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					            Metastatic Colon Cancer: Today’s
                and Tomorrow’s Target
Tanios Bekaii-Saab, MD
Medical Director, GI Oncology
The Ohio State University-James Cancer Hospital
     Anti-VEGF Agents’ Proposed Mechanisms of Action
               Based on Preclinical Models




                May regress existing microvasculature1,2
          1     • Direct and rapid changes include a significant reduction in microvascular density, as
                seen in preclinical models1-3
                 May normalize surviving mature vasculature3-5
          2      • Reversal of structural and functional abnormalities may improve the vasculature’s
                 capacity for drug delivery, as seen in preclinical models3-5

                May inhibit vessel regrowth and neovascularization2,3,6
          3

1. Lee CG, Heijn M, di Tomaso E, et al. Cancer Res. 2000;60:5565-5570. ; 2. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.; 3.
Gerber HP, Ferrara N. Cancer Res. 2005;65:671-680.; 4. Jain RK. Science. 2005;307:58-62.; 5. Tong RT, Boucher Y, Kozin S, et al. Cancer Res.
2004;64:3731-3736.; 6. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.
                        First-Line Bevacizumab in MCRC:
                            Progression-Free Survival

                                      AVF2107g             NO16966                              BICC-C                                       TREE-2
                                              a
                                 12                                                    11.2
                                            10.6                     b
                                                                    9.4                                                                  9.9 10.3
                                 10                                             c
               PFS or TTP (mo)




                                                        8.0                     7.8                              8.3         8.3
                                  8
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aP<0.001; bP=0.0023; cP=0.003               vs mIFL.
Fuchs et al. ASCO, 2007. Abstract 4027; Hochster et al. ASCO, 2006. Abstract 3510;
Hurwitz et al. N Engl J Med. 2004;350:2335; Saltz et al. J Clin Oncol. 2008;26:2013.
                   First-Line Bevacizumab in MCRC:
                             Overall Survival

                              AVF2107g                 NO16966                            BICC-C                                    TREE-2


                         30                                                        28.0
                                                                                                                                  26.0 27.0
                                                                  b
                         25             a                               23.1
                                     20.3 19.9                   21.3                                                 20.7
                                                                                                          19.2
                         20                                                                 17.6
               OS (mo)




                              15.6
                         15

                         10

                          5

                          0
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aP<0.001; bP=0.0769.

Fuchs et al. ASCO, 2007. Abstract 4027; Hochster et al. ASCO, 2006. Abstract 3510;
Hurwitz et al. N Engl J Med. 2004;350:2335; Saltz et al. J Clin Oncol. 2008;26:2013.
                                   NO66: Bevacizumab in Combination With
                                     Oxaliplatin-Based Chemotherapy:


                                                  PFS                                                                            OS
                                     CapeOx/FOLFOX4 + bevacizumab                                                     CapeOx/FOLFOX4 + bevacizumab
                                     n=699; 513 events                                                                n=699; 420 events
                                     CapeOx/FOLFOX4 + placebo                                                         CapeOx/FOLFOX4 + placebo
                                     n=701; 547 events                                                                n=701; 455 events

                                     HR=0.83 (97.5% CI, 0.72-0.95)                                                    HR=0.89 (97.5% CI, 0.76-1.03)
                         1.0                                                                            1.0
                                     P=0.0023                                                                         P=0.0769
Proportion of patients




                                                                               Proportion of patients
                         0.8                                                                            0.8


                         0.6                                                                            0.6


                         0.4                                                                            0.4


                         0.2                                                                            0.2
                                            8.0     9.4                                                                        19.9       21.3
                          0                                                                              0
                               0        5          10         15     20   25                                  0   6     12        18        24        30   36
                                                    Months                                                                    Months



                Saltz et al. J Clin Oncol. 2008;26:2013.
      PIIR study of FOLFOX/Sunitinib vs
            FOLFOX/bevacizumab


                                                     Progression-Free Survival
                                                                                             Sunitinib (SU) + mFOLFOX6
                                          1.0                                                Median: 9.1 months (95% CI: 7.5–9.4)
                                                                                             Bevacizumab (BEV) + mFOLFOX6
                                                                                             Median: 11.2 months (95% CI: 9.1–15.6)
                   survival probability




                                          0.8
                    Progression-free




                                                                                                      HR =1.598 (95% CI: 0.9422.712)
                                                                                                      p = 0.96*
                                          0.6


                                          0.4


                                          0.2


                                           0
                                                0          2        4        6       8     10         12         14       16       18
                                                                                  Time (months)
           Patients at risk
           SU+ mFOLFOX6                         96    86       71       53   45    37   20      9     6      2        0        0   0
           BEV + mFOLFOX6                       95    86       73       55   48    34   21      14    12     4        2        1   0

           *p-value from 1-sided stratified log-rank test for superiority




Hecht et al , ASCO 2010                                    Higher toxicity with sunitinib
              VEGFR TKI’s in CRC
  Agent           #         mCRC Trials    CRC Patients
 Cediranib     AZD2171       2 Phase III       3,194
Semaxinib       SU5416       2 Phase III       2,084
 Vatalanib      PTK787       2 Phase III       2,050
 Sunitinib     SU11248       Phase III         1,623
 Brivanib     BMS-582664     Phase III         926
Regorafenib   BAY 73-4506    Phase III         730
 Sorafenib    BAY 43-9006    Phase IIB         814
Vandetanib      ZD6474       Phase IIB         356
  Axitinib    AG-013736      Phase IIB         299
 Linifanib     ABT-869       Phase IIB         147
 Vargateg     BIBF 1120       Phase II         166
 Tivozanib      AV-951        Phase II          80
Motesanib      AMG-706       Phase IB          148
Pazopanib     GW786034       Phase IB           94
                                            >10,000
               Courtesy of Scott Kopetz
                                        EGFR Activation
                               EGFR                                                         Metastatic
                             Activation                                                      Spread



                                                                                             Tumor




                                                                                                            Blood
                                                                                                            Vessel


                                                                                         Angiogenesis
                                                                                         Angiogenesis
                             Cell
                           Survival

                                                                                          Tumor




                                                                               Proliferation



Rowinsky EK. Annu Rev Med. 2004;55;433. Ritter CA, Arteaga CL. Semin Oncol 2003;30;3. Mendelsohn J. J Clin Oncol, 2002;20;1S.
Herbst RS, Shin DM, Cancer, 2002;94;1593-1611. Woodburn JR. Pharmacal Ther. 1999;82;241.
Colon Cancer Has Many Biologic Subsets That
 Differ in Response to EGFR-Targeted Agents


                                                  Low expression of EGFR ligands →
                                     EREG or AREG decreased response to EGFR targeted
                                                  agents




                                        EGFR
Mutant KRAS →
decreased response to
EGFR-targeted agents                                           PIP1

             KRAS                                PI3K                      PTEN

                                                                       PTEN loss of expression
                        Mutant BRAF →                          PIP3    → decreased response
         BRAF           ?decreased response to                         to EGFR-targeted agents
                        EGFR-targeted agents

                                    Signaling to the nucleus
    COIN Trial design
         Maughan et al

      Arm A    5FU or capecitabine
               oxaliplatin
       815
               CONTINUOUS CT until progression, toxicity or patient choice


               5FU or capecitabine
      Arm B    oxaliplatin
       815     cetuximab
               CONTINUOUS CT until progression, toxicity or patient choice




    >80% patients genotyped for KRAS, NRAS and BRAF
       43% KRAS mutation; 4% NRAS mutation; 8% BRAF mutation

.




                                                        Maughan et al; Abs 3502, ASCO 2010
      OS and PFS among KRAS wild-type patients

                                               Arm A   Arm B    Diff.                                      Arm A    Arm B        Diff.
                         Median OS : mo        17.9    17.0    -0.92                 Median PFS: mo         8.6      8.6        +0.07
                       2-year survival rates   36.1%   34.4%   -1.66%              2-year survival rates   8.83%    9.55%       +0.72%
    1.00
    0.75




                                     HR point estimate = 1.038                                     HR point estimate = 0.959
                                      95% CI = (0.90, 1.20)                                         95% CI = (0.84, 1.09)
                                        Χ2 = 0.18; p = 0.68                                           Χ2 = 0.27; p = 0.60
Survival
  0.50
    0.25




                   Arm A (OxFp)                                               Arm A (OxFp)

                   Arm B (OxFp + cetux)                                       Arm B (OxFp + cetux)
    0.00




           0   6        12      18     24        30     36     42       0      6         12       18    24     30          36     42
                               Time (months)                                                     Time (months)


                         Overall Survival                                     Progression-free Survival
                                                                    Maughan et al; Abs 3502, ASCO 2010
             PRIME Study – FOLFOX +/-
           Panitumumab in 1st Line mCRC

                                                                                Disease
                                               FOLFOX                          progression




                                                                                                                    Long term Follow up
                                                                                                 End of Treatment
                          Enrollment
              Screening




                                        Total n = 1,183




                                                                                                                                          End of study
                                        Stratification by:
                                        • Geographic Region
                                        • EGOG performance (0,1/2)




                                                FOLFOX +                        Disease
                                                                              progression
                                               panitumumab


          Study Description                                     Hypothesis                                                Endpoints
     A Randomized, Multicenter, Phase 3               The addition of panitumumab to          Primary Endpoint:
     Study to Compare the Efficacy of                 chemotherapy (FOLFOX) will increase     PFS
     Panitumumab in Combination with                  progression-free survival (PFS)
     Oxaliplatin/ 5-fluorouracil/ leucovorin          compared to chemotherapy (FOLFOX)       Secondary Endpoints:
     to the Efficacy of Oxaliplatin/ 5-               alone as first-line treatment of mCRC
                                                                                              OS, ORR, TTP, DOR, Safety
     fluorouracil/ leucovorin Alone in                among subjects with wild-type KRAS
     Patients with Previously Untreated               tumors and subjects with mutant KRAS
                                                      tumors.                                 Tertiary/Exploratory Endpoints:
     Metastatic Colorectal Cancer
                                                                                              TTR, Biomarkers, PRO

12
WT KRAS: Progression-Free Survival

                                                     Events         Median
                                                     n (%)      (95% CI) months
                     Panitumumab + FOLFOX            199 (61)    9.6 (9.2–11.1)
                     FOLFOX                          215 (65)    8.0 (7.5–9.3)
                     HR = 0.80 (95% CI: 0.66–0.97)
                     P-value = 0.02
WT KRAS: Overall Survival (Interim Analysis)
                                                             Events         Median
                                                             n (%)      (95% CI) months
                             Panitumumab + FOLFOX            106 (33)    NE (20.3, NE)

                             FOLFOX                          124 (37)   18.8 (17.2, NE)

                             HR = 0.83 (95% CI: 0.64–1.08)
                             P-value = 0.16
Summary of published Phase III 1st line CT + anti-EGFR
      combination data in KRAS WT patients

                                  CRYSTAL1                                COIN3                                 PRIME4
                             (FOLFIRI ± Cmab)                     (FOLFOX/XELOX ±                           (FOLFOX ± Pmab)
                           (from meta-analysis)                        Cmab)

                           Cmab               Control              Cmab              Control
                         (n = 316)           (n = 350)            (n = 668)         (n = 652)

    KRAS                              89%                                  81%                                       93%
    Ascertainment
    Rate

    RR (%)                 57.3               39.7                  49                 45                 55                      48

    Median PFS              9.9                8.4                  8.6               8.6                 9.6                     8.0
    (mos) (95% CI)



    Hazard                           0.696                                0.959                                       0.8
    Ratio                  (0.558 to 0.867, p = 0.0012)            (0.84 to 1.09; p = 0.60)                  (0.84 to 1.09; p = 0.60)
    (95% CI)

    Median OS              23.5               20.0                 17.0              17.9                 NE                     18.8
    (mos) (95%                                                 (22.2 to 27.8)     (19.2 to 25.7)
                                                                                                       (20.3 - NE)             (20.3 - NE)
    CI)


    Hazard                           0.796                                1.038                                         0.83
    Ratio                   (0.670 to 0.946, P = 0.0094)           (0.90 to 1.20; p = 0.68)                 (95% CI: 0.64–1.08)
    (95% CI)


1. Van Cutsem E, et al Eur J Can (suppl):a6.077, 3. Update from ECCO-ESMO , 2. Bokemeyer C, et al. Eur J Can(Supp)a6.079, 3. Saltz L, et al. J Clin Onc
2008;26:2013-2019, 4. Douillard et al ESMO 2009
Summary of 2nd line CT + anti-EGFR
combination data in KRAS WT patients
                                   EPIC1                                    1834
                           (Irinotecan ± Cmab)                        (FOLFIRI +/- Pmab)
                          KRAS WT Population                              KRAS WT

                         Cmab                       Control
                                                               FOLFIRI + Pmab          FOLFIRI
                        (n = 97)                    (n = 95)

KRAS Ascertain-ment                   23%                                       92%
Rate

                        10.3                         7.4            35                    10
RR (%)           (95%
CI)


                        3.98                        2.79            5.9                  3.9
PFS (mos) (95% CI)

                                      0.77                                      0.73
      Hazard Ratio                 (0.57 to 1.04)
      (95% CI)
                                                                     (0.59 to 0.90 p=0.004)


                        10.94                       11.56          14.5                 12.5
OS (mos) (95% CI)

      Hazard Ratio                    1.28                                      0.94
      (95% CI)                     (0.89 to 1.85)                     (0.76 to 1.15 p=0.55)
                      Conclusions
• The current standard of care for first line treatment of eligible
  patients with MCRC remains F-based chemotherapy +
  Bevacizumab.
    – Is Bevacizumab optimally used in combination with
      chemotherapy?
        • + FOLFIRI/XELIRI: Yes ( 5 mg/Kg qowk/7.5 mg/Kg q3wks)
        • + XELOX  Yes (7.5 mg/Kg q3wks)
        • + FOLFOX  Unclear in first line at 5 mg/Kg qowk – ?10 mg/Kg
          qowk? (ECOG 3200)
• Effect of bevacizumab on PFS and OS is independent of KRAS
  status
• In advanced CRC, evidence suggests that treating to
  progression may improve survival.
    – Balance effect with added risk of toxicity
                           Conclusions

• A role for EGFR inhibitors in first line treatment of select patients with
  potentially resectable disease is justifiable (KRAS WT).
• Anti-EGFR antibody therapy when added to oxaliplatin based therapy for
  patients with KRAS mutant tumors might be detrimental with respect to
  RR, PFS and OS. When combined with irinotecan , there is no added
  benefit to justify the added toxicities.
• Are EGFR inhibitors optimally used in combination with chemotherapy?
    – + Irinotecan  Cetuximab: Yes
                   Panitumumab: Yes
    – + Oxaliplatin  Cetuximab: No
                    Panitumumab: Yes
• Can Bevacizumab be safely combined with anti-EGFR mAbs?
    – + Cetuximab: No ( 1st line (CAIRO-2)
    – + Panitumumab: No (PACCE)
COIN : Mutations in Kras, Nras, Braf:
distribution and prognostic significance

                KRAS-mut            NRAS-mut                                                           Prognostic effect of mutational status
                n=565 (43%)         n=50 (4%)                                                                  Arm A                              Arm B




                                                                           Median PFS (months)
                                                                                                 12
 “All-wt”                                             BRAF-mut




                                                                                                 6
 n=581 (44%)                                          n=102 (8%)

                                         39




                                                                                                 0
                                    11




                                                                                                 18
                                                                           Median OS (months)
                                                102
                              554




                                                                                                 12
 Total
 n=1316 (81%)




                                                                                                 6
                                                                                                 0
                                                                                                 40
         Population                            N       Arm A       Arm B




                                                                           2-year OS (%)
                                                                                                 30
         ITT                                  1630       815        815




                                                                                                 20
         Assessed for mutations               1316       648        668


                                                                                                 10
         of which:
         - KRAS mutation                  565 (43%)      268        297
                                                                                                 0
         - NRAS mutation                    50 (4%)       18         32
                                                                                                        57         268         367         45         297 362
         - BRAF mutation                   102 (8%)       57         45                           N:         340         815         289        366      815  292
         KRAS wt                          729 (55%)      367        306                          Mutation status:
         KRAS/NRAS/BRAF-wt                                                                                BRAF mutation                          All patients
                                          581 (44%)      289        292
         “All wild-type”                                                                                  Any mutation                           KRAS wild-type
                                                                                                          KRAS mutation                          All wild-type
Mutations in Kras, Nras, Braf:
distribution and prognostic significance

                                                                  Prognostic effect of mutational status
                                                                          Arm A                              Arm B




                                      Median PFS (months)
                                                            12
                                                            6
                                                            0
 BRAF mutation: poorest prognosis




                                                            18
                                      Median OS (months)
                                                            12
                                                            6
                                                            0
                                                            40
                                      2-year OS (%)
                                                            30
 KRAS wt: superior prognosis


                                                            20
 compared to KRAS mut

                                                            10
                                                            0
                                                                   57         268         367         45         297 362
                                                             N:         340         815         289        366      815  292
                                                            Mutation status:

                                                                     BRAF mutation                          All patients
                                                                     Any mutation                           KRAS wild-type
                                                                     KRAS mutation                          All wild-type
Conclusions


• Strong prognostic effect of KRAS,
  BRAF and NRAS mutation status
  independent of the use of cetuximab
  – Limitation  No observation arm ( not
    really feasible)
N0147 : Is K-ras prognostic in
 FOLFOX treated patients?
                             100

                             90

                             80            Mut
                                           WT
  % Alive and Disease Free




                             70

                             60

                             50        K-ras Status    3 Year Rates               HR            P-value
                                                         (95% CI)              (95% CI)
                             40           WT                  75.8%               0.7            0.04
                                         N=902             (72.1-79.6%)        (0.5-0.9)
                             30
                                          Mut                 67.2%
                             20          N=374             (61.4-73.5%)

                             10

                              0
                                   0           6      12             18       24           30             36
                                                              Time (Months)
BRAF status is prognostic for OS but not RFS




 KRAS




 BRAF


             Relapse free survival (RFS)     Overal survival (OS)
                                           Roth, A. D. et al. J Clin Oncol; 28:466-474 2010
Cetuximab with chemotherapy (CT) as first-line treatment for metastatic
colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies
             according to KRAS and BRAF mutation status



• In this pooled analysis, a significant improvement in OS is
  demonstrated for patients with KRAS WT tumors receiving
  cetuximab plus chemotherapy vs. chemotherapy alone

• Patients with BRAF mutations appear to benefit from
  cetuximab, although a mutation in BRAF would appear to be an
  indicator of poor prognosis  BRAF is perhaps prognostic
  but not necessarily predictive.



        C. Bokemeyer, C.-H. Köhne, P. Rougier, C. Stroh, M. Schlichting, E. Van Cutsem
   KRAS mutation: Predictive and/or
           prognostic ?

PREDICTIVE – response to therapy
• KRAS mutation predicts non-response to EGFR inhibitor
  antibodies
PROGNOSTIC – outcome independent of treatment
• NO:
   –   PETACC 3
   –   3rd line Cetuximab / Panitumumab monotherapy trials
   –   CAIRO-2 – 1st line oxaliplatin / bevacizumab +/- cetuximab stage IV
   –   PACCE – 1st line chemo / bevacizumab +/- panitumumab stage IV


• YES:
   –   RASCAL – stage II/III colon cancer
   –   FOCUS – 1st line sequential treatment stage IV
   –   COIN – 1st line oxaliplatin / cetuximab stage IV
   –   N0147 – Adjuvant FOLFOX +/- cetuximab


• MAYBE:
   –   CRYSTAL – 1st line FOLFIRI / cetuximab stage IV
BRAF mutation: Predictive and/or prognostic ?


 • BRAF mutation is present in less than 10% of MCRC

 • BRAF mutation does not predict for EGFR resistance

 • BRAF mutation is prognostic for overall survival in MCRC ( including
   relapsed disease).

 • BRAF , TTR and tumor site predict for survival after relapse in
   patients with stage II and III CRC.
Future Biologics
   Hedgehog Inhibitors
• (Abstr 3530): Safety Analysis of a
  randomized phase II trial of hedgehog
  pathway inhibitor GDC-0449
  (vesmodegib) versus placebo with
  FOLFOX or FOLFIRI and bevacizumab in
  patients with previously untreated
  metastatic colorectal cancer (mCRC)

• Authors: Bendell, Hart, Firdaus, Gore,
  Hermann, Mackey, Graham, Zerivitz, Low,
  Berlin
                                    Hedgehog
        Hedgehog
Overexpression                                Mutation

                                   SMO        Celium Cell Membrane
        Patched
                 Mutation

                                   Gli            Activated    GDC-0449
         Inactive
         SMO                                         Gli
                            SuFu                                  Pathway Mechanism:
                                   Mutation                       Unknown
                            Nuclear Membrane


                                                          Hedgehog Gene
                                                          Targets: GLI1, BCL2, SNAIL, etc

                                              Proliferation and survival

                                              Stem Cell Maintenance

                                              Angiogenesis
    FOLFOX/ or FOLFIRI/B + GDC-0449


• Results: some concerning signals in tox data
   – More deaths in the GDC-0449 arm (4 vs 0)
   – Two sudden deaths; two pneumonias (unusual cause
     of death for colorectal patients?)
   – All deaths occurred before the median PFS for 1st line
     CRC (days 91, 95, 155, 231)
   – Slightly less exposure to conventional chemo and
     biologics in experimental arms

• No PK interactions (preliminary)
• Added toxicities consistent with phase I trial1
                        1Von Hoff, NEJM 2009
                 Perifosine


• (abstr 3531): Final results of a randomized
  phase II study of perifosine in combination with
  capecitabine (P-CAP) versus placebo plus
  capecitabine (CAP) in patients with second- or
  third-line metastatic colorectal cancer (mCRC)

• Authors: Richards, Nemunaitis, Vukelja,
  Hagenstad, Campos, Letzer, Hermann,
  Sportelli, Gardner, Bendell
                          Perifosine
                                                                    O       N




                                                                    =
                                                                    P
What is perifosine?                                             O
                                                                    O
                                                                        O

- Oral alkylphospholipid
- Related to miltefosine (FDA approved for breast CA cutaneous mets,
and leishmaniasis), which has significant GI side effects
- Mechanism of action is complex/unclear. Interacts with cell membrane
and inhibits AKT (indirectly?). Also inhibits NF-ĸB; facilitates degradation
of mTOR pathway members; activates JNK (apoptotic) pathway.
Phase I studies
-Phase I (daily dosing, 3 on, 1 off) in solid tumors (Eur J Ca 2002)
    - n=22, diarrhea and vomiting dose-limiting, MTD 200 mg/day
    - ½ life 105 hr; 11 CRC patients, no responses
- Phase I (weekly dosing) in solid tumors (Eur J Ca 2010)
    - n=36, diarrhea/vomiting, RP2D = 600 mg/wk
    - linear PK, ½-life 80 – 120 hr range, no responses
    Capecitabine +/- perifosine

• Small trial (n=38; interim analysis, no power
  calculation provided but primary endpoint TTP)
• Toxicity profile as expected; perifosine
  appeared to add fatigue, diarrhea, nausea,
  anemia. Also surprising rate of g3/4 HFS (30%)
  in combo arm
• Improvement in
  – Response rate (4 pts v 1 pt, n=35 total), most >1 yr
    (Only one response was in 5-FU refractory)
  - Time to progression (28 v. 11 weeks, HR=0.28)
  - Overall survival (17.7 v 10.9 mos, HR=0.41)
Results: capecitabine +/- perifosine


    ALL EVALUABLE PATIENTS                      5-FU REFRACTORY PATIENTS



              Median TTP: P-CAP:                            Median TTP: P-CAP:
           28 weeks [95% CI (12, 48)]                     18 weeks [95% CI (12, 36)]
               Median TTP: CAP:                               Median TTP: CAP:
            11 weeks [95% CI (9, 15.9)]                   10 weeks [95% CI (6.6, 11)]

                    p-value = 0.0012                               p-value = 0.0004

                      Hazard ratio: 0.284
                                                                      Hazard ratio: 0.186
                        (0.127, 0.636)
                                                                        (0.066, 0.521)




                                            Richards, ASCO 2010
    Signaling Pathway Target: PI3K
            Ligands



      p85                   PIP2          PIP3
                PI3K
               p110




Growth       PI3K inhibitors
Factor       (XL147, GDC-0941, PX-866,
Receptor     SF1126, BEZ235)                     AKT inhibitors
                                          AKT
                                                 (perifosine?, MK-2206
  Blocking the                                   GSK2141795, SR13668,
  Pathway                                        XL418, GSK690693)
                                   mTOR
                                          mTOR inhibitors
                                          (sirolimus, temsirolimus,
                                          everolimus, AP23573, AZD8055,
                                          OSI-027, palomid 529)
Combining Biologics ?
 Double-Targeting EGFR

EGFR




                    Compensatory
 Tyrosine Kinase    overexpression
 Inhibitor          of EGFR?

 Monoclonal
 Antibody




                    Endocytosis
                    of EGFR
EGFR
            Dual Targeting

•   EGFR + VEGFR ( mAB)  No Go
•   VEGF + mTOR  early signals
•   EGFR + VGFRR ( TKI)  Too toxic
•   Etc …
                  Conclusions
• Revealing the many molecules and pathways that go
  awry in tumor cells has and will allow us to develop
  precise strategies to attack cancer
   – Thousands of new drugs are being studied for cancer
     therapy
• We are moving to an era of predictive testing
  (enrichment strategies) and thus away from trial and
  error.
   – Kras mutational status and effectiveness of EGFR inhibitors
       • The example of Panitumumab and Cetuximab
   – Global gene expression profile as a tool to select targets

				
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