A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies

Ramalingam, Suresh S.; Egorin, Merrill J.; Ramanathan, Ramesh K.; Remick, Scot C.; Sikorski, Rachel; Lagattuta, Theodore F.; Chatta, Gurkamal S.; Friedland, David; Stoller, Ronald G.; Potter, Douglas M.; Ivy, S. Percy; Belani, Chandra P.

doi:10.1158/1078-0432.ccr-07-5088

Cited by 59 publications

(41 citation statements)

References 33 publications

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“…These results indicate that CLC604 functions as an Hsp90 inhibitor and causes HER2-overexpressing cancer cells to become sensitized to Taxol in vivo. Our data corroborated a previous report that higher efficiency was obtained when combining treatment with 17-AAG, an Hsp90 inhibitor, causing cancer cells to become sensitive to Taxol specifically and other clinical drugs when treating HER2-overexpressing cancer (40).…”

Section: Discussionsupporting

confidence: 91%

CLC604 preferentially inhibits the growth of HER2-overexpressing cancer cells and sensitizes these cells to the inhibitory effect of Taxol in vitro and in vivo

et al. 2013

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Abstract. HER2 has become a solicitous therapeutic target in metastatic and clinical drug-resistant cancer. Here, we evaluated whether or not 1-benzyl-3-(5-hydroxymethyl-2-furyl) indazole (YC-1) and its furopyrazole and thienopyrazole analogues repress the expression of the HER2 protein. Among the test compounds, (1-benzyl-3-(p-hydroxymethylphenyl)-5-methylfuro[3,2-c]pyrazol) (CLC604), an isosteric analogue of YC-1, significantly suppressed the expression of HER2, and preferentially inhibited cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Our results revealed that CLC604 reduced HER2 expression through a post-transcriptional mechanism and involvement of proteasomal activity. CLC604 disrupted the association of 90-kDa heat shock protein (Hsp90) with HER2 resulting from the inhibition of Hsp90 ATPase activity. Moreover, we found that CLC604 significantly enhanced the antitumor efficacy of clinical drugs against HER2-overexpressing tumors and efficiently reduced HER2-induced drug resistance in vitro and in vivo. These findings suggest that CLC604 should be developed further as a novel antitumor drug candidate for the treatment of drug-resistant cancer.

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Section: Discussionsupporting

confidence: 91%

CLC604 preferentially inhibits the growth of HER2-overexpressing cancer cells and sensitizes these cells to the inhibitory effect of Taxol in vitro and in vivo

et al. 2013

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“…3 have broad relevance as components of diverse drug regimens that constitute the frontline treatment for many human cancers (Table S1). This stands in contrast to synergistic combinations, where, for example, 17AAG and other Hsp90 inhibitors are not currently components of clinically established drug regimens (24). Thus, we were interested in expanding our analysis to examine larger combination regimens that are now the standard of care for B-cell malignancies.…”

Section: Examining the Pairwise Interaction Of Drugs Within Commonly mentioning

confidence: 99%

Defining principles of combination drug mechanisms of action

Pritchard¹,

Bruno²,

Gilbert³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

154

137

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Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their singledrug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood. Here, we combine RNAi-based functional signatures with complementary informatics tools to examine drug combinations. This approach seeks to bring to combination therapy what the knowledge of biochemical targets has brought to single-drug therapy and creates a statistical and experimental definition of "combination drug mechanisms of action." We show that certain synergistic drug combinations may act as a more potent version of a single drug. Conversely, unlike these highly synergistic combinations, most drugs average extant single-drug variations in therapeutic response. When combined to form multidrug regimens, averaging combinations form averaging regimens that homogenize genetic variation in mouse models of cancer and in clinical genomics datasets. We suggest surprisingly simple and predictable combination mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies.chemotherapy | lymphoma | RNAi signature | systems biology C urrent rationales for the design of combination chemotherapy regimens were developed in the 1940s and 1950s (1-5) and, remarkably, were concurrent with the identification of DNA as the genetic material. The development of these regimens in the absence of any knowledge of cancer genomics was a remarkable achievement. However, although our knowledge of the genetic drivers of cancer and the mechanisms of drug action has increased dramatically over the past 30 y, this information has been difficult to adapt to clinical practice. As such, even very successful combination regimens often fail to cure many patients (6, 7). We hypothesize that part of this failure is due to the absence of mechanistic information about how drugs in regimens interact to promote combination effects (we term these effects "combination mechanisms of action"). We sought to address this gap by investigating specific hypotheses concerning the "mechanisms of action" of combination therapy.The classic term "drug mechanism of action" refers to the description of a specific biochemical event, which is often the activation or inhibition of an enzymatic effect. However, in recent years, "signature"-based prediction has provided a powerful new strategy for examining drug mechanism. In signature-based approaches, a series of drug-induced molecular/phenotypic measurements are made in an experimental system. Collections of measurements from many small molecules form multivariate signatures that aim to fingerprint drugs based on their relative signature similarity (8-13). In several landmark studies using Saccharomyces cerevisiae; gene expression compendia (8); and, later, barcoded loss o...

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“…Many Hsp90 clients such as Akt/PKB, Raf, and Bcr-Abl are oncoproteins that are either mutated or overexpressed in cancer cells, which in turn depend on these proteins for growth and proliferation (Weinstein and Joe 2006). This makes Hsp90 an attractive target for cancer therapy and its inhibitors were promising in clinical trials (Modi et al 2007;Ramalingam et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Novel Hsp90 partners discovered using complementary proteomic approaches

Tsaytler

Krijgsveld

Goerdayal

et al. 2009

Cell Stress and Chaperones

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Hsp90 is an essential eukaryotic molecular chaperone that stabilizes a large set of client proteins, many of which are involved in various cellular signaling pathways. The current list of Hsp90 interactors comprises about 200 proteins and this number is growing steadily. In this paper, we report on the application of three complementary proteomic approaches directed towards identification of novel proteins that interact with Hsp90. These methods are coimmunoprecipitation, pull down with biotinylated geldanamycin, and immobilization of Hsp90β on sepharose. In all, this study led to the identification of 42 proteins, including 18 proteins that had not been previously characterized as Hsp90 interactors. These novel Hsp90 partners not only represent abundant protein species, but several proteins were identified at low levels, among which signaling kinase Cdk3 and putative transcription factor tripartite motif-containing protein 29. Identification of tetratricopeptide-repeat-containing mitochondrial import receptor protein Tom34 suggests the involvement of Hsp90 in the early steps of translocation of mitochondrial preproteins. Taken together, our data expand the knowledge of the Hsp90 interactome and provide a further step in our understanding of the Hsp90 chaperone system.

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A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies

Cited by 59 publications

References 33 publications

CLC604 preferentially inhibits the growth of HER2-overexpressing cancer cells and sensitizes these cells to the inhibitory effect of Taxol in vitro and in vivo

CLC604 preferentially inhibits the growth of HER2-overexpressing cancer cells and sensitizes these cells to the inhibitory effect of Taxol in vitro and in vivo

Defining principles of combination drug mechanisms of action

Novel Hsp90 partners discovered using complementary proteomic approaches

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