ovarian cancer in the genomics era...functional genomics what part of the genome is functional...
TRANSCRIPT
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Ovarian Cancer
in the Genomics Era
Christina M. Annunziata, MD, PhD
Women’s Malignancies Branch
National Cancer Institute
Bethesda, MD
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Cancer Genomics
Study of the genome
Chromosomes
Gene expression
Global analysis (not individual entities)
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The Genomics Era
1959 – Nowell and Hungerford
Study of chromosomes
Identified recurrent abnormality
Philadelphia chromosome
Chronic leukemia
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The Genomics Era
1959 – Nowell and Hungerford
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Genomics Era
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The Genomics Era
1984 – Groffen – BCR-ABL
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The Genomics Era
1996 – Drucker – blocking ABL
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Functional Genomics
What part of the genome is functional
Causes an effect
Transforms normal cells into cancer
Looking for “driver” alterations
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Functional Genomics
1981 – Shih – discovery of Her2/neu
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Functional Genomics
1984 – Schechter – neu and EGFR
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Functional Genomics
1985 – Coussens – Her2 on chromosome 17
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Functional Genomics
1987 – Slamon – HER2 in breast cancer
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Using genomics to
study ovarian cancer
Do we have any “drivers”?
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Ovarian Cancer
Most lethal gynecologic malignancy in the US
>16,000 deaths/yr
5th most common cancer death for women
70% diagnosed with advanced disease
< 35% of advanced stage patients alive at 5y
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Ovarian Cancer Stages
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Treatment for
Newly Diagnosed Ovarian Cancer
Complete surgical staging
Optimal reductive surgery
Chemotherapy
Clinical Trials
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The State of Treatment for
Newly Diagnosed Ovarian Cancer
Complete surgical staging
Optimal reductive surgery
Chemotherapy
Platinum = cisplatin or carboplatinAND
Taxane = paclitaxel or docetaxel
Intraperitoneal if Stage III, optimal reduction
Clinical Trials
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Treatment and Outcome
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Ovarian Cancer
Prevalence
Serous – 80%
Endometrioid – 10%
Clear cell – 5%
Mucinous – 3%
Other – 2%
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Ovarian Cancer
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Ovarian Cancer
Increasing our understanding about the
biological and biochemical events underlying
ovarian cancer progression will create
avenues for new treatments
Can we use Genomics?
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Clear cell,
Endometrioid
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Clear Cell cancers
5-10% of all cases (serous = 70%)
Worse response to standard chemotherapy
Associated with endometriosis (up to 40%)
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Clear cell ovarian cancer
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ARID1A mutations in clear cell
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ARID1A
SWI-SNF chromatin remodeling complex
Mutated in breast cancer, lung cancer
1p36: deleted 6% of all cancers
Tumor suppressor gene?
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ARID1A mutations
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Clear cell and endometrioid cancer
ARID1A mutated or lost in
Over 40% clear cell
30% endometrioid
Less than 1% serous
Unknown oncogenic mechanism
No indication of which resulting pathways affected
Unclear therapeutic utility
Diagnostic utility?
Not a ‘functional’ experiment
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Mucinous
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Mucinous ovarian cancer
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Gene expression
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K-ras mutations
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Low grade serous
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KRAS and BRAF mutations
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KRAS and BRAF
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RAS signaling pathway- a potential driver?
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MEK inhibitor
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Selumetinib responses
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RAS signaling
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High grade serous
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High grade serous cancers
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High grade serous cancers
Sample inclusion criteria
Newly diagnosed patients
ovarian serous adenocarcinoma
no prior treatment
companion normal tissue specimen
adjacent normal tissue,
peripheral lymphocytes,
or previously extracted germline DNA
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Genome copy number
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Mutated genes
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Altered pathways
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Altered pathways in HGS-OvCa
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TCGA – what next?
New therapeutic approaches?
50% with HR defects : PARP inhibitors
commonly deregulated pathways: RB, RAS/PI3K,
FOXM1, NOTCH, provide opportunities for
therapeutic treatment
Inhibitors exist for 22 genes in regions of recurrent
amplification
aberrant genes or networks: targeted
therapies selected to be effective ...
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Targeting deficient
Homologous
Recombination
PARP inhibitors
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BRCA mutations
Hall…King, Science, 1990
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High grade serous cancers
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BRCA mutations
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PARP inhibition
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PARP inhibitor
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Phase I/Ib study
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Phase Ib Study of Olaparib and Carboplatin
in BRCA1 or BRCA2 Mutation-Associated
Breast or Ovarian Cancer
Results: 45 enrolled patients 37 ovarian cancer
8 breast cancer
Phase 1 dose escalation = 30 patients
Phase 1b expansion = 15 patients
MTD = Carboplatin AUC5 on day 1 + Olaparib 400mg twice daily on days 1-7, every 21 days
Lee, et al. J Natl Cancer Inst Vol. 106(6) June 2014
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Phase 1b Study
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Phase 1b study
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Phase Ib Study of Olaparib and Carboplatin
in BRCA1 or BRCA2 Mutation-Associated
Breast or Ovarian Cancer
Conclusions:
Oral olaparib is well tolerated in combination with
carboplatin
Highly active in advanced, chemotherapy-refractory
BRCA-deficient cancer
Greater activity seen at the higher dose
Positive proof of the concept of the activity and
tolerability of genetically defined targeted therapy
with olaparib in BRCA-deficient cancers
Results of sporadic HGSOC cohort to be presented at
ASCO meeting 2015
Lee, et al. J Natl Cancer Inst Vol. 106(6) June 2014
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Exploration of new
targets
Functional Genomics
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“Actionable” mutations
Commercially available testing
e.g., Caris, Foundation One
Report “possible” or “unlikely” benefit
“Basket” clinical trials
e.g., NCI-MPACT
Assign treatment based on mutation
Typically no functional link
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“Actionable” mutations
“…depends in large part on the strength of the
data linking the target and targeted therapy.”
“For this trial design to work, two key conditions
must be met:
the tumor must depend on the target pathway, and
the targeted therapy must reliably inhibit the target.”
“Achieving both goals can be a matter of some
complexity.”
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“Actionable” targets
Need a functional experiment
Functional genomics
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Functional genomics
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shRNA Library Screen
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Functional Genomics of
ovarian cancer
Four ovarian cancer cell lines
OVCAR3 – serous
OVCAR5 – serous
Igrov1 – non-serous
A2780 – non-serous
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Common targets in ovarian
cancer – “drivers”?
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Common targets
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Functional genomics of
ovarian cancer
Following up in
6 additional cell lines
2 different RNAi constructs
Select “druggable” targets
Focused functional screens
Specific subgroup of serous ovarian cancer
NF-kappaB signaling pathway
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CHEK1
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CHEK signaling
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CHEK inhibitor
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CHEK inhibitor
Clinical trial ongoing
NCT02203513
Promising results in High grade serous non BRCA
Highlighted by a Functional Genomics approach
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Best response on clinical trial
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Duration on clinical trial
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Ovarian cancer
genomics
Summary
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Ovarian cancer genomics
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Functional Genomics
1981 – Shih – discovery of Her2/neu
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Controlling genes
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Ovarian cancer and genomics
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Women’s cancer team