michael birrer ian mcneish new developments in biology and targets of epithelial ovarian cancer
TRANSCRIPT
Michael BirrerMichael Birrer
Ian McNeishIan McNeish
New Developments in Biology andTargets of
Epithelial Ovarian Cancer
Ovarian CancerOvarian CancerHistoric PerspectiveHistoric Perspective
All serous tumors thought to arise from surface All serous tumors thought to arise from surface epithelium/inclusion cysts.epithelium/inclusion cysts.
75%75% patients present with advanced stage disease. patients present with advanced stage disease. 80%80% respond to chemotherapy. respond to chemotherapy. Vast majority of patients relapse and eventually develop Vast majority of patients relapse and eventually develop
drug resistant disease.drug resistant disease. MinimalMinimal increase in overall survival over last 30 years. increase in overall survival over last 30 years. All patients treated with surgery and chemotherapy.All patients treated with surgery and chemotherapy.
Integrating the models of Integrating the models of serous carcinogenesis – a serous carcinogenesis – a
binary modelbinary model
Levanon, Crum, and Drapkin, JCO, 2008
How does it affect How does it affect screening?screening?
Is the target lesion a 1mm lesion Is the target lesion a 1mm lesion in the fallopian tube?in the fallopian tube?
How rapidly do these progress? How rapidly do these progress? What about tumors arising from What about tumors arising from
the surface of the ovary? the surface of the ovary?
How does it affect treatment?
Two types of Serous Tumors?Two types of Serous Tumors?
Surface Epithelium versus Surface Epithelium versus Fallopian tubeFallopian tube
Are they biologically the Are they biologically the same?same?
OVARIAN AND ENDOMETRIAL CANCER OVARIAN AND ENDOMETRIAL CANCER SUBTYPESSUBTYPES
OVARIAN AND ENDOMETRIAL CANCER OVARIAN AND ENDOMETRIAL CANCER SUBTYPESSUBTYPES
SEROUSSEROUS ENDOMETRIOIDENDOMETRIOID CLEAR CELLCLEAR CELL
OV
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VA
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EN
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OVARIAN & ENDOMETRIAL OVARIAN & ENDOMETRIAL CANCER CANCER
OVARIAN ENDO & SEROUS
ENDOMETRIAL ENDO & SEROUS
OVARIAN CLEAR CELL ENDOMETRIAL CLEAR
CELL
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Zorn et. al. Clinical Cancer Research 2005
CLEAR CELL CANCER CLEAR CELL CANCER
OVARIAN ENDOMETRIAL RENAL
Zorn et. al. Clinical Cancer Research 2005
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Clinical Impact of Genomic Clinical Impact of Genomic Characterization of Clear Cell Characterization of Clear Cell
CancersCancers Remove clear cell tumors from Remove clear cell tumors from
ovarian cancer phase III trials.ovarian cancer phase III trials. Create clear cell specific phase II Create clear cell specific phase II
trials.trials. Utilize understanding of molecular Utilize understanding of molecular
pathways of clear cell cancers from pathways of clear cell cancers from other organs to better treat ovarian other organs to better treat ovarian cancer.cancer.
Expression Profiling of Expression Profiling of Clear Cell Tumors of the Clear Cell Tumors of the
OvaryOvary 15 clear cell cancers of the ovary15 clear cell cancers of the ovary Whole genome profilingWhole genome profiling Supervised clusteringSupervised clustering Pathway identificationPathway identification
Cell Cycle Progression
Glycolysis
HIF1alpha degradation
Angiogenesis
Clear Cell Ovarian Cancer HIF1 alpha Pathway
Cell Migration
Unsupervised Hierarchical Clustering of Serous Unsupervised Hierarchical Clustering of Serous Ovarian CancersOvarian Cancers
Ovarian CancerOvarian Cancer
Normal Cells
Papillary Serous Ovarian Tumors
LMP/Low GradeLMP/Low Grade
High GradeHigh GradeP53-
P53+
B-raf, rasBonome et al Cancer Research 2005
What About Papillary Serous Ovarian Cancer?What About Papillary Serous Ovarian Cancer?
90% of ovarian cancers are papillary serous tumors.All tumors high grade tumors treated with surgery and chemotherapy.Activated pathways remain unknown.
Copyright ©2008 American Association for Cancer Research
Tothill, R. W. et al. Clin Cancer Res 2008;14:5198-5208
Figure 5">
Optimally Debulked Suboptimally Debulked
Gene signatures predicts survival only for suboptimally debulked tumors
TCGATCGA
200 high grade serous ovarian 200 high grade serous ovarian cancerscancers
6000 genes sequenced6000 genes sequenced Expression profilingExpression profiling Copy number differencesCopy number differences Methylation statusMethylation status
Future DirectionsFuture Directions
Histo/grade specific trials and Histo/grade specific trials and regimens.regimens.
Identification of sub-groups of Identification of sub-groups of patients based upon genomic patients based upon genomic patterns and activated pathways.patterns and activated pathways.
Future ChallengesFuture Challenges Validation of prognostic and predictive Validation of prognostic and predictive
biomarkers.biomarkers. Larger numbers of carefully annotated Larger numbers of carefully annotated
specimensspecimens FFPE technologiesFFPE technologies
Identification and validation of small Identification and validation of small molecule inhibitors targeting pathwaysmolecule inhibitors targeting pathways Integrated biomarkers will be mandated.Integrated biomarkers will be mandated.
Molecular basis for resistanceMolecular basis for resistance Recurrent tumor biopsies should be a Recurrent tumor biopsies should be a
requirement.requirement.