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Ovarian Cancerin the Genomics Era
Christina M. Annunziata, MD, PhD
Medical Oncology Branch
National Cancer Institute
Stage Description Incidence Survival
I Confined to ovaries 20% 90%
II Confined to pelvis 5% 65%
III Spread IP or nodes 58% 45%
IV Distant metastases 17% <5%
Extent of Cytoreduction
Histology and Grade
Vital Organ Function
Platinum+Taxane Primary Therapy
Information from Second-Look Surgery
Time since initial surgery (years)
5 YR SURVIVAL ADVANCED DISEASE
Representative Chemotherapy AgentsPlatinum Paclitaxel Topotecan Gemcitabine DoxilTarget: DNA b-tubulin Topo-I RN-reductase, Nucleotide pool Topo-IIMechanism:DNA adduct formation TubulinAggregation Stabilize DNA-TopoDNA synth DNA Schedule:Independent Dependent(toxicity)Dependent(efficacy) Dependent Phosporylation Prolonged clearanceResistance:GSH, tolerance, retention MDR-MRP, tubulin mutations Topo-I, BCRP RN-reductase MDR-MRP Topo-IIPlatinumInteraction:N/A Platelet Sparing ---- Enhanced Toxicity ----
GOG 172: The new Standard of CareEpithelial Ovarian Cancer, Optimal Stage III, No prior therapy, Well balanced arms1. Intravenous therapy, Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h), 83% completed 6 cycles2. Intraperitoneal therapy, Cisplatin 100 mg/m2 IP d1Paclitaxel 135 mg/m2 (24 h) IV d1Paclitaxel 60 mg/m2 IP d8, 42% completed 6 cycles Open: 23-Mar-98Closed: 29-Jan-01Accrual: 416 pts (evaluable)
Median survival = 65.6 mo
Median survival = 49.7 mo
Ovarian Cancerin the Genomics Era
Integrated genomic analyses of ovarian carcinoma
The Cancer Genome Atlas Research Network*
Nature 474: 609-615
Background The Cancer Genome Atlas (TCGA) Clinically annotated HGS-OvCa samplesIdentify molecular abnormalities that influence pathophysiology,affect outcome and constitute therapeutic targets. Microarray analyses: 489 HGS-OvCa tumours, mRNA expression,microRNA (miRNA) expression, DNA copy number and DNA promoter methylation for and Whole exome DNA sequence: 316 samples.
MethodsSample inclusion criteriaNewly diagnosed patientsovarian serous adenocarcinomano prior treatmentregardless of surgical stage or histologic gradeEach frozen tumor specimen had to have a companion normal tissue specimen, which could be adjacent normal tissue, peripheral lymphocytes, or previously extracted germline DNA.
Methods Clinical data collectionClinical data can be accessed and downloaded from the TCGA Data Portal Demographics,histopathologic informationtreatment detailsoutcome parameters
Genome copy number abnormality Copy number profiles of 489 HGS-OvCa, compared with profiles of 197 glioblastoma multiforme (GBM) tumours. Copy number increases (red) and decreases (blue) are plotted as a function of distance along the normal genome (vertical axis, divided into chromosomes).
TCGA findings TCGA: large-scale integrative view of aberrations in HGS-OvCa Mutational spectrum “surprisingly simple” TP53 predominated = 96% BRCA1 and BRCA2 =22% Seven other significantly mutated genes = 2–6%HGS-OvCa is distinct from other histological subtypes Clear-cell: few TP53; recurrent ARID1A, PIK3CA mutationsEndometrioid: frequent CTNNB1, ARID1A and PIK3CA; fewer TP53Mucinous: prevalent KRAS mutations
TCGA findings “Remarkable degree of genomic disarray” “Striking contrast to previous TCGA findings in glioblastoma”Mutations and promoter methylation in putative DNA repair genes (HR) may explain the high prevalence of SCNAs.
TCGA – what next? New therapeutic approaches?50% with HR defects : PARP inhibitors commonly deregulated pathways: RB, RAS/PI3K, FOXM1, NOTCH, provide opportunities for therapeutic treatmentInhibitors exist for 22 genes in regions of recurrent amplificationaberrant genes or networks: targeted therapies selected to be effective ...
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer
American Society of Clinical Oncology, 2009
Presenter: M William Audeh
From genomic aberration to pathway
Cancer cell with BRCA deficiency
Repair by Homologous Recombination
No effective repair(No HR pathway)
Audeh, et al. Lancet 376:245 – 251 (2010)
NF-B: Deregulation and Targeting
A Genomic approach to Ovarian Cancer
Defining the Ovarian Cancer-specific IKK gene signature using IKK inhibitor and IKK shRNA
TNF: NF-kB activation or apoptosis? Normal cells:SMAC released from mitochondria, inhibiting cIAP 1 & removing blockade to activated caspase function apoptotic cell deathTumor cells: apoptosis is dysregulated due to low SMAC or upstream blockade e.g overexpression of IAPs
TNF: NF-kB activation or apoptosis? High immunohistochemical expression of TNFα in ovarian tumor & stroma Increased TNF-α serum concentrations reported in patients with endometrial carcinomaTNFα may activate NF-kB in the presence of IAP (Inhibitors of Apoptotic Proteins), but trigger apoptosis in its absence
New Hypothesis:The intersection of the NF-κB and caspase pathways provides a novel point of therapeutic intervention, where pro-survival signals can be switched to pro-apoptotic killing of cancer cells
Complete surgical staging
Optimal reductive surgery
Phase 2 study of SMAC-mimetic for relapsed ovarian cancer SMAC mimetic administered IV on days 1, 8, 15 of 28 day cycle 18g needle biopsy prior to start, and after 2 cycles CT scan restaging every 2 cycles
Primary Objectives Dual endpoint efficacy (GOG criteria):objective response (confirmed complete response [CR] of any duration or confirmed partial response [PR] of any duration defined by RECIST version 1.1 criteria)progression-free survival lasting greater than 6 months, in patients with relapsed platinum refractory or resistant ovarian cancer, primary peritoneal cancer, fallopian tube cancer treated with TL32711 at 47mg/m2
Correlative Studies on paired pre- and post-treatment tumor biopsies & on archival tissue. Immunohistochemistry for measurement of TNF alpha and TRAIL (NIH Core Facility)Gene expression profiling of NF-kappaB signature (Annunziata lab) Apoptosis gene signature (TetraLogic Pharmaceuticals)Response biomarkers:cIAP1 & cIAP2 (immediate targets of TL37211), with degradation of cIAP1 & 2 protein post-treatment activated caspase-8 – a measure of extrinsic pathwayPARP cleavage – a measure of activated caspase-3 and ultimate apoptosis pathway activation (both extrinsic and intrinsic pathways).
Correlative Studies on blood specimens PBMCCleaved caspase 3/7 levels in PBMCsCleaved PARP levels in PBMCscIAP1/2 levels in PBMCsPlasmaTNF alpha, TRAILIL-6, IL-8
What sequence of SMAC mimetic in combination
achieves maximal tumor cell death and
correlates with proteomic changes in apoptosis and NF-kB pathways
Biomarkers will be used in future clinical trials
Clinical application: Indvidualized therapy Therapeutic agents targeting each critical pathway can be tested for their ability to overcome molecularly defined cancers Ultimately, the benefit of signature-directed therapy will be assessed by prospectively profiling individual patients and allocating therapy based on the molecular defects identified at the bench
Medical Ovarian Cancer Team Anne Noonan, MDElise C. Kohn, MDJung-Min Lee, MDNicole Houston, RNJessica Hearn, RNMOB Fellows and Nursing Staff Translational scientists:Lidia Hernandez, MSMarianne Kim, PhDCarrie House, PhDEthan SagherBridget Hill