Grem JL, Morrison G, Guo XD, Agnew E, Takimoto CH, Thomas R et al.. Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23: 1885-1893
To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks.
Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m(2)) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells.
Toxicity was acceptable at doses up to 28 mg/m(2). The cohort was expanded to three patients at 40 mg/m(2) because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m(2) had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m(2); none had dose-limiting toxicity. The maximum plasma concentrations (C(max)) of 17-AAG at 40 and 56 mg/m(2) were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours.ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with >/= 14 mg/m(2) and decreased protein content of either Lck or Raf1 with >/= 28 mg/m(2) of 17-AAG.
17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.
"The present study demonstrated that X-ray irradiation is able to significantly attenuate the increase in the levels of Hsp70 in cells treated with NVP-BEP800. Since the higher levels of Hsp70 are associated with drug resistance to Hsp90 inhibitors (11,26,27), the effect of X-ray irradiation on Hsp70 levels may be another mechanism, in addition to the effect of NVP-BEP800 on the NF-κB signaling pathway, for the action of the combined treatment on glioblastoma cells. "
[Show abstract][Hide abstract] ABSTRACT: The present study aimed to investigate the effect of NVP-BEP800, a novel heat shock protein (Hsp) 90 inhibitor of the 2-aminothieno[2,3-d]pyrimidine class, in combination with radiation on glioblastoma cells. T98G human glioblastoma cells were treated with dimethyl sulfoxide (DMSO), NVP-BEP800, NVP-BEP800 in combination with X-ray irradiation (10 Gy, 20 min), or X-ray irradiation only, and cultured for 40 h. Cell viability was measured upon completion of the treatments. In addition, apoptosis was measured and immunoblot analysis was performed to analyze the expression levels of cellular protein inhibitory κB kinase β (IKKβ). The combined treatment with NVP-BEP800 and X-ray irradiation resulted in the synergistic destruction of malignant cells. Furthermore, NVP-BEP800 significantly induced apoptosis in the human glioblastoma cells. The immunoblot analysis data indicated that NVP-BEP800 markedly reduced the expression level of IKKβ. The results also revealed that X-ray irradiation significantly attenuated the increase in the level of Hsp70 in cells treated with NVP-BEP800. Since elevated levels of Hsp70 are associated with drug resistance induced by Hsp90 inhibitors, the effects of X-ray irradiation on Hsp70 levels may be associated with the enhanced effect on cells of the presence of irradiation. The results of the current study suggest that irradiation enhances the inhibitory effect of NVP-BEP800 on the proliferation of malignant glioblastoma cells by downregulating the expression level of cellular signaling protein IKKβ and attenuating the upregulation of Hsp70 that is induced by NVP-BEP800.
Experimental and therapeutic medicine 09/2014; 8(3):893-898. DOI:10.3892/etm.2014.1800 · 1.27 Impact Factor
"Although the Hsp90 inhibitor 17-AAG ultimately failed in initial phase I clinical trials in patients with advanced solid tumors , , , one patient with prostate cancer was reported to have achieved disease stabilization with a 25% reduction in PSA levels . This result lead to a phase II trial of 17-AAG treatment in patients with advanced metastatic castrate resistant prostate cancer, though unfortunately no clinical responses were observed  leading to decreased enthusiasm in further clinical development of Hsp90 inhibitors for prostate cancer treatment. "
[Show abstract][Hide abstract] ABSTRACT: First line treatment of patients with castrate resistant prostate cancer (CRPC) primarily involves administration of docetaxel chemotherapy. Unfortunately, resistance to docetaxel therapy is an ultimate occurrence. Alterations in androgen receptor (AR) expression and signaling are associated mechanisms underlying resistance to docetaxel treatment in CRPC. Heat shock protein 90 (Hsp90) is a molecular chaperone, which regulates the activation, maturation and stability of critical signaling proteins involved in prostate cancer, including the AR. This knowledge and recent advances in compound design and development have highlighted Hsp90 as an attractive therapeutic target for the treatment of CRPC. We recently reported the development of a MYC-CaP castrate resistant (MYC-CaP/CR) transplant tumor model, which expresses amplified wild type AR. Within, we report that a second generation Hsp90 inhibitor, NVP-AUY922, inhibits cell growth and significantly induces cell death in MYC-CaP/CR and Pten-CaP/cE2 cell lines. NVP-AUY922 induced proteasome degradation of AR, though interestingly does not require loss of AR protein to inhibit AR transcriptional activity. Further, NVP-AUY922 increased docetaxel toxicity in MYC-CaP/CR and Pten-CaP/cE2 cell lines in vitro. Finally, NVP-AUY922/docetaxel combination therapy in mice bearing MYC-CaP/CR tumors resulted in greater anti-tumor activity compared to single treatment. This study demonstrates that NVP-AUY922 elicits potent activity towards AR signaling and augments chemotherapy response in a mouse model of CRPC, providing rationale for the continued clinical development of Hsp90 inhibitors in clinical trials for treatment of CRPC patients.
PLoS ONE 07/2014; 9(7):e103680. DOI:10.1371/journal.pone.0103680 · 3.23 Impact Factor
"There are a number of HSP90 inhibitors under clinical development, both as single agents and in combination with other agents [19, 20]. Hepatotoxicity has been reported in both the early and late stages of development of geldanamycin-based HSP90 inhibitors [21, 22]. In this study in Japanese patients with advanced solid tumors, single-agent AUY922 demonstrated an acceptable safety profile at dose levels of 8–70 mg/m2 with potential clinical activity (DCR 36 %). "
[Show abstract][Hide abstract] ABSTRACT: Purpose
AUY922 is a potent non-geldanamycin inhibitor of heat-shock protein 90. This study was carried out in Japanese patients to determine the maximum tolerated dose (MTD), and to characterize safety, tolerability and pharmacokinetics of single-agent AUY922.
Japanese patients with advanced solid tumors whose disease had progressed on at least one line of standard therapy, or for whom no standard therapy existed, were treated with AUY922 (intravenous, once-weekly, 28-day cycle, starting dose 8 mg/m2).
Thirty-one patients were treated. Two DLTs were reported in one patient of the 54 mg/m2 cohort; fatigue and decreased appetite (both Grade 3, resolving to Grade 1 within 8 days). No MTD was determined, and the dose recommended for Phase II studies was determined to be 70 mg/m2 once-weekly. Most common drug-related toxicities were diarrhea, night blindness and nausea. Grade 1 and 2 visual toxicities at high AUY922 doses ≥22 mg/m2 were observed. Ten patients (32 %) achieved a best overall response of stable disease, and one patient (3 %) achieved a confirmed partial response.
Overall, AUY922 exhibited acceptable toxicities and demonstrated potential clinical activity in Japanese patients, with similar safety and pharmacokinetic profiles to those reported in a preceding global Phase I study in Western patients (CAUY922A2101).
Cancer Chemotherapy and Pharmacology 07/2014; 74(3). DOI:10.1007/s00280-014-2521-x · 2.77 Impact Factor
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