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					        Angiogenesis
    in Ovarian Cancer

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%
Stage shift at diagnosis might improve
Ovarian Cancer Outcome.         Cases
    Deaths Fractional Death

Breast             210,600 41,000                                              19%
Ovary              21,000 16,414                                               78%

                  ACTUAL      5 Year Survival
                                                         WITH EARLY DETECTION

                              Stage at diagnosis
   100                                             100


   75                                              75


   50                                ?             50


   25                                              25


    0
                                                    0
         I   II    III   IV                                I   II   III   IV

                                                                                Based upon ACS 2006
Ovarian Cancer: Prognostic Factors

   Stage                     Platinum+Taxane
   Extent of                  Primary Therapy
    Cytoreduction             Intraperitoneal
   Histology and Grade        therapy
   Performance Status        Information from
                               Second-Look Surgery
   p53 Status
                              Genotype BRCA1/2
   Vital Organ Function
                              VEGF Production
   Physiologic Age
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
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
   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
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 < 1 cm


   Third Precept:          Chemotherapy
   Fourth Precept:         Clinical Trials
      Optimal Cytoreduction
Proportion surviving




                                                             0 cm



                                                            0-1 cm
                                                            1-2 cm
                                                             >2 cm
                       Time since initial surgery (years)
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
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/carboplatin was developed and the 5
year survival was 35%.
●In 2000 paclitaxel/carboplatin was given ip and the 5
year survival was 40%.
  Representative Chemotherapy Agents
      include Platinum, Paclitaxel,
   Topotecan, Gemcitabine and Doxil


               Platinum Paclitaxel Topotecan Gemcitabine                    Doxil
                                                          RN-reductase,
    Target:       DNA        b-tubulin       Topo-I
                                                         Nucleotide pool
                                                                            Topo-II

                                            Stabilize
               DNA adduct   Tubulin
Mechanism:      Formation Aggregation
                                           DNA-Topo        DNA synth       DNA synth
                                           Complex
                             Dependent     Dependent       Dependent       Prolonged
 Schedule:     Independent
                              (toxicity)    (efficacy)   Phosporylation    clearance
                   GSH,      MDR-MRP,
                                             Topo-I,                       MDR-MRP
Resistance:     tolerance,    tubulin
                                             BCRP
                                                          RN-reductase
                                                                            Topo-II
                 retention   mutations
   Platinum                   Platelet
                   N/A
                              Sparing
                                                 ---- Enhanced Toxicity ----
Interaction:
GOG 172: The new Standard of Care.
●Stage I uses Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2 (24 h)
●Stage II uses Cisplatin 100 mg/m2 IP d1
Paclitaxel 135 mg/m2 (24 h) IV d1
Paclitaxel 60 mg/m2 IP d8
GOG 172: The new Standard of Care

                           Median survival = 65.6 mo




         Median survival = 49.7 mo
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.
             Angiogenesis
         in Ovarian Cancer




Preclinical studies
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.
Angiogenesis in Ovarian Cancer. VEGF levels in peritoneal
effusions were 2575 in ovarian cancer patients, 182 in

borderline tumors and 185 in benign cysts.
Angiogenesis in Ovarian Cancer
VEGF levels in peritoneal
effusions


                       over 2575




                   under 2575
Angiogenesis in Ovarian Cancer
Micro-vessel density and
survival




                     ALIVE       DEAD
                      Status at median
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
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?
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
               Angiogenesis
           in Ovarian Cancer




Targeted agents and tissue proteomics
Hitting the target…?
    Microdissection of core biopsies
              Tumor       Stroma

      T
              S
S

                  T
          T




                      l
         Reverse-Phase
  Protein Arrays. Quantitative
 method for assessing proteins
  and activation patterns from
small quantities of cells or tissue.




               CHROMAGEN
       NON-TARGET        ANTIBODY
       PROTEINS


          *** ***
           target   target
           protein  protein
          NITROCELLULOSE
                                                              Functional proteomics:
                                                        Quality optimization and assurance
                                                              Buffer 1                                                                                    473Ser-pAKT
                                                                                                                                    105
           9000
                  y = 0.9606x + 557.55
           8000        2
                      R = 0.9834
           7000                                                                                                                     78
           6000
36 Slide




           5000                                                                                                                     57
           4000
           3000                                                                                                                     47
                                                                                    Buffer 5
           2000
           1000
                                            9000
             0                              8000
                                                       y = 0.9015x + 300.18

                                                                                                                                                                                                   .....




                                                                                                                                                                                             1:8
                                                                                                                                                                                             1:4
                                                                                                                                                                                             1:2
                  0     1000                2000       3000   R24000 5000
                                                                 = 0.7662      6000     7000    8000    9000
                                            7000
                                                                 1st Slide
                                                                                                                                                                                        N
                                            6000
                               36th Slide




                                            5000
                                            4000
                                            3000
                                            2000
                                            1000                                                                                                                         pAKT
                                               0
                                                   0      1000      2000     3000     4000     5000    6000    7000   8000   9000
                                                                                       1st Slide                                                        2500


                                                                                                                                     Signal Intensity
                                                                                                                                                        2000
                                                                                                                                                        1500
                                                                                                                                                        1000
                                                                                                                                                        500
                                                                                                                                                          0
                                                                                                                                                               1   2 3   4   5 6    7   8 9 10 11 12
                                                                                                                                                                             Dilution Step
         EGFR (ErbB1, Her1)
• Elevated in 50 - 70% ovarian ca

•   Targeted therapy
•   Gefitinib
•   Erlotinib
•   Cetuximab
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
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?
Gefitnib Therapy: Patient A
                                                                 Patient A- Tumor


                                              200




                       Relative Signal
                          Intensity
                                              150
                                                                                            Pre gefitinib
                                              100
                                                                                            Four weeks
                                                  50
                                                  0
                                                         pEGFR       pAKT            pERK

                                                                 Patient A- Stroma


                                            900



                Relative Signal Intensity
                                            800
                                            700
                                            600
                                            500                                             Pre gefitinib
                                            400                                             Four weeks
                                            300
                                            200
                                            100
                                              0
                                                       pEGFR       pAKT              pERK
Gefitnib Therapy: Patient B
                                                          Patient B- Tumor


                                            800




                Relative Signal Intensity
                                            700
                                            600
                                            500                                      Pre gefitinib
                                            400
                                                                                     Four weeks
                                            300
                                            200
                                            100
                                              0
                                                  pEGFR     pAKT              pERK


                                                          Patient B- Stroma


                                            700


                Relative Signal Intensity
                                            600
                                            500
                                            400                                      Pre gefitinib
                                            300                                      Four weeks
                                            200
                                            100
                                             0
                                                  pEGFR     pAKT              pERK
Proteomic profile. Clinical Objective: clinical activity and toxicity
profile of imatinib

Translational 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.
                                                  Proof of Target:
 c-Kit Phosphorylation is Reduced in
Tumor and Stroma By Imatinib Therapy
                                    160                                                                         160
                                                                                                                                                     Pre-Tx
                                                                        Pre-Tx                                                                       On Tx
                                                                        On Tx

                                    140                                                                         140




                                    120                                                                         120
     Normalized Protein Intensity




                                                                                 Normalized Protein Intensity
                                    100                                                                         100


                                                                                                                                                              Pre-tx
                                    80                                                                          80


                                                                                                                                                              1 mo
                                    60                                                                          60




                                    40                                                                          40




                                    20
                                                                                                                20




                                     0
                                                                                                                 0
                                          D   L   J   K     M   N   P     B
                                                                                                                      D   L   J   K     M    N   P      B
                                                      Patient
                                                                                                                                  Patients
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…
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
Combination Therapy:
LESS of each = MORE is better
? Hypothesis:

Partial inhibition at points in
series or parallel pathways may
translate into greater therapeutic
benefit of new molecularly
targeted agents in solid tumors.
    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.
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.
    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
    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
                                                         First imaging
   PET 15 of Sorafenib or Bev. A MRI will be performed at cycle 2. ●In
    day                                                  reassessment
    phase II a PET, biopsy and MRI will be performed at day 15 of both
Biopsy
    Sorafenib and Bev. The first imaging reassessment will be
    MRI
    performed at cycle 3.
                      Patient 6 - Epithelial ovarian cancer
                          DL 1, continued PR > 2 yrs

    On study                                        C9d1




               1200
               1000
CA125 (U/mL)




                800
                600
                400
                200
                  0
                                          11

                                               13
                  1

                      3

                          5

                              7

                                     9




                                  Cycle
 Reduced vascular flow with single agent
       and combination therapy

On-study   2 weeks   6 weeks

                               DCE-MRI yielded Rx-related changes
                                 0. 9


                                 0. 8                                      ktrans
                                                                           kep
                                 0. 7


                                 0. 6


                                 0. 5


                                 0. 4


                                 0. 3


                                 0. 2


                                 0. 1


                                   0
                                        Baseline     2 weeks   4 weeks   6 weeks




                                                   Azad, Choyke, Chen, Kohn, et al
Preliminary results: proof of concept
Greater reduction in ERK activation with sorafenib.
   ERK is downstream of both VEGFR2 and Raf




            Sorafenib    Bevacizumab
  bx2/bx1




                                              Yu and Henning
Targeted therapy in parallel. Hypothesis: Dual VEGFR- and

EGFR-targeted agents will be synergistic. Endothelial cell
              proliferation and migration
           Increased vascular permeability
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.
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
Translational Oncology is
based on observation,
hypothesis, experiment/trial,
result and analysis
               Angiogenesis in
               Ovarian Cancer




…a promising target