Castration-Resistant Prostate Cancer: Are We Done with Hormone Therapy?

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The clinical data from abiraterone acetate and enzalutamide confirm continued androgen receptor (AR) addiction in a significant proportion of castration-resistant prostate cancers (CRPC). Abiraterone acetate is a specific inhibitor of CYP17A1 and results in significant suppression of serum androgenic steroids and estrogen. Enzalutamide is a potent AR antagonist. Both agents improve the survival of CRPC patients. However patients invariably progress, often with a rise in PSA suggesting resumption of transcription of hormone-regulated genes. If abiraterone or enzalutamide-resistant cancers remain addicted to steroid receptor signaling, including but not exclusive to AR, how does reactivation occur? Or if cancers lose this addiction, do the same hormone-regulated oncogenic mechanisms continue to drive the disease? The future development of therapeutics for CRPC should be informed by an understanding of the mechanisms underlying disease progression following treatment with these novel agents. Tumor responses are being observed with sequential targeting of AR or steroidogenesis after abiraterone or enzalutamide but preliminary reports suggest lower response rates. This highlights the requirement for patient selection for future successful Phase III trials. Our experience with obtaining CRPC tumor biopsies and using them for molecular characterization will be discussed together with data obtained from circulating biomarkers including circulating tumor cells and circulating plasma nucleic acids.



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Castration-Resistant Prostate Cancer: Are We Done with Hormone Therapy?

  1. 1. Are  We  Done  with  Hormone  Therapy?  Gerhardt  A6ard  MD  MRCP  PhD  Cancer  Research  UK  Clinician  ScienAst  The  InsAtute  of  Cancer  Research  and    the  Royal  Marsden  NHS  FoundaAon  Trust  
  2. 2. Financial  disclosure  •  Abiraterone  was  developed  at  The  InsAtute  of  Cancer  Research  and  is  licensed  to  Cougar  Biotechnology/J&J.  The  ICR  also  has  a  commercial  interest  in  the  development  of  inhibitors  of  PI3K,  AKT  and  HSP90.  •  I  am  included  in  The  ICR  co-­‐inventors’  reward  scheme  of  abiraterone.  •  I  receive  research  funding  from  Astra  Zeneca  and  Genentech.  •  I  have  received  honoraria,  lecture  fees  and  travel  support  from  Sanofi,  Janssen,  Veridex,  Ipsen,  NovarAs,  Millenium  PharmaceuAcals,  Ventana/Roche.      
  3. 3. Survival  of  paAents  with  CRPC  is  improving  Omlin/Pezaro  Eur  Urol,  2013  •  259  chemo-­‐  naïve  paAents  •  median  OS  of  30.6  months    (95%  CI  27.6  –  36.5)    •  Treated  between  2003  and  2011  in  one  insAtuAon  Ø  Old  prognos:c  nomograms  under-­‐es:mate  median  survival  
  4. 4. ExciAng  Ames  for  CRPC  *Denotes  products  that  are  not  approved  for  use;  approval  dates  are  an  esAmate  only  2004        2005        2006        2007        2008        2009        2010        2011        2012        2013        2014        2015        2016        2017        2018  Abiraterone  Cabazitaxel  Sipuleucel-­‐T  Docetaxel  Mitoxantrone  (1996)  Androgen-­‐deprivaFon  therapies  EstramusFne  (1981)  Enzalutamide  CabozanFnib*  Prostvac  VF*  Ipilimumab*  Tasquinimod*  CusFrsen*  Radium-­‐223*  Orteronel*  
  5. 5. ExciAng  Ames  for  CRPC  –  and  the  AR  takes  center  stage  *Denotes  products  that  are  not  approved  for  use;  approval  dates  are  an  esAmate  only  2004        2005        2006        2007        2008        2009        2010        2011        2012        2013        2014        2015        2016        2017        2018  Abiraterone  Cabazitaxel  Sipuleucel-­‐T  Docetaxel  Mitoxantrone  (1996)  Androgen-­‐deprivaFon  therapies  EstramusFne  (1981)  Enzalutamide  CabozanFnib*  Prostvac  VF*  Ipilimumab*  Tasquinimod*  CusFrsen*  Radium-­‐223*  Orteronel*  
  6. 6. Treatments  in  development  for  CRPC  *Not  approved  for  use;  approval  dates  are  an  esAmate  only  2004        2005        2006        2007        2008        2009        2010        2011        2012        2013        2014        2015        2016        2017        2018  Abiraterone    Cabazitaxel  Sipuleucel-­‐T  Docetaxel  Mitoxantrone  (1996)  Androgen-­‐deprivaFon  therapies  EstramusFne  (1981)  CabozanFnib*  Prostvac  VF*  Ipilimumab*  Tasquinimod*  CusFrsen*  Radium-­‐223*  Orteronel*  Galeterone*  ARN-­‐509*  OGX-­‐047*  OMD-­‐201*  PARPi*  Enzalutamide  
  7. 7. Challenges  we  face  as  physicians  treaAng  CRPC  •  Is  there  a  role  for  sequencing  2nd  and  3rd  generaAon  AR  targeAng  drugs?  •  Is  there  a  role  for  combinaAons  of  AR  targeAng  drugs?  •  How  do  we  select  paAents  for  one  drug  versus  another?  •  Which  drug/class  of  agents  do  we  prioriAse  for  combinaAon  studies?  A@ard  and  de  Bono,  Clin  Cancer  Res,  2011  
  8. 8. Ø A  significant  number  of  paAents  with  castraAon-­‐resistant  prostate  cancer  have  disease  that  remains  driven  by  ligand  acAvaAon  of  the  androgen  receptor  
  9. 9. Abiraterone:  CYP17A1  inhibitor  Updated  Analysis  (775  Events)  •  Median  duraAon  of  follow-­‐up:  20.2  months  •  Median  duraAon  of  treatment:  AA,  8  months  vs  placebo,  4  months  Median  OS  Benefit:  4.6  Months  de  Bono  et  al,  NEJM  2011  
  10. 10. Ø Abiraterone  inhibits  adrenal  CYP17A1  and  causes  significant  suppression  of  serum  androgens  and  estrogens  Ø Tumor  CYP17A1-­‐dependent  synthesis  of  steroidogenic  ligands  has  been  demonstrated  in  preclinical  models  but  remains  unproven  in  paAents  (albeit  supported  by  strong  circumstanAal  data)    
  11. 11. Enzalutamide:  new  generaAon  AR  antagonist    Scher  H  et  al,  NEJM  2012  Survival(%)1008060MDV3100 800 775 701 627 400 211 72 7 0Placebo 399 376 317 263 167 81 33 3 0MDV3100: 18.3 months(95% CI: 17.3, NYR)Placebo: 13.6 months(95% CI: 11.3, 15.8)HR = 0.631 (0.529, 0.752) P < 0.000137% Reduction in Risk of Death402000 3 6 9Duration of Overall Survival, Months12 15 18 21 24Median  OS  Benefit:  4.8  Months  
  12. 12. Disease  progression  in  prostate  cancer  Chemotherapy  Tumor  volume  &  acFvity  NOTE:  This  diagram  represents  typical  disease  progression.  Some  paAents  are  metastaAc  at  diagnosis    and  are  thus  sAll  castraAon  sensiAve.    Abiraterone  &  enzalutamide  Abiraterone  PREVAIL  ongoing  
  13. 13. Abiraterone doubled time to rPFS inchemotherapy-naïve mCRPCIA3 data. rPFS assessed by investigator review at prespecified IA.1008060402000SubjectsWithoutProgressionorDeath(%)6 12 18 30 36245465423892442401331577820700AbirateronePrednisone11745Months From RandomizationAbirateronePrednisoneAbiraterone  (median,  mos):     16.5  Prednisone  (median,  mos):     8.3  HR  (95%  CI):     0.53  (0.45-­‐0.62)  p  Value:     <  0.0001  1593 21 27 334854063111761959913162662040Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)
  14. 14. OS favors abiraterone pre-chemotherapyIA3 data. aPrespecified significance level by O’Brien-Fleming Boundary = 0.0035.100806040200SubjectsWithoutDeath(%)6 12 18 30 3624546542524508482465421400686700AbirateronePrednisone333283Months From RandomizationAbirateronePrednisoneAbiraterone  (median,  mos):     35.3  Prednisone  (median,  mos):     30.1  HR  (95%  CI):     0.79  (0.66-­‐0.95)  p  Valuea:     0.0151  1593 21 27 33538534503492452437393361175153159Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)0
  15. 15. The challenge of demonstrating anOS benefit in pre-chemotherapy ptsaFirst patient crossover after unblinding on 7 May 2012. IA3 data clinical cut-of f date on 22 May 2012.bPrior to unblinding (eg. not per protocol). IA3 data.Abiraterone(n = 419)n (%)Prednisone(n = 482)n (%)No. with selected subsequenttherapy for mCRPCa 274 (65) 347 (72)Docetaxel 239 (57) 304 (63)Cabazitaxel 60 (14) 70 (15)Ketoconazole 39 (9) 63 (13)Abirateroneb 38 (9) 78 (16)Sipuleucel-T 33 (8) 28 (6)Ryan et al NEJM 2012
  16. 16. Ø However,  although  >90%  of  paAents  respond  to  castraAon,  the  response  rate  to  subsequent  AR  targeAng  is  up  to  50-­‐60%  
  17. 17. PSA  declines  with  abiraterone  (or  enzalutamide)  
  18. 18. PSA  declines  with  abiraterone  (or  enzalutamide)  
  19. 19. What  is  the  evidence  to  support  conAnued  targeAng  of  the  AR?  •  Hypothesis  1:  AR/steroid  receptor  signaling  remains  important  in  a  significant  proporAon  of  paAents  progressing  on  abi/enza  •  PSA  rising  at  progression  in  a  significant  number  of  paAents  Ø  Is  this  AR  driven?  •  Responses  with  repeated  targeAng  of  AR  •  AR  shows  conAnued  nuclear  expression  in  a  proporAon  of  paAents  
  20. 20. Combined    Image  DAPI   AR   Pan-­‐CK  Ki-­‐67   CD45  Nuclear  expression  of  AR  in  a  paAent  progressing  on  abiraterone  Combined  
  21. 21. TargeAng  the  AR  in  abi/enza  resistant  CRPC  •  Hypothesis  2:  CYP17A1  inhibiAon  without  concomitant  exogenous  glucocorAcoids  will  improve  efficacy  in  addiAon  to  reducing  toxicity      
  22. 22. Mechanism  of  acAon  of  abiraterone  in  humans  pregnenolone   progesterone   11-­‐DOC   corAcosterone   aldosterone  17α-­‐OH-­‐preg   17α-­‐OH-­‐prog  corAsol   corAsone  5α-­‐pregnane-­‐  17α-­‐ol-­‐3,20-­‐dione  5α-­‐pregnane-­‐  3α,17α-­‐diol-­‐20-­‐one  DHEA  DHEA-­‐S  androstenedione  testo   5α-­‐DHT   androstanediol   androsterone  CYP17A1  17α-­‐hydroxylase  CYP17A1  C17,20-­‐lyase  CYP17A1  C17,20-­‐lyase  A@ard  et  al,  J  Clin  Oncol  2008;  A@ard  et  al,  JCEM  2012  
  23. 23. Mechanism  of  acAon  of  abiraterone  in  humans  pregnenolone   progesterone   11-­‐DOC   corAcosterone   aldosterone  17α-­‐OH-­‐preg   17α-­‐OH-­‐prog  corAsol   corAsone  5α-­‐pregnane-­‐  17α-­‐ol-­‐3,20-­‐dione  5α-­‐pregnane-­‐  3α,17α-­‐diol-­‐20-­‐one  DHEA  DHEA-­‐S  androstenedione  testo   5α-­‐DHT   androstanediol   androsterone  CYP17A1  17α-­‐hydroxylase  CYP17A1  C17,20-­‐lyase  CYP17A1  C17,20-­‐lyase  A@ard  et  al,  J  Clin  Oncol  2008;  A@ard  et  al,  JCEM  2012  
  24. 24. Mechanism  of  acAon  of  abiraterone  in  humans  pregnenolone   progesterone   11-­‐DOC   corAcosterone   aldosterone  17α-­‐OH-­‐preg   17α-­‐OH-­‐prog  corAsol   corAsone  5α-­‐pregnane-­‐  17α-­‐ol-­‐3,20-­‐dione  5α-­‐pregnane-­‐  3α,17α-­‐diol-­‐20-­‐one  DHEA  DHEA-­‐S  androstenedione  testo   5α-­‐DHT   androstanediol   androsterone  CYP17A1  17α-­‐hydroxylase  CYP17A1  C17,20-­‐lyase  CYP17A1  C17,20-­‐lyase  
  25. 25. pregnenolone   progesterone   11-­‐DOC   corAcosterone   aldosterone  17α-­‐OH-­‐preg   17α-­‐OH-­‐prog  corAsol   corAsone  5α-­‐pregnane-­‐  17α-­‐ol-­‐3,20-­‐dione  5α-­‐pregnane-­‐  3α,17α-­‐diol-­‐20-­‐one  DHEA  DHEA-­‐S  androstenedione  testo   5α-­‐DHT   androstanediol   androsterone  CYP17A1  17α-­‐hydroxylase  CYP17A1  C17,20-­‐lyase  CYP17A1  C17,20-­‐lyase  ACTH  hypokalemia  hypertension  fluid  overload  Suppression  of  Renin  
  26. 26. AddiAon  of  exogenous  glucocorAcoids  suppresses  the  ACTH  drive  pregnenolone   progesterone   11-­‐DOC   corAcosterone   aldosterone  17α-­‐OH-­‐preg   17α-­‐OH-­‐prog  corAsol   corAsone  5α-­‐pregnane-­‐  17α-­‐ol-­‐3,20-­‐dione  5α-­‐pregnane-­‐  3α,17α-­‐diol-­‐20-­‐one  DHEA  DHEA-­‐S  androstenedione  testo   5α-­‐DHT   androstanediol   androsterone  CYP17A1  17α-­‐hydroxylase  CYP17A1  C17,20-­‐lyase  CYP17A1  C17,20-­‐lyase  …although  someAmes  incompletely  …are  long-­‐term  steroids  detrimental  in  a  propor:on  of  pa:ents?  
  27. 27. VT-­‐464:  can  complete  &  irreversible  C17,20-­‐lyase  inhibiAon  be  achieved  without  corAsol  suppression?      CompoundHuman CYP17Lyase IC50 (mM)Human CYP17HydroxylaseIC50 (mM)Human CYP17Lyase/HydroxylaseSelectivityVT-464 0.069 0.670 9.7Abiraterone 0.015 0.0025 0.170  10  20  30  Abiraterone   VT-­‐464   Vehicle  ng/ml  Pregnenolone  0  5  10  ng/ml  DeoxycorFcosterone  0  10  20  30  40  Abiraterone   VT-­‐464   Vehicle  ng/ml  Progesterone  0  200  400  Abiraterone   VT-­‐464   Vehicle  ng/ml  CorFcosterone  Eisner  et  al,  ENDO  2012    VT-­‐464  is  almost  60-­‐fold  more  lyase-­‐selecAve  than  abiraterone.  
  28. 28. VT-­‐464:  can  complete  &  irreversible  C17,20-­‐lyase  inhibiAon  be  achieved  without  corAsol  suppression?      Phase  1/2  study  underway  in  chemotherapy-­‐naïve  CRPC  paAents:  •  Exogeneous  glucocorAcoids  not  required  to  date  •  Dose-­‐related  decreases  in  androgens  observed  with  no  impact  on  corAsol,  pregnenolone,  progesterone  or  corAcosterone  levels  •  PSA  responses  observed  in  current  dose  cohort  (one  confirmed  response  @  12  weeks  with  92%  decrease  from  baseline)    •  Safety  and  tolerability  acceptable  to  date  A6ard,  PCF  Annual  retreat  Oct  2012,  Oral  PresentaAon  Royal  Marsden/University  of  Athens/St  Gallen  
  29. 29. TargeAng  the  AR  in  abi/enza  resistant  CRPC  •  Hypothesis  3:  LBD  targeAng  using  structurally  different  AR  antagonists/  with  funcAonally  disAnct  properAes  (AR  degradaAon?)/  lower  drug  brain  levels  will  prove  effecAve  •  (or  new  AR  targe:ng  drugs  can  be  posi:oned  differently)  •  ARN-­‐509    
  30. 30. ODM-­‐201:  significant  acAvity  (pre-­‐abiraterone/enzalutamide)  Massard  et  al,  ESMO  2012  
  31. 31. Sequencing  of  MDV3100  followed  by  abiraterone  MDV3100   abiraterone  Bianchini  et  al,  ESMO  2012  
  32. 32. Sequencing  of  MDV3100  followed  by  abiraterone  Bianchini  et  al,  ESMO  2012  
  33. 33. PSA  declines  on  docetaxel  aver  abiraterone  -­‐  clinical  evidence  for  cross-­‐resistance?  Mezynski,  Annals  of  oncol,  2012  Pa:ents  who  were  resistant  to  abiraterone  also  proved  resistant  to  docetaxel  
  34. 34. TargeAng  the  AR  in  abi/enza  resistant  CRPC  •  Hypothesis  4:  Re-­‐acAvaAon  of  AR  occurs  through  LBD-­‐independent  mechanisms    –  Repeated  LBD  targeAng  will  prove  ineffecAve  in  the  majority  of  paAents  •  Do  AR  splice  variants  cause  resistance?        
  35. 35.  Can  HSP90  inhibiAon  reverse  abiraterone  resistance  by  impacAng  AR  stability?  Centenera  et  al,  Clin  Cancer  Res  2012  Ø Two-­‐part  Phase  I/II  study  of  AT13387  alone  or  in  combinaAon  with  abiraterone      Ø Accrual  ongoing  Ø Mul:ple  CRPC  biopsies,  CTC  studies      OGX-­‐427  –  targeAng  HSP27  
  36. 36. TargeAng  the  AR  in  abi/enza  resistant  CRPC      Ø  Hypothesis  5:  EvaluaAon  of  an  unselected  paAent  populaAon  will  be  unsuccessful    Ø  AcAvity  in  treatment-­‐naïve  CRPC  but  can  a  survival  advantage  be  achieved  post  abi/enza?  
  37. 37. AR-­‐independent  disease  progression  •  75  year  old  previously  progressed  on  castraAon,  bicalutamide,  dexamethasone      –  Started  abiraterone  and  prednisone  in  Jan  2010  –  Baseline  PSA  50ng/dl    –  Good  PSA  response  (nadir:  6.7,  July  2010)    March 2011 June 1 Sep 15 Nov 8 Dec10 11 18 18 11Biopsied  x2  
  38. 38. AR  IHC   ERG  IHC   ERG  FISH  Pre-­‐treatment  biopsy  Tumor  biopsy  whilst  responding  to  treatment  New  liver  metastasis      CirculaAng  tumor  cells  N=36  
  39. 39. How  can  we  select  paAents?  Ø  Response  rates  to  abiraterone  are  equivalent  in  PTEN  loss  and  PTEN  normal  paAents  
  40. 40. ERG Rearranged ERG Normal TotalNo 20 42 6290% decline 12 3 1532 45 77P=0.001ERG Rearranged ERG Normal TotalNo 12 27 3950% decline 20 18 38Total 32 45 77P=0.07ERG Rearranged ERG Normal TotalNo 12 27 6250% -89% 8 15 3890% decline 12 3 1532 45 77P=0.007ERG  and  magnitude  of  PSA  decline  with  abiraterone  Attard et al, Cancer Res 2009
  41. 41. Will  paAents  with  AR  negaAve  CTC  prove  unresponsive  to  treatment?  •  AR  expression  levels  and  subcellular  localizaAon  can  be  quanAtated  on  each  CTC          Composite        DAPI                  CK                  CD45              AR          Composite        DAPI                  CK                  CD45              AR  Nuclear  AR  localizaFon  Cytoplasmic  AR  localizaFon  CD45  DAPI  CK  AR    CD45  DAPI  CK  AR    In  collaboraAon  with  Epic  Sciences  –  posters  presented  by  Dena  Marrinucci  and  Ryan  Di6amore  
  42. 42. Hit  the  AR  as  hard  as  possible  in  AR-­‐driven  prostate  cancer  •  Hypothesis  6:  Can  we  improve  the  efficacy  of  AR  targeAng  by  combining  CYP17A1  inhibitors  with  AR  antagonists?  
  43. 43. Hit  the  AR  as  hard  as  possible  in  AR-­‐driven  prostate  cancer  •  Hypothesis  6:  Can  we  improve  the  efficacy  of  AR  targeAng  by  combining  CYP17A1  inhibitors  with  AR  antagonists?  •  Does  abiraterone  achieve  a  truly  ligand  free  state?    
  44. 44. Residual  urinary  androgens  and  estrogens  in  paAents  treated  with  abiraterone  A@ard  et  al,  JCEM  2012  N=24  
  45. 45. Can  resistance  occur  through  selecAon  of  AR  mutaAons  acAvated  by  exogenous  glucocorAcoids  given  with  abiraterone?  T877A  L701H  AR    found  in    MDA  Pca  2b  cells  Richards  et  al,  Cancer  Res  2012  Zhao  et  al,  Nature  Med  2000  
  46. 46. Ø Abiraterone  is  a  weak  AR  antagonist  in  addiAon  to  a  potent  CYP17A1  inhibitor  Ø Uncertain  relevance  in  paAents    Ø Could  explain  some  of  the  acAvity  reported  in  preclinical  models  
  47. 47. Abiraterone  inhibits  growth  of  AR+  cancer  cells  grown  in  normal  medium  Ø  How  much  of  this  effect  is  AR  antagonism  versus  CYP17A1  inhibiAon?  Richards  et  al,  Cancer  Res  2012  
  48. 48. Abiraterone  inhibits  R1881  sAmulated  ARR3-­‐luciferase  acAvity  Ø  No  acAvaAon  observed  with  previously  described  AR  mutaAons  
  49. 49. Ø AddiAon  of  an  anA-­‐androgen  to  abiraterone  could  reverse  resistance  (or  increase  response  rate)  
  50. 50. Ø AddiAon  of  an  anA-­‐androgen  to  abiraterone  could  reverse  resistance  (or  increase  response  rate)  Ø Is  there  any  benefit  to  adding  a  CYP17A1  inhibitor  to  an  anA-­‐androgen?  
  51. 51. AR  inhibiAon  by  MDV3100  is  associated  with  an  increase  in  androgen  biosynthesis  T  Change  in  Bone  Marrow    Aspirate(%)  -­‐100  -­‐90  -­‐75  -­‐50  -­‐30  0  25  50  75  100  37  pa:ents  33  pa:ents  T  Change  in  Blood  (%)  -­‐100  -­‐90  -­‐75  -­‐50  -­‐30  0  25  50  75  100  Efstathiou  et  al.  J  Clin  Oncol  2011;  29(Suppl)  Bone  Marrow   Blood  
  52. 52. Blood  Testosterone    0.00  0.05  0.10  0.15  0.20  0.25  Week  8    ConcentraFon    (ng/mL)  Pretreatment                                                  Bone  Marrow  Testosterone  0.00  0.05  0.10  0.15  0.20  0.25  0.30  Week  8  ConcentraFon    (ng/mL)  End  of  Study    Pretreatment      Sustained  depleAon  of  testosterone    following  abiraterone  End  of  Study  Efstathiou  et  al.  J  Clin  Oncol    2012  
  53. 53. Increased  hormone  levels  reduce  inhibiAon  of  AR  acAvity  by  MDV3100  Richards et al, Cancer Res 2012
  54. 54. ADT + zoledronic acid + docetaxelADT + docetaxelADT-aloneADT + zoledronic acidADT + celecoxibADT + zoledronic acid + celecoxibSTAMPEDE  study  evaluaAng  AR  targeAng  in  hormone  therapy-­‐naïve  paAents  ABCDEPast accrual Possible future accrual Follow-upF2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017ADT + abiGADT + M1/RTHADT + enza+abiJ
  55. 55. Challenges  we  face  as  physicians  treaAng  CRPC  •  Is  there  a  role  for  sequencing  2nd  and  3rd  generaAon  AR  targeAng  drugs?  YES  BUT  IDEALLY  IN  SELECTED  PATIENTS  •  Is  there  a  role  for  combinaAons  of  AR  targeAng  drugs?  EVALUATION  WARRANTED  •  How  do  we  select  paAents  for  one  drug  versus  another?  MILLION  DOLLAR  QUESTION  •  Which  drug/class  of  agents  do  we  prioriAse  for  combinaAon  studies?  INHIBITORS  OF  PI3K/AKT….  A@ard  and  de  Bono,  Clin  Cancer  Res,  2011  
  56. 56. Acknowledgements  RMH/ICR  Prostate  Targeted  Therapy  Group  Johann  de  Bono,  Alison  Reid,  David  Olmos  Carmel  Pezaro,  Debbie  Mukherjee,  Dile6a  Bianchini,  Jo  Hunt,  Liz  Sheridan  Gal  Maier,  Bindu  Baikady,  Ajit  Sarvadikar  The  ICR  Alan  Ashworth,  Paul  Workman,  Elaine  Barrie  RMH  Academic  Urology  Unit  David  Dearnaley,  Chris  Parker  RMH  Academic  Biochemistry  M  Dowse6,  L  Folkerd  University  of  Birmingham  Wiebke  Arlt,  Angela  Taylor          The  ICR  Cancer  Biomarkers  Team  Roberta  Ferraldeschi,  Penny  Flohr,  Suzanne  Carreira,  Juliet  Richards,  Ai  Chiin  Lim,  Anna  Wingate,  Jane  Goodall,  Ruth  Riisnaes,  Susana  Miranda,  Ines  Figuereido,  Karolina  Nowakowska,  Mateus  Crespo,  Somi  Hedayat  University  of  Michigan  Rich  Auchus  Epic  Sciences  Dena  Marrinucci  and  Ryan  Di6amore  J&J/Cougar  Biotechnology  Arturo  Molina,  Thian  Kheoh  The  paFents  and  their  families    

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