Transcript Webinar presentation () - The Cholangiocarcinoma Foundation

Of mice and men – Development of
a mouse model for intrahepatic
cholangiocarcinoma
Targeting BAP1 mutations in intrahepatic
cholangiocarcinoma
The Cholangiocarcinoma Foundation
March 30, 2016
Overview
Background
• Intrahepatic cholangiocarcinoma and BAP1
• How we study cancer
• Mouse models
• The KPC mouse
An example
ICC and
BAP1
• Existing ICC models
• BAP1 GEMM development
Overview
Background
• Intrahepatic cholangiocarcinoma and BAP1
• How we study cancer
• Mouse models
• The KPC mouse
An example
ICC and
BAP1
• Existing ICC models
• BAP1 GEMM development
Cholangiocarcinoma
Primary liver cancer
Develops from the bile ducts
Arises from the cells lining the bile ducts
Can arise anywhere in the biliary tree
•
•
•
•
Intrahepatic
Perihilar (Klatskin)
Extrahepatic
Gallbladder
Can arise anywhere in the biliary tree
•
•
•
•
Intrahepatic
Perihilar (Klatskin)
Extrahepatic
Gallbladder
Intrahepatic cholangiocarcinoma (ICC)
• Located within the liver
• Aggressive disease
• Incidence increasing in many Western countries
2016 Saha et al. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. The Oncologist. 21:1–6
Intrahepatic cholangiocarcinoma (ICC)
Genetics changes
contributing to the
development of ICC are
not fully understood
Mutations in many wellstudied genes have been
noted
Unique compared to
mutations in extrahepatic
cholangiocarcinoma &
gallbladder cancer
• Oncogenes: Kras, IDH1, IDH2
• Tumor suppressor genes: p53, BAP1,
PBRM1
Gene
Extrahepatic
Intrahepatic
2015 Teh et al Pathogenesis of CCA genetics to signaling pathways Best Practice & Research Clinical Gastroenterology 29, 233-44
Molecular alterations in ICC
BAP1
Encodes a protein
involved in DNA
remodeling
1. Renal cell carcinoma
2. Uveal melanoma
3. Malignant
mesothelioma
Studying cancer
• Discovery of tumor-specific targets, like
mutations in BAP1, is required to improve
detection and treatment of cancer at earlier
stages
• Cancer models helps make these discoveries
▫ In vitro models
▫ In vivo models
In vitro models
Limitations
• AnimalAdvantages:
and human cancer cell lines
• Used to study
how different pathways
in these
Selection when
Discovery of
adapting to in
molecular
cells work
vitro conditions
mechanisms
:
Controlled
conditions
Mutations can
arise over time
Homogeneity
Homogeneous
population
Reproducibility
No TME
In vivo models
• Animal models that mimic the natural history of
human cancers and their clinical response to
therapy
In vitro
In vivo
2014 Cekanova and Rathore. Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Design, Development and Therapy 8: 1911-22
Mouse models
Chemically-induced
mouse models of
cancer
Xenografts
Genetically engineered
mouse models
(GEMMs) of cancer
GEMMs
Carry mutations in genes that are associated with
specific human diseases → mimic the diseases
Can be used as experimental and preclinical
model systems
Classified as transgenic or endogenous
Questions?
Overview
Background
• Intrahepatic cholangiocarcinoma and BAP1
• How we study cancer
• Mouse models
• The KPC mouse
An example
ICC and
BAP1
• Existing ICC models
• BAP1 GEMM development
Pancreatic cancer
• Most commonly pancreatic ductal
adenocarcinoma (PDAC)
• Many things in common with ICC…
▫ Aggressive disease
▫ Increasingly common cause of death in the United
States
• Several GEMMs of pancreatic cancer have
been developed
The KPC mouse
• Expression of oncogenic Kras and mutant p53 in
all cells of the pancreas
GEMMs
Carry mutations in genes that are associated with
specific human diseases → mimic the diseases
Can be used as experimental and preclinical
model systems
Classified as transgenic or endogenous
The KPC mouse
• Expression of oncogenic Kras and mutant p53 in
all cells of the pancreas
2013 Harno et al. Metabolic pitfalls of CNS Cre-based technology. Cell Metabolism 18: 21-28
The KPC mouse
• Expression of oncogenic Kras and mutant p53 in
all cells of the pancreas
• Most widely used of all pancreatic cancer
GEMMs
• Genetically and histopathologically similar to
human pancreas cancer
Genetically similar…
Histopathologically similar…
2015 Gopinathan et al. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model & Mech 8, 1185-1200
The KPC mouse
• Expression of oncogenic Kras and mutant p53 in
all cells of the pancreas
• Most widely used of all pancreatic cancer
GEMMs
• Genetically and histopathologically similar to
human pancreas cancer
• Successfully used to study different strategies for
targeting PDAC including early detection,
prevention & treatment
Overview
Background
• Intrahepatic cholangiocarcinoma and BAP1
• How we study cancer
• Mouse models
• The KPC mouse
An example
ICC and
BAP1
• Existing ICC models
• BAP1 GEMM development
PDAC and ICC share many features
Multi-stage progression
from normal tissue to
invasive cancer
Tumors surrounded by
dense connective tissue
Early invasion and
spread
Late detection /
diagnosis → limited
treatment options
ICC cont.
Genetics changes
contributing to the
development of ICC are
not fully understood
Mutations in many wellstudied genes have been
noted
Unique compared to
mutations in extrahepatic
cholangiocarcinoma &
gallbladder cancer
• Oncogenes: Kras, IDH1, IDH2
• Tumor suppressor genes: p53, BAP1,
PBRM1
ICC cont.
Genetics changes
contributing to the
development of ICC are
not fully understood
Mutations in many wellstudied genes have been
noted
Unique compared to
mutations in extrahepatic
cholangiocarcinoma &
gallbladder cancer
• Oncogenes: Kras, IDH1, IDH2
• Tumor suppressor genes: p53, BAP1,
PBRM1
Current ICC GEMMs
1. Activating mutation of Kras + deletion of p53
▫
Multistage progression of ICC


▫
Premalignant biliary lesions
Development of stroma-rich tumors
Genetically & histopathologically faithful model
of ICC
2012 O'Dell et al. KrasG12D and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Res 72(6), 1557–67
Current ICC GEMMs
2. Activating mutation of Kras + mutant IDH2
▫ Multistage progression of ICC
 Liver cell expansion
 Premalignant biliary lesions
▫ Model of ICC that provides a functional link
between mutation and cancer
2014 Saha et al. Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer. Nature 513(7516), 110-4
ICC cont.
Genetics changes
contributing to the
development of ICC are
not fully understood
Mutations in many wellstudied genes have been
noted
Unique compared to
mutations in extrahepatic
cholangiocarcinoma &
gallbladder cancer
• Oncogenes: Kras, IDH1, IDH2
• Tumor suppressor genes: p53, BAP1,
PBRM1
ICC cont.
Genetics changes
contributing to the
development of ICC are
not fully understood
Mutations in many wellstudied genes have been
noted
Unique compared to
mutations in extrahepatic
cholangiocarcinoma &
gallbladder cancer
• Oncogenes: Kras, IDH1, IDH2
• Tumor suppressor genes: p53, BAP1,
PBRM1
Development of a new ICC GEMM
• Activating mutation of Kras + deletion of BAP1
Molecular alterations in ICC
BAP1
Encodes a
protein involved
in DNA
remodeling
Development of a new ICC GEMM
• Activating mutation of Kras + deletion of BAP1
Development of a new ICC GEMM
• Activating mutation of Kras + deletion of BAP1
• Multistage progression of ICC including
premalignant lesions
▫ Genetically and histopathologically faithful
Development of a new ICC GEMM
Development of a new ICC GEMM –
Future directions
• Activating mutation of Kras + deletion of BAP1
• Multistage progression of ICC including
premalignant lesions
▫ Genetically and histopathologically faithful
• Determine functional link between BAP1
mutations and ICC
• Use as a preclinical model to study different
strategies for detecting and treating ICC
Overview
Background
• Intrahepatic cholangiocarcinoma and BAP1
• How we study cancer
• Mouse models
• The KPC mouse
An example
ICC and
BAP1
• Existing ICC models
• BAP1 GEMM development
Conclusions
ICC is a cancer of the bile ducts that currently has limited
treatment options
BAP1 is involved in DNA remodeling and has an incompletely
understood role in ICC
GEMMs mimic human cancers
• Used as experimental & preclinical models
BAP1-mutant GEMMs can improve our understanding of ICC
• May result in improved detection and treatment of ICC in humans
Further questions
• Rebecca Marcus, MD
▫ [email protected]
• http://cholangiocarcinoma.org/
Thank you for attending
(and interacting)!
• A recording of this Webinar will be available at
http://cholangiocarcinoma.org/videos/
• Powerpoint slides also available online
References







Cekanova and Rathore. Animal models and therapeutic molecular
targets of cancer: utility and limitations. Drug Design,
Development and Therapy. 2014,8: 1911-22
Gopinathan et al. GEMMs as preclinical models for testing
pancreatic cancer therapies. Dis Model & Mech. 2015,8: 1185-1200
Harno et al. Metabolic pitfalls of CNS Cre-based technology. Cell
Metabolism. 2013,18: 21-28
O'Dell et al. KrasG12D and p53 mutation cause primary
intrahepatic cholangiocarcinoma. Cancer Research. 2012,72(6):
1557–67
Saha et al. Forty-Year Trends in Cholangiocarcinoma Incidence in
the U.S.: Intrahepatic Disease on the Rise. The Oncologist.
2016,21: 1–6
Saha et al. Mutant IDH inhibits HNF-4a to block hepatocyte
differentiation and promote biliary cancer. Nature.
2014,513(7516): 110-4
Teh et al Pathogenesis of CCA genetics to signaling pathways. Best
Practice & Research Clinical Gastroenterology. 2015,29: 233-44
BAP1
PBRM1