Synergy Team 3 Annual DOD Site Visit 2004

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Synergy Team 3 Annual DOD Site Visit 2004
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DoD
Synergy Teams Opportunity for
Translational Investigation Bench
Bedside Therapeutic Trinity Tests OPpy

• LIPID RAFTsAR-gtPIP3-gtAKT-gtANTIAPOPTOSIS
• PTEN -/- TOR SENSITIVE/EGFR INDEPENDENT HRPCA
• LuCAP35 Model/2me2 anti HIF/hre ADM Project
• LuCAP35 Models/LuCAP21/LuCAP41 /AR-coactivator-cor
  epressor Signal
• Output targeting

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Synergy Map Year 1 New Candidate LuCAP35
Models/LuCAP21/LuCAP41 /AR-coactivator-corepresso
r Signal Output targeting Sawyers/Rosen/Vessella
P Nelson R Vessella
(UW/Fred Hutchinson SPORE)
M Freeman (Harvard SPORE), M Rubin
M Cher
N Rosen (MSK SPORE)
R Rodriguez (JHU SPORE) T DeWeese
AH Reddi
T Guise
C Sawyers (UCLA SPORE)
L Chung, J Simons, JT Dong, M Amin, R Lyles
K Koeneman JT Hsieh
Chen et al Nature Medicine Jan 2004 1033-39
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Synergy Map Year 1 New Candidate LuCAP35 Model
/2me2 anti HIF/ hre ADM Project Guise/Simons/Vesse
lla/Chung
P Nelson R Vessella
(UW/Fred Hutchinson SPORE)
M Freeman (Harvard SPORE), M Rubin
M Cher
N Rosen (MSK SPORE)
R Rodriguez (JHU SPORE) T DeWeese
AH Reddi
T Guise
C Sawyers (UCLA SPORE)
L Chung, J Simons, JT Dong, M Amin, R Lyles
K Koeneman JT Hsieh
Selective Osteoblast Inhibition Teams 1,2,3
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Synergy Map Year 1 Candidate PTEN -/- TOR
SENSITIVE/EGFR INDEPENDENT HRPCA
SAYWERS/NELSON/RUBIN/ROSEN
P Nelson R Vessella
(UW/Fred Hutchinson SPORE)
M Freeman (Harvard SPORE), M Rubin
M Cher
N Rosen (MSK SPORE)
R Rodriguez (JHU SPORE) T DeWeese
AH Reddi
T Guise
C Sawyers (UCLA SPORE)
L Chung, J Simons, JT Dong, M Amin, R Lyles
K Koeneman JT Hsieh
Selective Dx/Rx Profile PTEN -/ PTEN -/- EGFR
RESISTANT/TOR-CCI 779 SENSITIVE Teams 3,4,5
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Synergy Map Year 1 Candidate LIPID
RAFTsAR?PIP3?AKT?ANTIAPOPTOSIS FREEMAN/RODRIGUEZ/D
EWEESE
P Nelson R Vessella
(UW/Fred Hutchinson SPORE)
M Freeman (Harvard SPORE), M Rubin
M Cher
N Rosen (MSK SPORE)
R Rodriguez (JHU SPORE) T DeWeese
AH Reddi
T Guise
C Sawyers (UCLA SPORE)
L Chung, J Simons, JT Dong, M Amin, R Lyles
K Koeneman JT Hsieh
Selective Dx/Rx Profile ATK-1 SIGNALING Teams 4,
2, 3
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New Pardigm

•    Published online 21
  December 2003, doi10.1038/nm972January 2004
  Volume 10 Number 1 pp 33 - 39  Molecular
  determinants of resistance to antiandrogen
  therapyCharlie D Chen1, 5, 8, Derek S Welsbie3,
  5, 8, Chris Tran1, 4, Sung Hee Baek4, 6, Randy
  Chen1, Robert Vessella7, Michael G Rosenfeld4, 6
  Charles L Sawyers1, 2, 3, 4, 5 
• Using microarray-based profiling of isogenic
  prostate cancer xenograft models, we found that a
  modest increase in androgen receptor mRNA was the
  only change consistently associated with the
  development of resistance to antiandrogen
  therapy. This increase in androgen receptor mRNA
  and protein was both necessary and sufficient to
  convert prostate cancer growth from a
  hormone-sensitive to a hormone-refractory stage,
  and was dependent on a functional ligand-binding
  domain. Androgen receptor antagonists showed
  agonistic activity in cells with increased
  androgen receptor levels this antagonist-agonist
  conversion was associated with alterations in the
  recruitment of coactivators and corepressors to
  the promoters of androgen receptor target genes.
  Increased levels of androgen receptor confer
  resistance to antiandrogens by amplifying signal
  output from low levels of residual ligand, and by
  altering the normal response to antagonists.
  These findings provide insight toward the design
  of new antiandrogens.
•   

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New Paradigm