Ovarian Cancer in the Genomics Era
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Ovarian Cancer in the Genomics Era

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. Ovarian Cancer. Stage Description Incidence SurvivalIConfined to ovaries20
Ovarian Cancer in the Genomics Era

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1. Ovarian Cancer in the Genomics Era Christina M. Annunziata, MD, PhD Medical Oncology Branch National Cancer Institute Bethesda, MD

2. 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 is the 5ht leading cause of cancer death in women. Its incidence is around 20k/yr, and it is curable surgically when diagnosed at early stage. However, the fractional death rate for ovarian cancer is >75% because most women are diagnosed at late stages of disease.Ovarian cancer is the 5ht leading cause of cancer death in women. Its incidence is around 20k/yr, and it is curable surgically when diagnosed at early stage. However, the fractional death rate for ovarian cancer is >75% because most women are diagnosed at late stages of disease.

3. 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

4. Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging Optimal reductive surgery Chemotherapy Clinical Trials

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

6. Surgical staging of ovarian cancer The complete surgical staging of ovarian cancer requires full assessment of the entire abdomen and pelvis. Ovarian cancer typically arises in the pelvis, but spreads by dissemination rather than invasion. Therefore the pattern of spread follows the flow of peritoneal fluid?The complete surgical staging of ovarian cancer requires full assessment of the entire abdomen and pelvis. Ovarian cancer typically arises in the pelvis, but spreads by dissemination rather than invasion. Therefore the pattern of spread follows the flow of peritoneal fluid?

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 My slide to put tx issue into contextMy slide to put tx issue into context

8. Optimal Cytoreduction Survival based on amount of tumor left behind at surgery?Survival based on amount of tumor left behind at surgery?

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 My slide to put tx issue into contextMy slide to put tx issue into context

10. Timeline of Treatment and Outcome for Advanced Ovarian Cancer changes and paradigms by decade and survival changes. Addition of platinum - first time where people lived 5 years after Dx of ov ca! next big advance was taxanes?changes and paradigms by decade and survival changes. Addition of platinum - first time where people lived 5 years after Dx of ov ca! next big advance was taxanes?

11. 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 ---- Highlight platinum interactionHighlight platinum interaction

12. 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) Article in NEJM showed survival advantage of using chemotherapy IP - and that was the stimulus for NCI to put out the clinical alert. Article in NEJM showed survival advantage of using chemotherapy IP - and that was the stimulus for NCI to put out the clinical alert.

13. GOG 172: The new Standard of Care

14. Ovarian Cancer in the Genomics Era Preclinical studies

15. Translational Oncology Observation Hypothesis Experiment / Trial Result Analysis

16. Integrated genomic analyses of ovarian carcinoma The Cancer Genome Atlas Research Network* Nature 474: 609-615

17. 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.

18. 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.

19. Methods Clinical data collection Clinical data can be accessed and downloaded from the TCGA Data Portal Demographics, histopathologic information treatment details outcome parameters

20. Methods

21. Mutated genes in HGS-OvCa

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).

23. Gene and miRNA patterns: Molecular subtype and outcome prediction

24. Altered pathways in HGS-OvCa

25. Altered pathways in HGS-OvCa

26. Altered pathways in HGS-OvCa

27. Altered pathways in HGS-OvCa

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 mutations Endometrioid: frequent CTNNB1, ARID1A and PIK3CA; fewer TP53 Mucinous: prevalent KRAS mutations

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.

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 treatment Inhibitors exist for 22 genes in regions of recurrent amplification aberrant genes or networks: targeted therapies selected to be effective ...

31. The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging Optimal reductive surgery Chemotherapy Clinical Trials: targeted therapies My slide to put tx issue into contextMy slide to put tx issue into context

32. Translational Oncology Observation Hypothesis Experiment / Trial Result Analysis

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

34. PARP inhibition: BRCA-mutant cancers

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

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%).

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

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

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.?

40. NF-?B: Deregulation and Targeting A Genomic approach to Ovarian Cancer

41. Schematic of NF-?B signaling

42. Defining the Ovarian Cancer-specific IKK? gene signature using IKK? inhibitor and IKK? shRNA The ovarian cancer specific IKKb gene signatureThe ovarian cancer specific IKKb gene signature

43. IKK? gene signature is coordinately expressed in primary ovarian cancers The IKKb gene signatureThe IKKb gene signature

44. High IKK? activity associates with worse survival in ovarian cancer

45. Intersecting pathways cooperate with NF-?B in ovarian cancer RNAi sensitization screen shRNA library targeting human kinome (500 kinases) Combination with IKK? inhibitor (sub-lethal dose) To move this project forward?To move this project forward?

46. Clinical application: How can we leverage caspase 8?

47. 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

48. TNF: NF-kB activation or apoptosis? High immunohistochemical expression of TNFa in ovarian tumor & stroma Increased TNF-a serum concentrations reported in patients with endometrial carcinoma TNFa may activate NF-kB in the presence of IAP (Inhibitors of Apoptotic Proteins), but trigger apoptosis in its absence

49. New Hypothesis: The intersection of the NF-?B and caspase pathways provides a novel point of therapeutic intervention, where pro-survival signals can be switched to pro-apoptotic killing of cancer cells

50. TNFa enhances SMAC mimetic killing

51. SMAC mimetic blocks NF-kB and activates caspases

52. The State of Treatment for Newly Diagnosed Ovarian Cancer Complete surgical staging Optimal reductive surgery Chemotherapy Clinical Trials My slide to put tx issue into contextMy slide to put tx issue into context

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

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

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 pathway PARP cleavage ? a measure of activated caspase-3 and ultimate apoptosis pathway activation (both extrinsic and intrinsic pathways). The above proteins will be measured using tumor lysate arrays as described previously by our group or by other techniques should a better proteomic technique be discovered during the period of the study. The above proteins will be measured using tumor lysate arrays as described previously by our group or by other techniques should a better proteomic technique be discovered during the period of the study.

56. 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

57. Translational Oncology Observation Hypothesis Experiment / Trial Result Analysis

58. Future directions (?back to bench)

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)

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

61. 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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