Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

Lancet, Jeffrey E.; Gojo, Ivana; Burton, Michelle; Quinn, Mary Flanagan; Tighe, Sheila; Kersey, Kathryn; Zhong, Ziyang; Albitar, Mäher; Bhalla, Kapil N.; Hannah, Alison L.; Baer, Maria R.

doi:10.1038/leu.2009.292

Cited by 146 publications

(114 citation statements)

References 26 publications

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“…24 A number of prior studies have examined Hsp70 up-regulation, which reflects increased activity of the transcription factor HSF-1 after release from Hsp90, 1 as a marker of tanespimycin's action. 18,32,29 It is important to emphasize that Hsp70 up-regulation results in resistance to Hsp90 inhibitors, not sensitization. 40,41 In our study Hsp70 was up-regulated after tanespimycin administration in blasts from 83% of patients.…”

Section: Discussionmentioning

confidence: 99%

“…Although a recent phase I study of the Hsp90 inhibitor alvespimycin in patients with advanced myeloid leukemia produced only a modest 18% complete remission rate, 18 the realization that pathways targeted by Hsp90 inhibitors contribute to drug resistance raises the question of whether Hsp90 inhibitors could be used as sensitizing agents in combination chemotherapy. Previous studies have also provided the preclinical rationale for combining tanespimycin with a number of other agents, including imatinib, 19 Flt3 inhibitors, 20 histone deacetylase inhibitors, 21,22 etoposide 23 and cytarabine.…”

Section: Introductionmentioning

confidence: 99%

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Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Kaufmann¹,

Karp²,

Litzow³

et al. 2011

Haematologica

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BackgroundIn preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and MethodsPatients received cytarabine 400 mg/m 2 /day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. ResultsTwenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2 /day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. ConclusionsBecause exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Kaufmann¹,

Karp²,

Litzow³

et al. 2011

Haematologica

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“…NAE Nedd8 activating enzyme, Ubc12 E2 conjugating enzyme for neddylation pathway, Ub ubiquitin has been highly effective in multiple myeloma and highlights that targeting of key cellular pathways involved in protein degradation is indeed possible in patients without excessive toxicity. The high incidence of activation of Hsp90 client proteins such as Flt3, c-Kit, Akt, and mitogen-activated protein kinase in AML has provided a scientific rationale for early phase trials of alvespimycin and ganetespib [34]. A phase I study of alvespimycin in 24 patients with a median prior treatment of two induction regimen established a dose of 24 mg/m 2 IV twice weekly for phase II studies and showed promising single agent activity with 3 patients having achieved a CRi.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

“…Dose limiting toxicity was reached at 32 mg/m 2 where cardiac toxicity developed in two patients. Common side effects included neutropenia, fever, nausea and diarrhea [34]. A phase I/II trial of ganetespib has also been conducted but results have not yet been reported (http://www.clinicaltrials.org).…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

Novel agents in acute myeloid leukemia

Ungewickell

Medeiros

2012

Int J Hematol

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Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, longterm survivors represent only 10-15 % of all AML patients older than 60 years of age and \10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

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“…In a variety of other neoplasms, including pancreatic ductal adenocarcinoma (Song et al 2008), hepatocellular carcinoma ), breast cancer (Baselga 2010), non-small-cell lung cancer (Shimamura & Shapiro 2008), esophageal and gastric cancers (Lee et al 2009), multiple myeloma (Richardson et al 2010), acute myeloid leukemia (Lancet et al 2010), and prostate cancer (Altieri 2010, Suzuki et al 2010, heatshock protein (HSP) 90 has been considered a promising new therapeutic target. HSP90 is a molecular chaperone that comprises 1-2% of total cellular protein content and regulates the correct folding, activity, function, and stability of over 200 client proteins (Trepel et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Mayer

Harjung²,

Breinig³

et al. 2011

Endocrine-Related Cancer

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Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap-frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line b-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90a, HSP90b, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and b-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time-and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and b-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

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Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

Cited by 146 publications

References 26 publications

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Novel agents in acute myeloid leukemia

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

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