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Ovarian Cancer in the Genomics Era






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Ovarian Cancer in the Genomics Era. Christina M. Annunziata, MD, PhD Medical Oncology Branch National Cancer Institute Bethesda, MD. Stage Description Incidence Survival I Confined to ovaries 20% 90% II Confined to pelvis 5% 65% III Spread IP or nodes 58% 45%
Ovarian Cancer in the Genomics Era

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Slide 1

Ovarian Cancerin the Genomics Era

Christina M. Annunziata, MD, PhD

Medical Oncology Branch

National Cancer Institute

Bethesda, MD

Slide 2

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

Slide 3

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

Ovarian Cancer: Prognostic Factors

Slide 4

Treatment for Newly Diagnosed Ovarian Cancer

  • Complete surgical staging

  • Optimal reductive surgery

  • Chemotherapy

  • Clinical Trials

Slide 5

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

Slide 6

Surgical staging of ovarian cancer

Slide 7

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

Slide 8

Optimal Cytoreduction

0 cm

Proportion surviving

0-1 cm

1-2 cm

>2 cm

Time since initial surgery (years)

Slide 9

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

Slide 10

Timeline of Treatment and Outcome for Advanced Ovarian Cancer

ALKYLATORS

CISPLATIN/ALKYLATOR

COMBINATIONS

INTRA-

PERITONEAL

1960

1980

2000

1970

1990

CISPLATIN

PACLITAXEL/

CARBOPLATIN

0

5%

15%

35%

40%

1960

1970

1980

1990

2000

5 YR SURVIVAL ADVANCED DISEASE

Slide 11

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 ----

Slide 12

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)

Slide 13

GOG 172: The new Standard of Care

Median survival = 65.6 mo

Median survival = 49.7 mo

Slide 14

Ovarian Cancerin the Genomics Era

Preclinical studies

Slide 15

Translational OncologyObservationHypothesisExperiment / TrialResultAnalysis

Slide 16

Integrated genomic analyses of ovarian carcinoma

The Cancer Genome Atlas Research Network*

Nature 474: 609-615

Slide 17

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.

Slide 18

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.

Slide 19

Methods Clinical data collectionClinical data can be accessed and downloaded from the TCGA Data Portal Demographics,histopathologic informationtreatment detailsoutcome parameters

Slide 20

Methods

Slide 21

Mutated genes in HGS-OvCa

Slide 22

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).

Slide 23

Gene and miRNA patterns: Molecular subtype and outcome prediction

Slide 24

Altered pathways in HGS-OvCa

Slide 25

Altered pathways in HGS-OvCa

Slide 26

Altered pathways in HGS-OvCa

Slide 27

Altered pathways in HGS-OvCa

Slide 28

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

Slide 29

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.

Slide 30

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 ...

Slide 31

The State of Treatment for Newly Diagnosed Ovarian Cancer

  • Complete surgical staging

  • Optimal reductive surgery

  • Chemotherapy

  • Clinical Trials: targeted therapies

Slide 32

Translational OncologyObservationHypothesisExperiment / TrialResultAnalysis

Slide 33

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

Slide 34

PARP inhibition: BRCA-mutant cancers

PARP

inhibitor

Replicating cells

Cancer cell with BRCA deficiency

Normal cell

Repair by Homologous Recombination

No effective repair(No HR pathway)

CELL DEATH

Survival

Slide 35

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

Slide 36

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%).

Slide 37

Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer

Audeh, et al. Lancet 376:245 – 251 (2010)

Slide 38

Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer

Slide 39

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.”

Slide 40

NF-B: Deregulation and Targeting

A Genomic approach to Ovarian Cancer

Slide 41

Schematic of NF-B signaling

Slide 42

Defining the Ovarian Cancer-specific IKK gene signature using IKK inhibitor and IKK shRNA

Slide 43

IKK gene signature is coordinately expressed in primary ovarian cancers

Slide 44

High IKKactivity associates with worse survival in ovarian cancer

Slide 45

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)

Slide 46

Clinical application: How can we leverage caspase 8?

Slide 47

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

X

SMAC

SMAC

Slide 48

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

Slide 49

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

Slide 50

TNFa enhances SMAC mimetic killing

Slide 51

SMAC mimetic blocks NF-kB and activates caspases

Slide 52

The State of Treatment for Newly Diagnosed Ovarian Cancer

Complete surgical staging

Optimal reductive surgery

Chemotherapy

Clinical Trials

Slide 53

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

Slide 54

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

Slide 55

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).

Slide 56

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

Slide 57

Translational OncologyObservationHypothesisExperiment / TrialResultAnalysis

Slide 58

Future directions (…back to bench)

Slide 59

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)

Slide 60

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

Slide 61

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


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