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6th International Symposium
on Translational Research
in Oncology
October 11-14, 2007
Dublin, Ireland
This program is supported by educational grants from
6th International Symposium
on Translational Research
in Oncology
Dennis J. Slamon, MD, PhD
Chief, Division of Hematology/Oncology
David Geffen School of Medicine at UCLA
Los Angeles, California
John Crown, MD, MPH
Head, Medical Oncology Research
St Vincent’s Hospital
Elm Park
Dublin, Ireland
Image crop is 3.5 x 5
6th International Symposium on Translational Research in Oncology
Program Overview
Now in its sixth year, this annual symposium has a firmly
established reputation as a premier meeting at which the world’s
leading researchers gather to present and discuss new directions
in oncology research with a focus on translating the most recent
laboratory developments into improved clinical outcomes for
cancer patients. Under the direction of John Crown, MD, MPH,
and Dennis J. Slamon, MD, PhD, the program includes didactic
presentations and interactive discussions. Faculty are carefully
selected from among the researchers at the forefront of the
translational work in the topic, whether from academia,
government, or industry. The program encourages networking and
interaction between the attendees and the renowned faculty
members.
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6th International Symposium on Translational Research in Oncology
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
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
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
We are grateful to Hasan Korkaya, DVM, PhD, the chair of the session, who
aided in the preparation of this slideset.

We are also grateful to the speakers in the session who gave us permission to
use a select group of their slides from the meeting to make this slideset
possible: Michael Lahn, MD; James Carmichael, MD; Marian L. Waterman,
PhD; and Hasan Korkaya, DVM, PhD.
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clinicaloptions.com/oncology
Session VII: Malignant Stem Cells
as Targets in Oncology
Hasan Korkaya, DVM, PhD
Research Fellow
Internal Medicine
Hematology/Oncology
University of Michigan
Ann Arbor, Michigan
The Role of TGF-β in
Translational Medicine
6th International Symposium on Translational Research in Oncology
Cancer Stem Cell Concept
 In 1867, Cohnheim proposed that cancer originates from
stem cells because of similarities between fetal
development and certain types of tumors such as
teratocarcinomas[1]
 Although the heterogeneity of tumor cells was known,
Cohnheim’s hypothesis was not confirmed until 1994
when Lapidot and colleagues reported that acute myeloid
leukemia is maintained by a rare population of stem cells[2]
1. Cohnheim J. Path Anat Physiol Klin Med. 1867;40:1-79.
2. Lapidot T, et al. Nature. 1994;367:645-648.
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6th International Symposium on Translational Research in Oncology
Cancer Stem Cell Concept:
Tumor Resistance
 The cancer stem cell concept may explain why
conventional therapies fail and provides molecular
targets for the effective treatment of advanced tumors
 Researchers are actively studying how to target cellular
self-renewal and differentiation pathways[1,2]
1. Shugar RC, et al. Gene Ther. 2007;Nov 8:[Epub ahead of print].
2. Korkaya H, et al. BioDrugs. 2007;21:299-310.
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6th International Symposium on Translational Research in Oncology
Cancer Stem Cells:
Malignant Transformation

Malignant transformation of tissue stem cells is believed to result from
dysregulation of self-renewal pathways including
– PI3K-Akt[1,2]
– Wnt/-catenin[3]
– TGF-[4,5]
– Tumor suppressor proteins: p53 and PTEN[6]

The deregulation of such pathways has been reported in a number of
malignancies including breast, colon, and prostate cancer
1. Takahashi K, et al. Biochem Soc Trans. 2005;33:1522-1525.
2. Welham MJ, et al. Biochem Soc Trans. 2007;35(pt 2):225-228.
3. Tannishtha R, et al. Nature. 2005;434:843-850.
4. Ruscetti FW, et al. Oncogene. 2005;24:5751-5763.
5. Fortunel NO, et al. Blood. 2000;96:2022-2036.
6. Korkaya H, et al. BioDrugs. 2007;21:299-310.
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6th International Symposium on Translational Research in Oncology
Signal Transduction of TGF-ß
TGF-ß ligands
Receptor
Receptor
type II
type I
P
P
Smad 2,3
Smad
4
P
P
P
Gene transcription
or repression
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6th International Symposium on Translational Research in Oncology
TGF- in Cancer: Introduction

Many advanced tumors have abrogated the TGF- growth inhibitory pathway

Overexpression of TGF- has been observed in
– Breast cancer
– Prostate cancer
– Colon cancer
– Lung cancer

TGF- overexpression correlates with poor prognosis in many tumor types

Preclinical antitumor efficacy has been observed in mouse models with
TGF-–neutralizing antibodies, soluble receptors, and small-molecule kinase
inhibitors targeting the TGF-RI kinase
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6th International Symposium on Translational Research in Oncology
TGF- in Cancer: Tumorigenesis
Normal
epithelium
Carcinoma
in situ
Invasive
carcinoma
Tumor cells
Metastasis
Growth
factors
T cells
Fibrosis
Immune
suppression
EMT
TGF-
TGF-
TGF-
IL-11
PTHrP
Bone
osteolysis
Smooth
muscle
VEGF
CTGF
Vessels
angiogenesis
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TGF-–Associated Therapeutic Targets
AP-12009
AP-11014
TGF- mRNA
Vaccine NovaRx
TGF-
TGF-
SR2F
PKB/Akt
TGF- DNA
Lerdelimumab
Metelimumab
GC-1008
TGF-
P II I P
PI3
RhoA
JNK
P
P
SMAD2/3
Cytoplasm
SMAD2/3 P
LY580276
SB-505124
SD-208
TAK1
p38
Ras
SMAD4
ERK1,2
Nucleus
TF
Lahn M, et al. Expert Opin Investig Drugs. 2005;14:629-643.
TF
Target gene expression
6th International Symposium on Translational Research in Oncology
TGF- Inhibitors: Clinical Investigation
Overview
Compound
Company/
Sponsor
Preclinical
Antitumor Activity
Clinical Studies
Antisense Oligonucleotide
AP 12009
Antisense
Pharma
Glioblastoma
Pancreatic cancer
Phase I/II in
glioblastoma
AP 11014
Antisense
Pharma
NSCLC
Prostate cancer
Colon cancer
N/A
NovaRx
Glioblastoma
Phase I/II in
glioblastoma
Phase I/II in NSCLC
NovaRx
Lahn M, et al. Expert Opin Investig Drugs. 2005;14:629-643.
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6th International Symposium on Translational Research in Oncology
TGF- Inhibitors: Clinical Investigation
Overview (cont’d)
Compound
Company/Sponsor
Preclinical
Antitumor Activity
Clinical Studies
Large-Molecule Inhibitors
Lerdelimumab
CAT
N/A
N/A
Metelimumab
CAT/Genzyme
N/A
N/A
GC-1008
CAT/Genzyme
N/A
Phase I
NCI/NIH
N/A
N/A
SR-2F
Small-Molecule Inhibitors
LY2157299
Eli Lilly & Co
Breast cancer
NSCLC
Ongoing phase I study
SB-505124
GlaxoSmithKline
N/A
N/A
Biogen
Mesothelioma
N/A
Scios
Glioblastoma
Multiple myeloma
N/A
SM16
SD-208
Lahn M, et al. Expert Opin Investig Drugs. 2005;14:629-643.
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6th International Symposium on Translational Research in Oncology
Patient Selection Strategies
 Patients with activated pSMAD in circulation or high levels
of TGF-1
– Study JBAG: nondrug interventional trial to determine
pharmacodynamic markers for future application in drug
trials of LY2157299
– Patients with skeletal metastasis
– Evaluation of pSMAD expression in PBMCs
– Evaluation of TGF-1 levels
 Patients with a specific gene expression profile based on
their original tumor biopsy (data not shown)
Lahn M, et al. Expert Opin Investig Drugs. 2005;14:629-643.
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6th International Symposium on Translational Research in Oncology
TGF-β in Cancer: Conclusions
 TGF- inhibitors may be appropriately used in patients
with advanced metastatic malignancies
 Nonclinical data can be applied to establish PK/PD models
and reduce the uncertainty in phase I studies
 Baseline patient selection methods may be used to further
optimize the role of TGF- inhibitors either as single
agents or in combination with other anticancer drugs
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PARP Inhibition
6th International Symposium on Translational Research in Oncology
Targeting DNA Repair in Oncology:
Rationale
DNA damage frequently occurs in all cells
Why is DNA
repair a good
target?
DNA repair defects lead to increased
cancer susceptibility and increased
sensitivity to DNA-damaging agents
Normal cells have multiple DNA repair
pathways but some are lost in cancer cells
Inhibiting DNA repair in cancer cells that have
impaired repair pathways leads to selective
cell killing and an increased therapeutic ratio
Novel targeted therapeutic approach
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6th International Symposium on Translational Research in Oncology
Types of DNA Damage and Repair
Type of
damage:
Repair
pathway:
Singlestrand
breaks
Doublestrand
breaks
Base Recombinational
repair
excision
repair
HR
Repair
enzymes:
O6Bulky
alkylguanine
adducts
Insertions
and deletions
Mismatch
repair
NucleotideDirect
excision
reversal
repair
NHEJ
PARP ATM DNA-PK
XP,
poly- MSH2, AGT
merases MLH1
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6th International Symposium on Translational Research in Oncology
PARP and Base Excision Repair
DNA damage
PARP
NAD+
poly(ADP-ribose)
PARP recruitment
PARP activation and
assembly of repair factors
PARP
PARG
PARP
XRCC1
LigIII
pol β
PAR degradation via PARG
PNK 1
XRCC1
LigIII
PNK 1
End processing,
gap filling, and ligation
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6th International Symposium on Translational Research in Oncology
Targeted Killing of Cancer Cells With
Defective DNA-Repair Mechanisms
Double-stranded break
Cancer cell with
defective repair
Normal cell
Repair by HR
pathway
Survival
BRCA deficient or
deficiency of other
HR proteins
No repair
(No HR pathway)
Cell death
Exploits inherent weakness of cancer cells that have
defective DNA repair
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6th International Symposium on Translational Research in Oncology
Inhibition of DNA Repair in Cancer
Cells
AB
Loss of repair pathway
B
AB
Genomic instability
Tumor cell
Healthy cell
B
AB
Pathway B inhibitor
Death
Survival
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6th International Symposium on Translational Research in Oncology
DNA Repair Inhibitors in Cancer Cells:
2 Modes of Action
 Potentiation
– Inhibition of DNA repair following DNA-damaging agents
– Original hypothesis
 Synthetic lethality
– Selected cancer cells lose DNA repair pathways, whereas
normal cells remain unaffected
– Targeting these defective cells may cause selective cell kill
with an increased therapeutic ratio
– May allow for a novel targeted approach to cancer treatment
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StrongResearch
familyinhistory
6th International Symposium on Translational
Oncology
Ovarian BRCA1-/23 mm
clinicaloptions.com/oncology
Unpublished data.
6th International Symposium on Translational Research in Oncology
Hereditary Ovarian Cancer:
Responses and CA-125 Levels
BRCA1 185delAG mutation
1400
300
1000
PR+
CA-125 (U/mL)
600
0
50
100
150
-100
-250
-150
5000
4000
3000
2000
1000
-40
-20
50
100
-20
BRCA1 185delAG mutation
200
PR+
79% decline*†
50
150
150
BRCA1 4184delTCAA mutation
93% decline*
-50 0 50
0
20
16
40
60
80
100
120
BRCA1 4693delAA mutation
12
8
PR
36% decline
0
20
40
*GCIG CA-125 response.
(Rustin G, et al. J Clin Oncol. 2004;22:4035-4036)
†Ongoing response.
Unpublished data.
0
150
PR
50
-350
-50
250
350 Family history
150
76% decline*†
100
200
250
SD+
200
98% decline*†
200
-100 -50
BRCA1 185delAG mutation
400
60
80
100 -20 -10
PR+
4
Nonsecretor†
0
10
20
30
40
50
60
Days
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The Role of HER2 in Regulating
Cancer Stem Cell Self-Renewal
6th International Symposium on Translational Research in Oncology
HER2 in Malignant Transformation of
Mammary Epithelium
 HER2 is amplified in 20% to 30% of human breast cancers
and is associated with a poor clinical outcome[1]
 Although trastuzumab produces significant clinical benefit
in the treatment of HER2-amplified breast tumors, one
third of patients do not respond to trastuzumab and a
majority of initial responders demonstrate disease
progression within 1 year of treatment[2,3]
1. Slamon DJ, et al. Science. 1989;244:707-712.
2. Miller KD. Oncologist. 2004;9(suppl 3):16-19.
3. Seidman AD, et al. J Clin Oncol. 2001;19:2587-2595.
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6th International Symposium on Translational Research in Oncology
Potential Mechanisms of Trastuzumab
Resistance
 Cell signaling pathways, including PTEN, PI3K/Akt, and
IGF-I, have been implicated in the resistance of breast
tumors to trastuzumab therapy
 The mechanism of resistance is not well understood
Nagata Y, et al. Cancer Cell. 2004;6:117-127.
Chan CT, et al. Breast Cancer Res Treat. 2005;91:187-201.
Grothey A, et al. J Cancer Res Clin Oncol. 1999;125:166-173.
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6th International Symposium on Translational Research in Oncology
Malignant Transformation of Mammary
Stem Cells
Wnt/-catenin
Notch, Hedgehog
Bmi-1
Self renewal
HER2
PI3-K/Akt
SC
SCSC
PTEN
Cancer stem cell
p53
SC
Mutations,
deregulation of pathways
Early progenitor cells
Cancer stem cell
ER+
Progenitor cells
Differentiation
Myoepithelial cells
Alveolar epithelial cells
Ductal epithelial cells
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6th International Symposium on Translational Research in Oncology
Advanced Tumors: Targeting and
Elimination of Cancer Stem Cells
Normal stem cell
CSC
Dead CSC
Differentiated cell
Dead cell
Tumor
regrowth
Tumor shrinkage
CSC targeted
therapies
Conventional
therapies
Elimination
Elimination
of tumor
of CSCs
Differentiation
of CSCs
Elimination
of tumor
Korkaya H, et al. BioDrugs. 2007;21:299-310.
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6th International Symposium on Translational Research in Oncology
Identifying Cancer Stem Cells in
Tumors
Tumor Type
Acute myeloid leukemia
Breast
Brain
Colon
Head and neck
Prostate
Metastatic melanoma
Colorectal
Pancreatic
Lung adenocarcinoma
Bone sarcoma
Tang C, et al. FASEB J. 2007;11:[Epub ahead of print].
Cell Surface Markers
CD34+CD38CD44+CD24-ESA+
CD133+
CD133+
CD44+
CD44+
CD20+
EpCAMhighCD44+CD166+
CD24+CD44+ESA+
Scal+CD45-Pecam-CD34+
Strol+CD105+CD44+
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6th International Symposium on Translational Research in Oncology
GFP
HER2
HER2 Increases Mammosphere
Formation in Normal Mammary Cells
HER2
Suspension culture counts
Tubulin
HER2
400
DsRed Control
HER2
350
300
250
200
150
100
50
0
1
Unpublished data.
GFP
2
# passages
3
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6th International Symposium on Translational Research in Oncology
HER2 Expression in NMEC Cells
Increases Outgrowths in Mice
H&E
H&E
SMA
Ki67
HER2
DsRed
10x
40x
Cell #
Unsorted
Aldefluor Positive
Aldefluor Negative
Constructs
10,000
5000
5000
500
250
5000
250
DsRed
8
2
4
0
0
0
0
HER2
23
11
53
5
3
0
0
Unpublished data.
clinicaloptions.com/oncology
6th International Symposium on Translational Research in Oncology
Aldefluor-Positive Cells (%)
HER2 Overexpression Expands
Aldefluor-Positive Cell Populations
40
35
30
25
20
15
10
5
0
MCF7DsRed
Unpublished data.
MCF7- Sum149- Sum149- Sum159- Sum159HER2
DsRed
HER2
DsRed
HER2
clinicaloptions.com/oncology
6th International Symposium on Translational Research in Oncology
Tumor Initiation by Aldefluor-Positive
Breast Cancer Cells
Primary tumor
Sum159-HER2
Cells
Aldefluor
-
0.08%
36%
+
HER2
DEAB inhibited
Secondary tumor
0.1%
Unpublished data.
DEAB inhibited
37%
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6th International Symposium on Translational Research in Oncology
ALDH+
ALDH-
140
120
100
80
60
40
20
0
MCF7DsRed
Unpublished data.
MCF7HER2
Invading Cells/Well
Invading Cells/Well
Invasive Potential Observed With
Aldefluor-Positive Breast Cancer Cells
ALDH+
ALDH-
800
700
600
500
400
300
200
100
0
SUM159DsRed
SUM159HER2
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6th International Symposium on Translational Research in Oncology
Trastuzumab Treatment: Resistant and
Sensitive Breast Cancer Cell Lines
Aldefluor-Positive Cells (%)
40
Trastuzumab Trastuzumab+
35
30
25
20
15
10
5
0
Sum159DsRed
Unpublished data.
Sum159HER2
MDA-MB453
JIMT-1
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6th International Symposium on Translational Research in Oncology
Akt Phosphorylation of Resistant and
Sensitive Breast Cancer Cell Lines
MDA-MB-453
Trastuzumab
-
+
Sum159-HER2
-
+
pHER2
HER2
pAkt
Tubulin
Unpublished data.
clinicaloptions.com/oncology
6th International Symposium on Translational Research in Oncology
Embryonic and Adult Stem Cell SelfRenewal and Maintenance
 The PI3K/Akt pathway is important for the survival and
maintenance of pluripotent embryonic stem cells[1]
 This pathway also plays a role in adult stem cell selfrenewal[2]
 Increased Akt activation appears to mediate the resistance
of cancer stem cells to chemotherapy[3]
1. Takahashi K, et al. Biochem Soc Trans. 2005;33(pt 6);1522-1525.
2. Welham MJ, et al. Biochem Soc Trans. 2007;35(pt 2):225-228.
3. Ma S, et al. Oncogene. 2007;[Epub ahead of print].
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The Wnt/Beta-Catenin Pathway
6th International Symposium on Translational Research in Oncology
Cancers Linked to Aberrant Wnt
Signaling
Overexpression of Wnt ligands
Overexpression of frizzled receptors

Colon cancer

Colon cancer

Breast cancer

Breast cancer

Melanoma

Head and neck cancer

Head and neck cancers

Gastric cancer

Lung cancers

Synovial sarcoma

Gastric cancer
Loss of APC function

Mesothelioma

Colon cancer

Barrett’s esophagus

Barrett’s esophagus
Barker N, et al. Nat Rev Drug Discov. 2006;5:991-1014.
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6th International Symposium on Translational Research in Oncology
Cancers Linked to Aberrant Wnt
Signaling (cont’d)
-catenin gain-of-function
Other Wnt signaling components

Colon cancer

Colon cancer

Gastric cancer

Mesothelioma

Hepatocellular cancer

Cervical cancer

Hepatoblastoma

Bladder cancer

Wilms’ tumor

Prostate cancer

Endometrial ovarian cancer

Breast cancer

Adrenocortical tumors

Leukemia

Pilomatricoma

Non-small-cell lung cancer
Loss of Axin 1/2 function

Colon cancer (microsatellite instability)

Hepatocellular cancer

Hepatoblastomas
Barker N, et al. Nat Rev Drug Discov. 2006;5:991-1014.
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6th International Symposium on Translational Research in Oncology
Wnt Signaling and Stem Cells

Hematopoietic stem cells
– Self-renewal of HSCs, HSC proliferation[1,2]

Intestinal epithelial cells
– TCF-4 necessary for stem cell compartments in mouse intestine[3]

Skin
– -catenin overexpression causes higher density of hair follicle formation[4]
– Deletion of -catenin or LEF1 eliminates hair follicles[5]

Wound repair

Follicular neogenesis in skin after wound repair is dependent on Wnt
signaling[6]
1. Reya T, et al. Nature. 2003;423:409-414. 2. Willert K, et al. Nature. 2003;423:448-452.
3. Korinek V, et al. Nat Genet. 1998;19:379-383. 4. Gat U, et al. Cell. 1998;95:605-614.
5. Huelsken J, et al. Cell. 2001;105:533-545. 6. Ito M, et al. Nature. 2007;447:316-320.
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6th International Symposium on Translational Research in Oncology
Wnt Signal Transduction
E-cadherin
GSK3 CK1
APC WTX
Axin
-catenin
LEF/TCF
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
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6th International Symposium on Translational Research in Oncology
Wnt Signaling and Cancer Stem Cells
Chronic myelogenous leukemia: Wnt signaling increases self-renewal capacity
in blast crisis and in imatinib-resistant cancers; increases in nuclear -catenin and
LEF1 have also been detected
-catenin
-catenin
Blast crisis granulocyte
macrophage precursors
CML stem
cells
Multipotent
progenitors
Jamieson CH, et al. N Engl J Med. 2004;351:657-667.
Blasts
Pro-T cells
T cells
Pro-B cells
B cells
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6th International Symposium on Translational Research in Oncology
Wnt Signaling: Mechanism of Action
and Biological Outcome
 Treatment of mES cells (no feeder layer, no serum) with Wnt3a
plus IQ-1 enabled long-term culture of embryoid bodies (48
days) with maintenance of pluripotency
Miyabayashi T, et al. Proc Natl Acad Sci U S A. 2007;104:5668-5673.
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6th International Symposium on Translational Research in Oncology
Targeting Wnt Signal Transduction
 NSAIDs reduce levels of -catenin in adenomatous polyps
and colon cancer cell lines
– aspirin, indomethacin, sulindac
– rofecoxib, celecoxib, valdecoxib
– NO-ASA (NO-releasing aspirin)
?
-catenin
Barker N, et al. Nat Rev Drug Discov. 2006;997-1014.
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6th International Symposium on Translational Research in Oncology
Small-Molecule Inhibitors
-catenin/TCF interactions - HTS of natural compounds
LEAD
IC50
PKF115-584
3.2 M
PKF222-815
4.1 M
CGP049090
Lepourcelet M, et al. Cancer Cell. 2004;5:91-102.
8.7 M
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6th International Symposium on Translational Research in Oncology
Stem Cell Differentiation in Intestine
Differentiation:
Goblet cells
Enterocytes
Enteroendocrine
Progenitor cells
Ki-67
positive
Stem cells
Differentiated
Paneth cells
Wnt Notch
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6th International Symposium on Translational Research in Oncology
Stem Cell Differentiation Pathways in
Intestine
Differentiation:
Goblet cells
Enterocytes
Enteroendocrine
Notch
?
Progenitor cells
Stem cells
Differentiated
Paneth cells
Wnt
Wnt
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6th International Symposium on Translational Research in Oncology
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Analysis panel discussions exploring clinical implications
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