Serial Microenvironment Targeted   Therapy Of Prostate Cancer Christopher J. Logothetis, M.D.
•   Chemotherapy•   The role of bone•   Accelerating progress•   Summary advances
Docetaxel in Castrate Resistant & Metastatic Prostate Cancer                                          Tannock et al
Solid Tumor Therapy              ParadigmOptimize therapy in advanced setting:Expect increased benefit when applied       ...
Accepted Model ofCancer ProgressionTreatment Sensitive   Treatment Resistant
Accepted Model ofCancer Progression                                                                         No effect on s...
Solid Tumor Therapy          ParadigmTherapeutic agents effective   in far advanced disease states will be more effective ...
Proposed Progression Model                                                                Chemotherapy resistance         ...
•   Chemotherapy•   The role of bone•   Accelerating progress•   Summary advances
Bone -Epithelial Central toProstate Cancer Progression          Epithelial         Bone development         program
Bone Consolidation Trial                   1                                                          Non-Randomized      ...
MDA-BF-1 in ActivatedOsteoblasts in Bone Metastasis     Vakar-Lopez et al. J. Pathol. 2004, 203: 688-695
MDA-BF-1 inhibits osteolytic   response of PC-3 cells in vivo PC3                        6 weeks          control SidePC/M...
MDA- BF1 in Progressive                         Prostate Cancer             Localized      Lymph            Androgen      ...
osteoblastPCa cells                              bone            MDA-BF-1                                    old          ...
“Two Compartment Model” Interaction of Autocrine &Paracrine loops in Epithelial and Host drives the organ   specific progr...
Microenvironment in  Prostate Cancer     Epithelial    Bone    microenvironment
Prostate Cancer Progression Model           Bone Microenvironment                DependenceNora Navone et al
Endocrine-to-Paracrine Androgen Signaling                Transition         Normal       Early       Invasive    Early-Sta...
Androgen-Mediated Progression      of Prostate Cancer Endocrine             Testosterone  Gonadal  Adrenal                ...
Androgen-Mediated Progression      of Prostate Cancer Endocrine                  Microenvironment             Testosterone...
Where Androgen Signaling & Tumor   Microenvironment Transect   Endocrine                  Microenvironment               T...
Adaptive Response of Androgen Signaling in CRPC                            Androgen        rich                           ...
Adaptive Response of Androgen Signaling in CRPC                          Androgen        rich                             ...
COU-AA-301: Abiraterone Acetate Improves              Overall Survival in Metastatic CRPC                      100        ...
Bone Discovery Platform                              Study Design                 Bone Marrow Biopsy and Aspirate Interval...
Maximizing Yield of “Blind” Transilial       Bone Marrow Biopsy   CT Directed
Cancer Acquisition Rates(“Directed” Transilial Bone Marrow Biopsy)Abiraterone Acetate Bone Marrow Trial            2007-05...
Modulation of Serum PSA Following                   Abiraterone Acetate Treatment                 100                     ...
Pretreatment Androgen SignalingPretreatment               0           1                   2          3Androgen Signaling  ...
Persistent Androgen Signaling in CRPC        With Bone MetastasesAR                 CYP17
Pretreatment CYP17 Expression in the        Tumor Correlates With Increased BMA             Testosterone Concentration    ...
Sustained Depletion of Testosterone  Following Abiraterone Acetate                                             Blood Testo...
Intense and Homogeneous Nuclear AR     Expression With CYP17 Co-expression    Correlate With Longer Treatment Duration    ...
Persistent nuclear AR expression in patients        with benefit from ABI at end of treatment    Nuclear AR Overexpression...
Modulation of AR Copy Number                                   (Preliminary Observations)           Primary Resistance, 8 ...
Adaptive Response of Androgen Signaling in CRPC                          Androgen        rich                             ...
Bone Marrow Biopsy Study                 MDV 3100Baseline           Week 8      Progression
Modulation of Serum PSA Following       MDV3100 Treatment                  100                        ≥ 30% Reduction: 56%...
Shift in AR subcellular localization                  following MDV3100            in patients with PSA declinePretreatmen...
AR Inhibition (MDV 3100) Increased                               Testosterone Concentration                     100       ...
Persistent androgen signaling driven by altered receptor oradaptive steroid synthesis is a  hallmark of prostate cancer   ...
Increased pSrc expression correlates           with resistance to MDV3100                           Non responders   Respo...
Adaptive Response of Androgen Signaling in CRPC                        Androgen        rich                               ...
Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone                      ...
Activation of Src kinase signaling in MDA-Pca-133 donor tumor and xenograft  AR                                 Phospho-Sr...
Effect of dastinib, a Src kinase inhibitor, in tumor                                             growth of MDA-Pca-133 xen...
Effect of dastinib, a Src kinase inhibitor, in tumor                                             growth of MDA-Pca-133 xen...
Dasatinib Inhibits Growth ofBone-selected MDA PCA 118b Cells Growing Intratibially                             MRI      Co...
Osteoclast Function:Dasatinib Inhibits Formation of Multi-nucleated Osteoclasts                                           ...
Phase 1/2 Dasatinib + Docetaxel         Trial on Metastatic Prostate   Dasatinib was administered orally on a once-daily ...
Maximum UNTx change from baseline                              100                                80   Bisphosphonate   No...
PSA response curve during and post docetaxel (continued on          Dasatinib)        9/09 Last        Docetaxel          ...
PSA response curve during and post docetaxel (continued on          Dasatinib)     5/09 Last     Docetaxel                ...
Dasatinib In Castrate Resistant &              Metastatic Prostate Cancer mCRPC                 Docetaxel 75 mg/m2 1st lin...
•   Chemotherapy•   The role of bone•   Accelerating progress•   Summary advances
Docetaxel in Castrate Resistant &  Metastatic Prostate Cancer                            Tannock et al
Prostate Cancer
New Approach       No.CVD    30KAVE   30                     1st             η = µ +αY + βZTE+E   30                     2...
Current Practice                 α         +      α           PatientRegimen   +                                  success ...
Protocol Allocation     Prostate Cancer                 TEE   KAVE   CVD   TECFirst Regimen           61    57   48    66S...
Most Efficacious     SequenceCVD (1)       TEC (2)
Beneficial Effect of a  “Reasoned” Treatment Approach           1.0           0.8                                         ...
Relative Impact of SerialTherapy on Overall Survival                            1.0                            0.8        ...
Chemotherapy & Castrate     Resistant Prostate Cancer• Castrate Resistant Prostate Cancer is a    chemotherapy sensitive C...
Serial Application of Therapy           Interaction   ImpactRelative            Between      OverallEfficacy           Reg...
Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone                      ...
Synergy Between       Microenvironment Targeting               Therapies              R        Sunitinib +         Sunitin...
Effect of Serial      Targeted TherapiesT1                 T2               T3     A+S vs. A+D        A+S → A+D        All...
Serial Application of Therapy           Interactio               n        ImpactRelative                           Link To...
Microenvironment pathways  implicated in resistance tomaximal androgen ablation are prioritized for individualized     the...
XL184 :Initial Clinical Observations                          woven bone
•   Chemotherapy•   The role of bone•   Accelerating progress•   Summary advances
Androgen Receptor Signaling in Prostate     Cancer Involves Multiple Pathways                                     Growth F...
Genetic Networks                      (anticipated outcome)         DHTDihydrotestosterone
Cancer Detection in REDUCE byTime, Treatment and Gleason Score                             Years 1-2               Years 3...
Genetic Networks                      (anticipated outcome)         DHT                    ARDihydrotestosterone         A...
“Earlier” Use of Androgen Biosynthesis Inhibitor                                       ABI
Genetic Networks                      (anticipated outcome)         DHT                    AR                   Non       ...
Chronic Myelogenous Leukemia                   “Oncogene                   Addiction”                                     ...
Proposed Progression Model                                                                   Chemotherapy resistance      ...
Small Cell Carcinoma
The “Anaplastic” Prostate CarcinomasMorphologically heterogeneousProstate Cancers with clinical featurescommon to small ce...
“A Phase II Study of Carboplatin plus Docetaxel in Patients with Anaplastic                                 Prostate Carci...
DNA Methylation Profiles of the             Anaplastic Prostate CarcinomasSCC-1 (MDA 40)    AR    SCC-2 (MDA 46)          ...
Androgen Signaling Networks                     (Progression)                                                       -     ...
Control Primary                             Systemic Therapy                Control Primary               SystemicNo Thera...
AcknowledgmentsM. D. Anderson Cancer CenterGenitourinary Medical Oncology W. Arap                  M. Karlou J. Araujo    ...
Adaptive Response of Androgen Receptor Signaling in CRPC                            Androgen        rich                  ...
Current Landscapes in the Management of Prostate Cancer
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Current Landscapes in the Management of Prostate Cancer

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Christoper Logothetis, M.D., Dept. Chair, Dept. of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center: Current Landscapes in the Management of Prostate Cancer

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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Current Landscapes in the Management of Prostate Cancer

  1. 1. Serial Microenvironment Targeted Therapy Of Prostate Cancer Christopher J. Logothetis, M.D.
  2. 2. • Chemotherapy• The role of bone• Accelerating progress• Summary advances
  3. 3. Docetaxel in Castrate Resistant & Metastatic Prostate Cancer Tannock et al
  4. 4. Solid Tumor Therapy ParadigmOptimize therapy in advanced setting:Expect increased benefit when applied in earlier disease state. Control Primary Systemic Therapy
  5. 5. Accepted Model ofCancer ProgressionTreatment Sensitive Treatment Resistant
  6. 6. Accepted Model ofCancer Progression No effect on survival (androgen dependent PCa) A 1.0 Median (95% CI) Androgen Ablation 65 (56, 93) 0.8 Chemohormonal 74 (61, 120+) Overall Survival Probability P = 0.41 0.6 0.4 0.2Treatment Sensitive Treatment Resistant 0 0 20 40 60 80 100 120 Months from Initiation of Hormone Therapy # At Risk, "AA": 135 92 55 27 12 # At Risk, "CH": 125 92 58 32 7
  7. 7. Solid Tumor Therapy ParadigmTherapeutic agents effective in far advanced disease states will be more effective in earlier states
  8. 8. Proposed Progression Model Chemotherapy resistance Autocrine Lethality Paracrine Epithelial Physiology dysregulation Time
  9. 9. • Chemotherapy• The role of bone• Accelerating progress• Summary advances
  10. 10. Bone -Epithelial Central toProstate Cancer Progression Epithelial Bone development program
  11. 11. Bone Consolidation Trial 1 Non-Randomized Sr-89/Adriamycin .8 Adriamycin OnlyOverall Survival .6 .4 .2 0 0 10 20 30 40 50 60 70 80 Time from Registration, mo Tu et al Lancet 2003
  12. 12. MDA-BF-1 in ActivatedOsteoblasts in Bone Metastasis Vakar-Lopez et al. J. Pathol. 2004, 203: 688-695
  13. 13. MDA-BF-1 inhibits osteolytic response of PC-3 cells in vivo PC3 6 weeks control SidePC/MDA- 6 weeksBF1 control Side
  14. 14. MDA- BF1 in Progressive Prostate Cancer Localized Lymph Androgen Node independent BoneEpitheliumStroma
  15. 15. osteoblastPCa cells bone MDA-BF-1 old lamella bone new MDA- woven BF-1 bone
  16. 16. “Two Compartment Model” Interaction of Autocrine &Paracrine loops in Epithelial and Host drives the organ specific progression of prostate cancer
  17. 17. Microenvironment in Prostate Cancer Epithelial Bone microenvironment
  18. 18. Prostate Cancer Progression Model Bone Microenvironment DependenceNora Navone et al
  19. 19. Endocrine-to-Paracrine Androgen Signaling Transition Normal Early Invasive Early-Stage Lethal Physiologic Cancer Cancer Metastatic Cancer State Cancer Proposed Model of Prostate Cancer Progression Role of endocrine-to-paracrine androgen signaling transition Efstathiou et al. Clin Cancer Res. 2010.
  20. 20. Androgen-Mediated Progression of Prostate Cancer Endocrine Testosterone Gonadal Adrenal AR DHT
  21. 21. Androgen-Mediated Progression of Prostate Cancer Endocrine Microenvironment Testosterone Gonadal Adrenal AR DHT CYP17
  22. 22. Where Androgen Signaling & Tumor Microenvironment Transect Endocrine Microenvironment Testosterone Gonadal Adrenal AR DHT CYP17
  23. 23. Adaptive Response of Androgen Signaling in CRPC Androgen rich AR AR AR PSA AR Genomic Signaling Castration/ Disease Progression SRC/ SH2 P mAR P AR AR mAR mAR Cell survival/anti-apoptotic CYP17 PSA Increased intracrine AR overexpression Interface of AR signaling steroid biosynthesis mutant/isoform AR with other pathways (src, cMET, Hh and others)
  24. 24. Adaptive Response of Androgen Signaling in CRPC Androgen rich AR AR AR PSA AR Genomic Signaling Castration/ Disease Progression AR CYP17 Increased Intracrine steroid biosynthesis
  25. 25. COU-AA-301: Abiraterone Acetate Improves Overall Survival in Metastatic CRPC 100 HR = 0.646 (0.54-0.77) P < 0.0001 FDA Approved Apr 28, 2011 80 Abiraterone acetate: 14.8 months (95% CI: 14.1-15.4) Survival (%) 60 40 Placebo: 10.9 months (95% CI: 10.2-12.0) 20 AA Placebo 0 0 3 6 9 12 15 18 21 Time to Death (Months)CRPC, castrate resistant prostate cancer. De Bono et al. N Engl J Med. In press.
  26. 26. Bone Discovery Platform Study Design Bone Marrow Biopsy and Aspirate Intervals Abiraterone AcetateBaseline* Week 8* Maximum Progression* Response*/** *Tissue: 1) Serum and plasma blood and bone marrow aspirate 2) Transilial bone marrow biopsy **Variable time point/optional
  27. 27. Maximizing Yield of “Blind” Transilial Bone Marrow Biopsy CT Directed
  28. 28. Cancer Acquisition Rates(“Directed” Transilial Bone Marrow Biopsy)Abiraterone Acetate Bone Marrow Trial 2007-0590 (56 pts)Bone marrow involvement detected by transilial 30 (54%)biopsy (all time points)Baseline tumor infiltrated bone marrow 27 (48%)Paired tumor infiltrated bone marrow (>5%) 17 (30%)Baseline specimens evaluable for IHC (>5% tumor 25 (45%)infiltration)Baseline tumor infiltration ≥20% (FISH) 15 (27%)Bone marrow aspirates 50 (89%)
  29. 29. Modulation of Serum PSA Following Abiraterone Acetate Treatment 100 ≥ 30% Reduction: 59% (34/56) 75 ≥ 50% Reduction: 48% (28/56) 50 ≥ 90% Reduction: 16% (9/56)PSA Change (%) 25 0 -30 -50 -75 -90
  30. 30. Pretreatment Androgen SignalingPretreatment 0 1 2 3Androgen Signaling No (<25%) (25%-75%) (>75%)Components expressionNuclear AR 0 0 8 17CYP17 4 5 8 8 Mean Range in ng/mL (n)Bone marrow aspirate 0.056testosterone (ng/mL) 0.0000-0.257 (50)Bone marrow aspirate 0.001dihydrotestosterone (0.000-0.04)Blood testosterone 0.044(ng/mL) 0.0000-0.214 (52)Blood 0.01dihydrotestosterone (0.00-0.0459)
  31. 31. Persistent Androgen Signaling in CRPC With Bone MetastasesAR CYP17
  32. 32. Pretreatment CYP17 Expression in the Tumor Correlates With Increased BMA Testosterone Concentration BMA-T.Plasma MS (ng/mL) 0.25 0.20 0.15 0.10 0.05 0.0 CYP17 ≥10% No CYP17 Expression CYP17 Expression No CYP17 Expression P Value, in Tumor ≥10% in Tumor Wilcoxon BMA-T, ng/mL (mean ± SD) 0.074 ± 0.070 0.026 ± 0.019 0.045BMA, bone marrow aspirate; BMA-T, bone marrow aspirate, testosterone.
  33. 33. Sustained Depletion of Testosterone Following Abiraterone Acetate Blood Testosterone 0.25Concentration 0.20 (ng/mL) 0.15 0.10 0.05 0.00 Pretreatment Week 8 End of Study Bone Marrow Testosterone 0.30 Concentration 0.25 (ng/mL) 0.20 0.15 0.10 0.05 0.00 Pretreatment Week 8 End of Study
  34. 34. Intense and Homogeneous Nuclear AR Expression With CYP17 Co-expression Correlate With Longer Treatment Duration Primary Resistance* Stable Response P Value N (%) N (%)>90% nuclear AR expression and≥10% CYP17 expressionin the tumor epithelium 1 (7) 13 (93) <0.001Lack of one or both 10 (91) 1 (9) 1.0 Progression Proportion 0.8 0.6 0.4 0.2 0.0 *Time to treatment 0 100 200 300 400 500 discontinuation Time (Days) <4 months (122 days)
  35. 35. Persistent nuclear AR expression in patients with benefit from ABI at end of treatment Nuclear AR Overexpression at Progression Pretreatment End of TreatmentBenefit 9/11Primary 2/6Resistance (P value :0.04)
  36. 36. Modulation of AR Copy Number (Preliminary Observations) Primary Resistance, 8 wks 0 wks Primary Resistance 8 wks 0 wks Responder, 8 wks 0 wks Responder , 8 wks 0 wks Responder , 8 wks 0 wks Responder , 8 wks 0 wks 0 20 40 60 80 100 120 140 160 180 Copy NumberqPCR on ≥500 cells.
  37. 37. Adaptive Response of Androgen Signaling in CRPC Androgen rich AR AR AR PSA AR Genomic Signaling Castration/ Disease Progression mAR AR mAR mAR CYP17 PSA Increase steroid AR Overexpression biosynthesis mutant/isoform AR
  38. 38. Bone Marrow Biopsy Study MDV 3100Baseline Week 8 Progression
  39. 39. Modulation of Serum PSA Following MDV3100 Treatment 100 ≥ 30% Reduction: 56% (29/52) 75 ≥ 50% Reduction: 46% (24/52) 50 ≥ 90% Reduction: 20% (10/52) PSA Change (%) 25 0 -30 -50 -75 -90
  40. 40. Shift in AR subcellular localization following MDV3100 in patients with PSA declinePretreatment Week 8Nuclear Localization Cytoplasmic Localization
  41. 41. AR Inhibition (MDV 3100) Increased Testosterone Concentration 100 100 80 80 T Change in Plasma (%) 60 60 40 40T Change in BM (%) 20 20 -20 -20 -40 -40 -60 -60 -80 -80 -100 -100 Patients Patients Pretreatment Week 8 P value (mean) (mean) (wilcoxon) Bone Marrow Τ 0.026 0.04 0.0001 Bone Marrow DHT 0.0 0.003 0.335 Blood Τ 0.041 0.066 <0.0001 Blood DHT 0.002 0.007 0.008
  42. 42. Persistent androgen signaling driven by altered receptor oradaptive steroid synthesis is a hallmark of prostate cancer progression and a central component of the tumor microenvironment
  43. 43. Increased pSrc expression correlates with resistance to MDV3100 Non responders Responders P value Wilcoxon’s rank testMean pSrc Expression (%) 70 10 0.002 (Range) (0-90) (0-30)
  44. 44. Adaptive Response of Androgen Signaling in CRPC Androgen rich AR AR AR PSA AR Genomic Signaling Castration/ Disease Progression SRC/ SH2 P mAR P AR AR mAR mAR Cell survival/anti-apoptotic CYP17 PSA Increase steroid Generation of mutant Non-genomic AR signaling biosynthesis /isoform AR Activation of SRC kinase, cMET,Hh
  45. 45. Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone Acetate (Preliminary Observations) Pretreatment End of Treatment Phospho-Src Increase at End of TreatmentBenefit 4/8 P-SrcPrimary 5/6resistance (P value: 0.05) H&E Patient with primary resistance to abiraterone acetate
  46. 46. Activation of Src kinase signaling in MDA-Pca-133 donor tumor and xenograft AR Phospho-Src Donor tumor AR Phospho-Src Xenograft V. Tzelepi
  47. 47. Effect of dastinib, a Src kinase inhibitor, in tumor growth of MDA-Pca-133 xenograft 2000 Control, n=5Tumor growth (Mean sem) mm3 Castrated, n=4 1500 Dasatinib, n=5 Cast/Dasatinib, n=4 1000 500 0 Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32 Days of Dasatinib treatment J. Song and G. Gallick
  48. 48. Effect of dastinib, a Src kinase inhibitor, in tumor growth of MDA-Pca-133 xenograft 2000 Control, n=5 Inhibition of Paracrine AR signaling & interacting ”SE” will enhance efficacy ofTumor growth (Mean sem) mm3 Castrated, n=4 therapy 1500 Dasatinib, n=5 Cast/Dasatinib, n=4 1000 500 0 Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32 Days of Dasatinib treatment J. Song and G. Gallick
  49. 49. Dasatinib Inhibits Growth ofBone-selected MDA PCA 118b Cells Growing Intratibially MRI Control Treated P=0.045 155.5 mm3 30.5 mm3 Park, Gallick, Navone
  50. 50. Osteoclast Function:Dasatinib Inhibits Formation of Multi-nucleated Osteoclasts M-CSF MCSF + RL Cont. 1500 1.25nM Osteoclasts/well 1000 5nM 500 +TRAP 0 10nM M-CSF + RL: + + + + + + Dasat (nM): 0 . 1.3 2.5 5 10 20 20nM Araujo and Darnay, unpublished
  51. 51. Phase 1/2 Dasatinib + Docetaxel Trial on Metastatic Prostate  Dasatinib was administered orally on a once-daily schedule  Docetaxel was administered intravenously every 21 days  At least three patients were enrolled at each dose level Day 3 Continuous daily dasatinib Day 21 Day 1 Day 14 Docetaxel Docetaxel (Dasatinib Docetaxel Docetaxel (Combination(PK analysis) PK analysis) PK analysis) John Araujo, MD, PhD. PI
  52. 52. Maximum UNTx change from baseline 100 80 Bisphosphonate No bisphosphonate 60 40 20 Max % Change from Baseline 0 BENEFIT -20 -40 -60 -80 -100
  53. 53. PSA response curve during and post docetaxel (continued on Dasatinib) 9/09 Last Docetaxel 19 months on single agent dasatinib with undetectable PSA
  54. 54. PSA response curve during and post docetaxel (continued on Dasatinib) 5/09 Last Docetaxel 22 months on single agent dasatinib
  55. 55. Dasatinib In Castrate Resistant & Metastatic Prostate Cancer mCRPC Docetaxel 75 mg/m2 1st line R Dasatinib 100 mg po dailyStratification A Prednisone 5 mg po BIDPS 0, 1 vs. 2 NUrinary NTX D O M Docetaxel 75 mg/m2 I Prednisone 5 mg po daily Z Placebo E
  56. 56. • Chemotherapy• The role of bone• Accelerating progress• Summary advances
  57. 57. Docetaxel in Castrate Resistant & Metastatic Prostate Cancer Tannock et al
  58. 58. Prostate Cancer
  59. 59. New Approach No.CVD 30KAVE 30 1st η = µ +αY + βZTE+E 30 2ndTE+C 30 120
  60. 60. Current Practice α + α PatientRegimen + success ∆ to β β β - + + • Rapid selection of most effective regimen • Arrives to patient success rapidly
  61. 61. Protocol Allocation Prostate Cancer TEE KAVE CVD TECFirst Regimen 61 57 48 66Second Regimen 22 13 13 25 TOTAL 83 70 61 91
  62. 62. Most Efficacious SequenceCVD (1) TEC (2)
  63. 63. Beneficial Effect of a “Reasoned” Treatment Approach 1.0 0.8 Serial CHT 0.6 0.4 0.2Taxotere 0.0 0 20 40 60 80 Months from initiation of chemotherapy
  64. 64. Relative Impact of SerialTherapy on Overall Survival 1.0 0.8 0.6 Serial CHT 0.4 0.2 Taxotere 0.0 0 20 40 60 80 Months from initiation of chemotherapyTaxotere vs Mitanzantrone Taxotere vs. Serial chemotherapy* *simulation
  65. 65. Chemotherapy & Castrate Resistant Prostate Cancer• Castrate Resistant Prostate Cancer is a chemotherapy sensitive Combination(s) may provide advantage• Serial use of chemotherapy applied based on “principles of cancer therapy” can provide further benefit• Integration into primary treatment
  66. 66. Serial Application of Therapy Interaction ImpactRelative Between OverallEfficacy Regimens Survival
  67. 67. Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone Acetate (Preliminary Observations) Pretreatment End of Treatment Phospho-Src Increase at End of TreatmentBenefit 4/8 P-SrcPrimary 5/6resistance (P value: 0.05) H&E Patient with primary resistance to abiraterone acetate
  68. 68. Synergy Between Microenvironment Targeting Therapies R Sunitinib + Sunitinib + A abiraterone abiraterone O N acetate acetate F D F OAbiraterone M acetate I S Z T A Dasatinib + Dasatinib + U T abiraterone abiraterone D I acetate acetate Y O N Circulating Microenvironment
  69. 69. Effect of Serial Targeted TherapiesT1 T2 T3 A+S vs. A+D A+S → A+D Allocation new Rx A+D → A+S
  70. 70. Serial Application of Therapy Interactio n ImpactRelative Link To Between OverallEfficacy Biology Regimen Survival s
  71. 71. Microenvironment pathways implicated in resistance tomaximal androgen ablation are prioritized for individualized therapy development
  72. 72. XL184 :Initial Clinical Observations woven bone
  73. 73. • Chemotherapy• The role of bone• Accelerating progress• Summary advances
  74. 74. Androgen Receptor Signaling in Prostate Cancer Involves Multiple Pathways Growth Factors and Their Receptors T T 5-alpha Reductase MAPKKK P13K (I,II,III) Caspase9 PTEN Bad MAPKK P27 DHT AKT MAPK DHT P P ARLi J. and Kim J., 2009
  75. 75. Genetic Networks (anticipated outcome) DHTDihydrotestosterone
  76. 76. Cancer Detection in REDUCE byTime, Treatment and Gleason Score Years 1-2 Years 3-4 Placebo Dutasteride Placebo DutasterideNo. Subjects Biopsied 3345 3929 2342 2446Gleason 5-6 401 290 216 147Gleason 7 (3+4) 125 99 51 47Gleason 7 (4+3) 32 28 6 17Gleason 8-10 18 17 1 12 (0.5%) (0.5%) (0.04%) (0.5%)
  77. 77. Genetic Networks (anticipated outcome) DHT ARDihydrotestosterone Androgen Signaling
  78. 78. “Earlier” Use of Androgen Biosynthesis Inhibitor ABI
  79. 79. Genetic Networks (anticipated outcome) DHT AR Non ARDidydrotestosterone Androgen Microenvironment Signaling Dependent
  80. 80. Chronic Myelogenous Leukemia “Oncogene Addiction” “Blast Crisis” BCR- ABLProstate Cancer “Microenvironment Dependence” Androgen S-E Signaling Independent Network Progression Elucidating signaling network will lead to combinatorial microenvironment targeting
  81. 81. Proposed Progression Model Chemotherapy resistance Autocrine Lethality Paracrine Epithelial Physiology dysregulation Time Microenvironment Dependence
  82. 82. Small Cell Carcinoma
  83. 83. The “Anaplastic” Prostate CarcinomasMorphologically heterogeneousProstate Cancers with clinical featurescommon to small cell carcinomasrepresent a significant subset of thelethal disease. APARICIO, A. 2009
  84. 84. “A Phase II Study of Carboplatin plus Docetaxel in Patients with Anaplastic Prostate Carcinoma” MDA 2006-0097 - PCCTC#c05-015 PSA at Registration 200 150 100 60 ng/dL 40 20 3.2 0 PSAAPARICIO, A. 2009
  85. 85. DNA Methylation Profiles of the Anaplastic Prostate CarcinomasSCC-1 (MDA 40) AR SCC-2 (MDA 46) -1,000 +500 Ward Linkage and Absolute Correlation Coefficient DistanceSCC-3 (MDA 91b) SCC-4 (MDA 144-13) 39.08 59.38 Similarity AC-1 (MDA 43) AC-2 (MDA 75) 79.69 100.00 SCC-4 SCC-2 SCC-1 SCC-3 AC-1 AC-4 AC-3 AC-2 Xenografts AC-3 (MDA 80) AC-4 (MDA 137) APARICIO, A. 2009
  86. 86. Androgen Signaling Networks (Progression) - DHT AR Non Non AR AR Didydro- Androgen Micro- ARtestosterone Signaling Environment Interference Dependent
  87. 87. Control Primary Systemic Therapy Control Primary SystemicNo Therapy Therapy Microenvironment Targeting
  88. 88. AcknowledgmentsM. D. Anderson Cancer CenterGenitourinary Medical Oncology W. Arap M. Karlou J. Araujo Z. G. Li D Tsavachidou A. Aparicio S. W. Lin T. Thompson P. Corn S. Maity S.M. Tu E. Efstathiou R. Millikan V. Tzelepi G. Gallick N. Navone X. Wan I. Gorlov R. Pasqualini J. Yang P. Sharma A. ZuritaPathology Urology ImagingP. Troncoso C. Pettaway V. Kundra J. Davis L. Pisters Rice UniversityTexas A& M University C. Farach-CarsonW. L. McKeehan Institute for Molecular MedicineF. Wang M .KoloninUniversity of Athens NijmegenE Efstathiou P. Friedl
  89. 89. Adaptive Response of Androgen Receptor Signaling in CRPC Androgen rich AR AR AR PSA AR Genomic Signaling Castration/Abiraterone treatment SRC/ SH2 P mAR P AR AR mAR mAR Cell survival/anti-apoptotic CYP17 PSA Increase steroid Generation of mutant Non-genomic AR signaling biosynthesis /isoform AR Activation of SRC kinase

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