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Ovarian Cancer in the Genomics Era Christina M. Annunziata, MD, PhD
Medical Oncology Branch
National Cancer Institute
Bethesda, MD Ovarian Cancer 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% Ovarian Cancer: Prognostic Factors Stage
Extent of Cytoreduction
Histology and Grade
Performance Status
p53 Status
Vital Organ Function
Physiologic Age Platinum+Taxane Primary Therapy
Intraperitoneal therapy
Information from Second-Look Surgery
Genotype BRCA1/2
VEGF Production Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging
Optimal reductive surgery
Chemotherapy
Clinical Trials The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging
Full assessment of abdomen and pelvis
Random biopsy of visually negative areas
Lymph node dissection (except Stage I)
Optimal reductive surgery
Chemotherapy
Clinical Trials Surgical staging of ovarian cancer The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging
Optimal reductive surgery
Stage I, II - Complete removal of all disease
Stage III, IV - Residual disease < 1 cm
Chemotherapy
Clinical Trials Optimal Cytoreduction 0 cm 0-1 cm 1-2 cm >2 cm Time since initial surgery (years) Proportion surviving The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging
Optimal reductive surgery
Chemotherapy
Platinum = cisplatin or carboplatin
AND
Taxane = paclitaxel or docetaxel
Intraperitoneal if Stage III, optimal reduction
Clinical Trials 1960 1970 1980 1990 2000 CISPLATIN/ALKYLATOR
COMBINATIONS INTRA-
PERITONEAL PACLITAXEL/
CARBOPLATIN ALKYLATORS CISPLATIN 5 YR SURVIVAL ADVANCED DISEASE 40% 35% 15% 5% 0 1960 1970 1980 1990 2000 Timeline of Treatment and Outcome for Advanced Ovarian Cancer Representative Chemotherapy Agents Platinum Paclitaxel Topotecan Gemcitabine Doxil Target: DNA b-tubulin Topo-I RN-reductase, Nucleotide pool Topo-II Mechanism:DNA adduct formation TubulinAggregation Stabilize DNA-TopoDNA synth DNA Schedule:Independent Dependent(toxicity)Dependent(efficacy) Dependent Phosporylation Prolonged clearance Resistance:GSH, tolerance, retention MDR-MRP, tubulin mutations Topo-I, BCRP RN-reductase MDR-MRP Topo-II Platinum Interaction:N/A Platelet Sparing ---- Enhanced Toxicity ---- GOG 172: The new Standard of Care Epithelial Ovarian Cancer, Optimal Stage III, No prior therapy, Well balanced arms 1. Intravenous therapy, Cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 (24 h), 83% completed 6 cycles 2. Intraperitoneal therapy, Cisplatin 100 mg/m2 IP d1 Paclitaxel 135 mg/m2 (24 h) IV d1 Paclitaxel 60 mg/m2 IP d8, 42% completed 6 cycles Open: 23-Mar-98 Closed: 29-Jan-01 Accrual: 416 pts (evaluable) GOG 172: The new Standard of Care Median survival = 49.7 mo Median survival = 65.6 mo Ovarian Cancer in the Genomics Era Preclinical studies Translational Oncology Observation Hypothesis Experiment / Trial Result Analysis 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 samples Identify 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. Methods Sample inclusion criteria Newly diagnosed patients ovarian serous adenocarcinoma no prior treatment regardless of surgical stage or histologic grade Each 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 collection Clinical data can be accessed and downloaded from the TCGA Data Portal Demographics, histopathologic information treatment details outcome parameters Methods Mutated genes in HGS-OvCa
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). Gene and miRNA patterns: Molecular subtype and outcome prediction Altered pathways in HGS-OvCa Altered pathways in HGS-OvCa Altered pathways in HGS-OvCa Altered pathways in HGS-OvCa 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 mutations Endometrioid: frequent CTNNB1, ARID1A and PIK3CA; fewer TP53 Mucinous: 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 treatment Inhibitors exist for 22 genes in regions of recurrent amplification aberrant genes or networks: targeted therapies selected to be effective ... The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging
Optimal reductive surgery
Chemotherapy
Clinical Trials: targeted therapies Translational Oncology Observation Hypothesis Experiment / Trial Result Analysis 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 PARP PARP inhibition: BRCA-mutant cancers Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer Olaparib (AZD2281)
novel, orally active PARP inhibitor
synthetic lethality in homozygous BRCA-mut cells
The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced refractory ovarian cancer Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer Results: 57 enrolled pts
39 BRCA1 deficient and 18 BRCA2 deficient
33 evaluable at 400 mg bid and 24 at 100 mg bid
ORR was 33% at 400 mg bd; 12.5% at 100 mg bd
Clinical benefit rate:
ORR and/or confirmed ≥50% decline in CA125
57.6% at 400 mg bd and 16.7% at 100 mg bd
Median PFS: 5.8 mo (med duration 9.6 mo)
Toxicity
grade 1/2 nausea (44%); fatigue (35%); anemia (14%)
Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%). Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer Audeh, et al. Lancet 376:245 – 251 (2010) Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer
Greater activity seen at the higher dose
Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers
“Positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers.” NF-B: Deregulation and Targeting A Genomic approach to Ovarian Cancer Schematic of NF-B signaling Defining the Ovarian Cancer-specific IKK gene signature using IKK inhibitor and IKK shRNA IKK gene signature is coordinately expressed in primary ovarian cancers High IKK activity associates with worse survival in ovarian cancer Intersecting pathways cooperate with NF-κB in ovarian cancer RNAi sensitization screen
shRNA library targeting human kinome (500 kinases)
Combination with IKK inhibitor (sub-lethal dose) Clinical application: How can we leverage caspase 8? TNF: NF-kB activation or apoptosis? Normal cells: SMAC released from mitochondria, inhibiting cIAP 1 & removing blockade to activated caspase function apoptotic cell death Tumor cells: apoptosis is dysregulated due to low SMAC or upstream blockade e.g overexpression of IAPs SMAC SMAC X 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 carcinoma TNFα 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 TNFa enhances SMAC mimetic killing SMAC mimetic blocks NF-kB and activates caspases The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging
Optimal reductive surgery
Chemotherapy
Clinical Trials 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 pathway PARP cleavage – a measure of activated caspase-3 and ultimate apoptosis pathway activation (both extrinsic and intrinsic pathways). Correlative Studies on blood specimens PBMC Cleaved caspase 3/7 levels in PBMCs Cleaved PARP levels in PBMCs cIAP1/2 levels in PBMCs Plasma TNF alpha, TRAIL IL-6, IL-8 Translational Oncology Observation Hypothesis Experiment / Trial Result Analysis Future directions (…back to bench) 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 Future directions (…back to bench) 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, MD Elise C. Kohn, MD Jung-Min Lee, MD Nicole Houston, RN Jessica Hearn, RN MOB Fellows and Nursing Staff Translational scientists: Lidia Hernandez, MS Marianne Kim, PhD Carrie House, PhD Ethan Sagher Bridget Hill
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