischen Universität Dresden
Germany
von Mäßenhausen Anne
Germany
Müller
Stefan C.
Germany
Wach
Sven
Germany
Neeb
Antje
Karlsruher Institut für Technologie
Germany
Wernert
Nicolas
Germany
Nettekoven
Gerd
Germany
Wetterauer
Ulrich
Germany
Nolte
Elke
Germany
Wiegel
Thomas
Universitätsklinikum Ulm
Germany
Nowak
Michael
Germany
Wullich
Bernd
Germany
Offermann
Anne
Germany
Yang
Cheng
Germany
Paprotka
Christine Deutsche Krebshilfe e. V., Bonn
Germany
Zacharias
Jens-Peter
Bundesverband Prostatakrebs Selbsthilfe e. V., Gehrden
Germany
Perner
Sven
Germany
32 Symposium 'Challenges and Chances in Prostate Cancer Research' Notes
Deutsche Krebshilfe e.V.
Buschstr. 32
53113 Bonn
Tel: 02 28 / 7 29 90-0
E-Mail: [email protected]
Internet: www.krebshilfe.de
Spendenkonto 82 82 82
Kreissparkasse Köln
BLZ 370 502 99
IBAN DE 23 3705 0299 0000 8282 82
SWIFT BIC COKSDE 33
Dresdner Bank Bonn
Konto Nr. 269 100 000
BLZ 370 800 40
Volksbank Bonn Rhein-Sieg eG
Konto Nr. 2 009 090 013
BLZ 380 601 86
PrograMME And AbstractS
Symposium
April 22 – 23, 2013

PrograMME and abstracts

Transcription

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