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 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 63" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
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