S229
ESTRO 36
_______________________________________________________________________________________________
Symposium with Proffered Papers: Novel approaches in
prostate tumour control
SP-0434 State of the art in prostate tumour
radiobiology
C. Peitzsch
1,2
1
OncoRay - Center for Radiation Research in Oncology,
University Hospital Carl Gustav Carus- Technische
Universität Dresden, Dresden, Germany
2
Nationales Centrum for Tumor diseases NCT- Dresden,
German Cancer Center DKFZ- Heidelberg, Dresden,
Germany
Prostate tumorigenesis is a multistep process from
intraepithelial
neoplasia
(PIN)
and
localized
adenocarcinoma, to castration-resistant prostate cancer
(CRPC) and further into an invasive and metastatic disease
stage with poor prognosis. Several driver and passenger
mutations e.g. within the androgen receptor (
AR
),
ETS
,
TP53
,
PTEN
,
BRCA1/2, CTNNB1
or
ATM
were identified, so
far, to be involved in this developmental process. Beside
this specific genetic features of prostate cancer cells,
cellular heterogeneity within prostate cancer describes
the observation that malignant cells differ within their
phenotypic features and functional properties. This tumor
heterogeneity and cellular plasticity of tumor cells are the
main driving forces for tumor growth, metastasis and
therapy resistance and can be explained by the cancer
stem cell (CSC) hypothesis in combination with clonal
evolution and epigenetic regulation. CSC-specific
molecular mechanisms of radioresistance mainly based on
increased DNA repair capacity, enhanced reactive oxygen
species (ROS) scavenging and induced epithelial-
mesenchymal transition (EMT) and is regulated e.g. by the
androgen-receptor
signaling,
the
tumor
microenvironment, growth factors and cytokines. Data
from our own group indicating that ionizing radiation
themself is modulating epigenetic mechanisms in prostate
cancer cells and thereby cellular plasticity. To translate
these basic research findings into clinically relevant data
primary model systems and mouse models can be used for
pre-clinical validation of radiosensitizer and biomarker
discovery.
SP-0435 Novel developments in molecular targeting of
prostate cancer
R. Bristow
1
1
Princess Margaret Cancer Centre University Health
Network, Radiation Oncology - Room 5-964, Toronto,
Canada
Prostate cancer (CaP) remains the most common male
malignancy worldwide. Although some localized cancers
can be indolent, others can manifest aggressive biology
with abnormal cancer metabolism and genetic instability.
These men need intensified treatment to prevent
metastatic castrate-resistant disease (mCRPC). Recent
studies have started to define the genomic landscape of
prostatic cancer heterogeneity in which mCRPC is
associated with increasing androgen receptor aberrations,
DNA repair deficiencies, mutations in PI3K and tumour
suppressor gene pathways, aberrant WNT-beta-catenin
signaling and defects in cell cycle control. For localized
disease amenable to radiotherapy,we have previously
shown that genetic instability and hypoxia are strong
prognostic factors for prostate cancer outcome.
Subsequently, we have gone on to analyze the whole-
genomes and methylomes of 194 men and the exomes of
479 men to discover multimodal genetic signatures for
responders and non-responders following precision
radiotherapy and surgery. We observed that intermediate
risk prostate cancers have a paucity of clinically-
actionable mutations; in distinct contrast to that reported
for mCRPC. However, all patients with an DDR-associated
ATM mutation failed therapy. A significant proportion of
tumours harbour recurrent non-coding aberrations,
important genomic rearrangements, and a novel
mechanism of PTEN inactivation whereby a local inversion
represses transcription of genes within its
boundaries. Chromothripsis and kataegis is evident in one
fifth of these tumours and can be associated with more
aggressive disease. Using driver mutations, copy-number
alterations and methylation, we were able to categorize
patients into prognostic categories which has less than 5%
or greater than 50% probability of relapse. The use of
genomic markers as prognostic factors for local failure and
for systemic disease are therefore novel risk-stratification
tools which help to triage patients to existing treatment
options, and potentially identification of molecular
targets for therapy. However, our data also suggest
that novel therapeutic approaches focus on recurrent non-
mutation targets. This new approach could then prevent
castrate-resistance by targeting genetic instability earlier
on the natural history of the disease when fewer driver
events are operational.
OC-0436 Cytokine-dependent regulation of prostate
cancer stem cell maintenance in response to
irradiation
C. Peitzsch
1,2
, M. Baumbach
1
, M. Cojoc
1
, L. Hein
1
, I.
Kurth
1,2
, M. Baumann
1,2,3,4,5
, M. Krause
1,3,4,5
, A.
Dubrovska
1,3,4
1
OncoRay - Center for Radiation Research in Oncology,
Faculty of Medicine and University Hospital Carl Gustav
Carus- Technische Universität Dresden, Dresden,
Germany
2
National Center for Tumor Diseases NCT, German
Cancer Research Center DKFZ, Dresden, Germany
3
German Cancer Consortium DKTK, German Cancer
Research Center DKFZ, Dresden, Germany
4
Institute of Radiation Oncology, Helmholtz-Zentrum
Dresden-Rossendorf, Dresden, Germany
5
Department of Radiation Oncology, Faculty of Medicine
and University Hospital Carl Gustav Carus- Technische
Universität Dresden, Dresden, Germany
Purpose or Objective
According to the cancer stem cell hypothesis prostate
cancer is driven by a malignant subpopulation with stem-
like properties. These cancer stem cells (CSC) contribute
to tumor-initiation, metastasis, therapy-resistance and
tumor relapse. In parallel, genetic mutations accumulate
over time and CSC subclones evolve. Therapeutic
interventions like radiotherapy provide selective pressure
for the expansion of resistant subclones with genetic
diversification. We hypothesize that the determination of
CSC-related biomarker in prostate cancer biopsies is
correlating with clinical parameter and can be used for
patient stratification and treatment selection to improve
personalized radiotherapy.
Material and Methods
We generated isogenic radioresistant prostate cancer cell
lines with a high expression of CSC marker, a epithelial-
to-mesenchymal transition (EMT) phenotype, higher self-
renewal properties, higher tumorigenicity and enhanced
DNA repair capacity. We applied comparative genomic,
proteomic, metabolomic, epigenomic and secretome
analysis to identify novel biomarker for prostate cancer
radioresistance and to unravel contributing molecular
mechanisms. Novel biomarkers were validated using the
Cancer Genome Atlas (TCGA) database and correlated
with the tumor-free survival of prostate cancer patients
after anti-cancer therapy including radiotherapy using
SUMO software calculation.
Results
Within our first proof-of-principle study, we could show
that ALDH-positive CSCs are radioresistant and maintained
directly by the Wnt/β-catenin signaling pathway. In