Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma.
OBJECTIVE
Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity.


METHODS
Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly x 6 weeks at 450 mg/m2. Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen.


RESULTS
Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1 expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho-extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results.


CONCLUSIONS
At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway.
Solit
David B
DB
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Osman
Iman
I
Polsky
David
D
Panageas
Katherine S
KS
Daud
Adil
A
Goydos
James S
JS
Teitcher
Jerrold
J
Wolchok
Jedd D
JD
Germino
F Joseph
FJ
Krown
Susan E
SE
Coit
Daniel
D
Rosen
Neal
N
Chapman
Paul B
PB
D000328:Adult; D000368:Aged; D016227:Benzoquinones / Q000627:therapeutic use*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf