Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma Journal Article

Authors: Solit, D. B.; Osman, I.; Polsky, D.; Panageas, K. S.; Daud, A.; Goydos, J. S.; Teitcher, J.; Wolchok, J. D.; Joseph Germino, F.; Krown, S. E.; Coit, D.; Rosen, N.; Chapman, P. B.
Article Title: Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma
Abstract: Purpose: Activation of the mitogen-activated protein kinase (MAPK) pathway and the phospha- tidylinositol 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. Experimental Design: 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 ×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 forV600E 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. © 2008 American Association for Cancer Research.
Keywords: signal transduction; mitogen activated protein kinase; adult; clinical article; controlled study; human tissue; protein expression; treatment response; aged; middle aged; unclassified drug; gene mutation; human cell; genetics; mutation; clinical trial; fatigue; raf protein; side effect; anorexia; edema; melanoma; metastasis; phase 2 clinical trial; map kinase signaling system; tumor biopsy; drug effect; coughing; fever; drug antagonism; multicenter study; urinary frequency; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; nausea and vomiting; dna sequence; heat shock protein 70; cyclin d1; b raf kinase; heart muscle ischemia; proto-oncogene proteins b-raf; braf protein, human; benzoquinones; lactams, macrocyclic; diaphoresis; 17-(allylamino)-17-demethoxygeldanamycin; benzoquinone derivative; macrocyclic lactam; musculoskeletal pain
Journal Title: Clinical Cancer Research
Volume: 14
Issue: 24
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2008-12-15
Start Page: 8302
End Page: 8307
Language: English
DOI: 10.1158/1078-0432.ccr-08-1002
PUBMED: 19088048
PROVIDER: scopus
PMCID: PMC2629404
Notes: --- - "Cited By (since 1996): 63" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Neal Rosen
    356 Rosen
  2. Jedd D Wolchok
    656 Wolchok
  3. David Solit
    431 Solit
  4. Paul Chapman
    246 Chapman
  5. Katherine S Panageas
    327 Panageas
  6. Daniel Coit
    415 Coit
  7. Susan Krown
    83 Krown