Angiogenesis in Ovarian Cancer

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Angiogenesis in Ovarian Cancer

• Christina M. Annunziata, MD, PhD
• Medical Oncology Branch
• National Cancer Institute
• Bethesda, MD

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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 lt5

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Stage shift at diagnosis might improve Ovarian
Cancer Outcome. Cases Deaths Fractional
DeathBreast 210,600 41,000 19Ovary 21,000 16,
414 78

Based upon ACS 2006
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Ovarian Cancer Prognostic Factors

• Stage
• Extent of Cytoreduction
• Histology and Grade
• Performance Status
• p53 Status
• Vital Organ Function
• Physiologic Age

• PlatinumTaxane Primary Therapy
• Intraperitoneal therapy
• Information from Second-Look Surgery
• Genotype BRCA1/2
• VEGF Production

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The State of Treatment for Newly Diagnosed
Ovarian Cancer

• First Precept Complete surgical staging
• Second Precept Optimal reductive surgery
• Third Precept Chemotherapy
• Fourth Precept Clinical Trials

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The State of Treatment for Newly Diagnosed
Ovarian Cancer

• First Precept Complete surgical staging
• Full assessment of abdomen and pelvis
• Random biopsy of visually negative areas
• Lymph node dissection (except Stage I)
• Second Precept Optimal reductive surgery
• Third Precept Chemotherapy
• Fourth Precept Clinical Trials

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Procedures required for surgical staging of
ovarian cancer. Scrapping of the underside of
the right, diaphragm, removal of the para-aortic
lymph nodes, removal of the pelvic lymph nodes,
removal of the omentum and peritoneal washing
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The State of Treatment for Newly Diagnosed
Ovarian Cancer

• First Precept Complete surgical staging
• Second Precept Optimal reductive surgery
• Stage I, II - Complete removal of all disease
• Stage III, IV - Residual disease lt 1 cm
• Third Precept Chemotherapy
• Fourth Precept Clinical Trials

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Optimal Cytoreduction
0 cm
Proportion surviving
0-1 cm
1-2 cm
gt2 cm
Time since initial surgery (years)
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The State of Treatment for Newly Diagnosed
Ovarian Cancer

• First Precept Complete surgical staging
• Second Precept Optimal reductive surgery
• Third Precept Chemotherapy
• Platinum cisplatin or carboplatin
• AND
• Taxane paclitaxel or docetaxel
• Intraperitoneal if Stage III, optimal reduction
• Fourth Precept Clinical Trials

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Timeline of Treatment and Outcome for Advanced
ovarian Cancer. ?In 1960 alkylators were
developed but the 5 year survival was 0. ?In
1970 cisplatin was developed and the 5 year
survival was 5. ?In 1980, cisplatin/alkylator
combinations were developed and the 5 year
survival was 15. ?In 1990 paclitaxel/carboplati
n was developed and the 5 year survival was
35.?In 2000 paclitaxel/carboplatin was given ip
and the 5 year survival was 40.
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Representative Chemotherapy Agents include
Platinum, Paclitaxel, Topotecan, Gemcitabine and
Doxil
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GOG 172 The new Standard of Care. ?Stage I
uses Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24
h)?Stage II uses Cisplatin 100 mg/m2 IP
d1Paclitaxel 135 mg/m2 (24 h) IV d1Paclitaxel
60 mg/m2 IP d8
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GOG 172 The new Standard of Care
Median survival 65.6 mo
Median survival 49.7 mo
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GOG 218 The NEXT Standard of Care ? Stage I
uses Paclitaxel, Carboplatin, Placebo x 6
followed by Placebo x 22. Stage II uses
Paclitaxel, Carboplatin, Bevacizumab x 6 followed
by Placebo x 22. Stage III uses Paclitaxel,
Carboplatin, bevacizumab x 6 followed by
Bevacizumab x 22.
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Angiogenesis in Ovarian Cancer

• Preclinical studies

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Angiogenesis in Ovarian Cancer. Preoperative
VEGF serum levels for 101 ovarian cancer patients
were 549, for 16 borderline tumors were 200 and
for 34 benign cysts were 228.
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Angiogenesis in Ovarian Cancer. VEGF levels in
peritoneal effusions were 2575 in ovarian cancer
patients, 182 in borderline tumors and 185 in
benign cysts.
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Angiogenesis in Ovarian Cancer VEGF levels in
peritoneal effusions
over 2575
under 2575
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Angiogenesis in Ovarian Cancer Micro-vessel
density and survival
ALIVE
DEAD
Status at median
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The State of Treatment for Newly Diagnosed
Ovarian Cancer

• First Precept Complete surgical staging
• Second Precept Optimal reductive surgery
• Third Precept Chemotherapy
• Fourth Precept Clinical Trials

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Angiogenesis in Ovarian Cancer

• Anti-VEGF therapy Bevacizumab
• GOG trial 170-D
• Recurrent ovarian cancer
• Second or third line therapy
• Overall response rate 18
• Stable disease 39
• Where do we go from here?

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Angiogenic targets in ovarian cancer

• Microenvironment
• EGFR, PDGFR
• Single agents (gefitinib, imatinib)
• Angiogenesis
• VEGFR
• Single agent (bevacizumab) effective
• GOG-170D, 18 RR, 39 PFS at 6mo
• Combined agents (bev sorafenib) promising
• Ongoing clinical trial at NCI

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Angiogenesis in Ovarian Cancer

• Targeted agents and tissue proteomics
• Hitting the target?

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Microdissection of core biopsies Tumor Stroma
l
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Reverse-Phase Protein Arrays. Quantitative
method for assessing proteins and activation
patterns from small quantities of cells or
tissue.
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Functional proteomicsQuality optimization and
assurance
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EGFR (ErbB1, Her1)

• Elevated in 50 - 70 ovarian ca
• Targeted therapy
• Gefitinib
• Erlotinib
• Cetuximab

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Phase II trial of Gefitinib in ovarian cancer

• Primary Objective demonstrate inhibition of
  EGFR, Akt, and ERK activation in tumor and skin.
• Secondary Objectives
• Assess clinical activity and toxicity
• Correlate biochemical effects with outcome and
  toxicity
• Treatment Gefitinib 500 mg/d
• Biopsy before starting and at 4wk

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Phase II trial of Gefitinib in ovarian cancer.
How / Why might gefitinib work in ovarian cancer?
What are downstream effectors of EGFR in ovarian
cancer?
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Gefitnib Therapy Patient A
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Gefitnib Therapy Patient B
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Proteomic profile. Clinical Objective clinical
activity and toxicity profile of
imatinibTranslational Objectives?To describe
tumor cell signaling pathways and their
modification by imatinib and to correlate with
outcome (biopsy on study 4 wks) ?To
investigate anti-angiogenic activity of
imatinib?To investigate other potential
molecular targets of imatinib ?To apply
SELDI-AI to serial serum samples for prediction
of response and/or toxicity.
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Proof of Target c-Kit Phosphorylation is
Reduced in Tumor and Stroma By Imatinib Therapy
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Tissue proteomics can validate targets

• Is the target there?
• Did you hit the target?
• Did you affect downstream signals?
• Was it important?
• True for antitumor activity
• and toxicity

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Angiogenic targets in ovarian cancer

• Microenvironment
• EGFR, PDGFR
• Single agents (gefitinib, imatinib) clinically
  ineffective
• Angiogenesis
• VEGFR
• Single agent (bevacizumab) effective
• GOG-170D, 18 RR, 39 PFS at 6mo
• Combined agents (bev sorafenib) promising
• Ongoing clinical trial at NCI

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Combination TherapyLESS of each MORE is
better ? HypothesisPartial inhibition at
points in series or parallel pathways may
translate into greater therapeutic benefit of new
molecularly targeted agents in solid tumors.
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Tumor angiogenesis involves 1. secretion of
angiogenic factors, 2. proteolytic destruction of
extracellular matrix, 3. endothelial cell
proliferation and migration, 4. appearance of new
tumor vasculature and 5. intravasation.
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Hypothesis Combining VEGF-targeted agents will
be synergistic. Anti-VEGF (bevacizumab) and
sorafenib will inhibit endothelial cell
proliferation and migration resulting in
increased vascular permeability.
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Phase I trial sorafenib bevacizumab in solid
tumors

• Primary Objective
• Safety and toxicity
• Biochemical changes in Ras-Raf-MAPK and VEGF
  pathways
• Secondary Objectives
• DCE-MRI and PET for tumor vascular flow CD31 IHC
  
• Pharmacogenomics of CYP3A4 on sorafenib
• Genotype Ras and Raf mutations
• Measure changes in circulating VEGF and other
  cytokines
• Eligibility Criteria
• All solid tumors (focused accrual in renal cell,
  melanoma, ovary)
• Biopsiable disease (cohort 2)
• Good end organ function
• No limitation for prior number of therapies

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Expansion Translational Study Group, Cohort 2
(Sorafenib 200 mg bid/ Bevacizumab 5 mg/kg q 2
weeks). ?In phase I a PET, biopsy and MRI will
be performed at cycle 1 and day 15 of Sorafenib
or Bev. A MRI will be performed at cycle 2. ?In
phase II a PET, biopsy and MRI will be performed
at day 15 of both Sorafenib and Bev. The first
imaging reassessment will be performed at cycle 3.
First imaging reassessment
PET
Biopsy
MRI
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Patient 6 - Epithelial ovarian cancerDL 1,
continued PR gt 2 yrs
C9d1
On study
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Reduced vascular flow with single agent and
combination therapy
DCE-MRI yielded Rx-related changes
Azad, Choyke, Chen, Kohn, et al
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Preliminary results proof of conceptGreater
reduction in ERK activation with sorafenib.ERK
is downstream of both VEGFR2 and Raf
Sorafenib
Bevacizumab
bx2/bx1
Yu and Henning
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Targeted therapy in parallel. Hypothesis Dual
VEGFR- and EGFR-targeted agents will be
synergistic. Endothelial cell proliferation and
migrationIncreased vascular permeability
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Vandetanib Study Design. At cycle 1 there is a
Bipsy and MRI. At day 3 there is a MRI. At day
15 there is a Biopsy and MRI. At cycle 3 there
is a first imaging reassessment.
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Exciting new directions

• Bevacizumab dasatinib (src inhibitor)
• Extending successful bev sor combination
• Phase I -- Opening Fall 2008
• L-aspargase in ovarian cancer
• Translated from CCR labs
• Pilot trial in ovarian cancer -- under review
• Endothelin inhibitor MEK inhibitor
• Translated from Kohn lab, Oncogene 2005
• Toxin-conjugated Ab to tumor/stroma antigen
• First-in-human Phase I trial under development

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Translational Oncology is based on observation,
hypothesis, experiment/trial, result and analysis

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Angiogenesis in Ovarian Cancer

• a promising target