A Phase I Trial of Twice-Weekly 17-Allylamino-Demethoxy-Geldanamycin in Patients with Advanced Cancer

Abstract

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins. Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one. Results: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m 2 . Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m 2 .There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells. Conclusions:The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m 2 . Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.Heat shock protein (HSP) 90 is part of a chaperone complex for multiple client proteins involved in cell signaling, proliferation, and survival (1 -5). HSP90 function can be disrupted by geldanamycin (6), which results in the dissociation and degradation of client proteins, such as HER-2, RAF, mutant p53, cyclin-dependent kinase 4, Src, focal adhesion kinase, AKT, nuclear factor-nB, and insulin-like growth factor receptor 1 (7 -9). The binding of geldanamycin and its analogues to HSP90 also induces a stress response, which is manifested in part by increased levels of cochaperone and other stress proteins, such as HSP70 (10). In fact, cells deficient in HSF1 do not induce a stress response and are more sensitive to geldanamycin (11). Geldanamycin caused hepatotoxicity in dogs in preclinical studies, so further development was terminated (12). The geldanamycin analogue 17-allylaminodemethoxy-geldanamycin (17-AAG, NSC 330507) was shown to be less toxic than geldanamycin and shown activity in mouse xenograft models (13 -17). 17-AAG is metabolized to 17-aminogeldanamycin (17-AG) by cytochrome P450 3A4/5 and is widely distributed in body tissues but not in the central nervous system (18,19). The 17-AAG metabolite, 17-AG, also binds to HSP90, disrupting its ability to chaperone client proteins.Goetz et al. (20) reported recently results of the phase I study of 17-AAG administered on a weekly schedule to patients with advanced cancer. The m...

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

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Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer

“…[8,9] In NSCLC, Hsp90 stabilizes oncogenic proteins such as EGFR, MET, HER2 and AKT. [9,10] We and some other studies have shown that geldanamycin (GM) and its analogues, the benzoquinone ansamycin class were somewhat disappointing [15][16][17][18][19] and new potent Hsp90 inhibitors have therefore been pharmacologically designed and synthesized to offer improved efficacy and acceptable toxicity. NVP-AUY922 (AUY922) is one of these newly designed small-molecule Hsp90 inhibitors based on the 4,5-diarylisoxazole scaffold; it has a much higher affinity for Hsp90 than previous GM analogues.…”

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

“…Numerous HSP90 inhibitors have been developed, including the ansamycins, that specifically inhibit the intrinsic ATPase activity of HSP90 (15). Effective ansamycin derivatives have been isolated, including 17-(allylamino)-17-demethoxygeldanamycin (17AAG) that has recently completed several phase I clinical trials (16)(17)(18)(19)(20)(21)(22)(23) and is now undergoing evaluation in phase II. Initial results are encouraging, although problems were noted with formulation and hepatotoxicity.…”