Pharmacodynamic markers of perifosine efficacy.
OBJECTIVE
It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3'-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain.


METHODS
A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy.


RESULTS
Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6.


CONCLUSIONS
Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.
Hennessy
Bryan T
BT
Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. bhennessy@mdanderson.org
Lu
Yiling
Y
Poradosu
Enrique
E
Yu
Qianghua
Q
Yu
Shuangxing
S
Hall
Hassan
H
Carey
Mark S
MS
Ravoori
Murali
M
Gonzalez-Angulo
Ana Maria
AM
Birch
Robert
R
Henderson
I Craig
IC
Kundra
Vikas
V
Mills
Gordon B
GB
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D040081:Protein Array Analysis / Q000379:methods*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt