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Antitumor Activity and Molecular Effects of the Novel Hsp 90 Inhibitor, IPI-504, in Pancreatic Cancer

ABSTRACT: Tumors from pancreatic cancer specimens obtained at surgery were used for efficacy testing and biologic analysis. These tumors were s.c. explanted in xenograft models for subsequent treatment experiments. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. Keywords: Pharmacogenetics

ORGANISM(S): Homo sapiens

PROVIDER: GSE12113 | GEO | 2009/07/15

SECONDARY ACCESSION(S): PRJNA113811

REPOSITORIES: GEO

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Transcription profiling by array of human pancreatic tumours in xenografts to investigate the antitumor activity and molecular effects of the novel Hsp 90 Inhibitor, IPI-504, in pancreatic cancer

Project description:Tumors from pancreatic cancer specimens obtained at surgery were used for efficacy testing and biologic analysis. These tumors were s.c. explanted in xenograft models for subsequent treatment experiments. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. Experiment Overall Design: Five tumor samples were profiled in treated and untreated with IPI504. Untreated samples were profiled in duplicate. The overall design is to identify differentially expressed genes in IPI504 treated versus untreated.

2009-08-07 | E-GEOD-12113 | biostudies-arrayexpress

Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib

Project description:IPI-504-06 is a Phase 3, randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of IPI-504 as compared to placebo in patients with metastatic and/or unresectable GIST following failure of at least imatinib and sunitinib. Approximately 195 patients will be randomized using a 2:1 ratio to receive either IPI-504 (N=130) or placebo (N=65). Upon unblinding, patients receiving either IPI-504 or placebo may receive IPI-504 in the open-label portion of the study if defined inclusion criteria are met. Early and frequent imaging timepoints (Weeks 2, 5, 8, 14 and every 6 weeks thereafter) are incorporated into this study to capture progression events and limit patient exposure to ineffective agents.

| 2056213 | ecrin-mdr-crc

Inhibition of embryonic HSP-90 function causes variation of cold tolerance in zebrafish

Project description:Accumulating evidence suggests that HSP90 plays roles in modulation of phenotype in vertebrate development, which is closely involved in adaptation and evolution. In this study, we showed that inhibition of embryonic HSP90 function, either by a chemical inhibitor （radicicol） or low conductivity stress, induced variation of cold tolerance in adult zebrafish.

2019-03-02 | GSE111359 | GEO

Hedgehog pathway inhibition in chondrosarcoma using the Smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth

Project description:Mice bearing primary human chondrosarcoma xenografts were treated with IPI 926, and mRNA levels of known Hh pathway genes and endpoint tumor volumes were measured. Gene expression profiling of IPI-926 treated tumors was conducted to identify potential novel Hh target genes.

2014-03-18 | GSE44581 | GEO

Hedgehog pathway inhibition in chondrosarcoma using the Smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth

2014-03-18 | E-GEOD-44581 | biostudies-arrayexpress

Hsp-90 and the biology of nematodes.

Project description:BackgroundHsp-90 from the free-living nematode Caenorhabditis elegans is unique in that it fails to bind to the specific Hsp-90 inhibitor, geldanamycin (GA). Here we surveyed 24 different free-living or parasitic nematodes with the aim of determining whether C. elegans Hsp-90 was the exception or the norm amongst the nematodes. We combined these data with codon evolution models in an attempt to identify whether hsp-90 from GA-binding and non-binding species has evolved under different evolutionary constraints.ResultsWe show that GA-binding is associated with life history: free-living nematodes and those parasitic species with free-living larval stages failed to bind GA. In contrast, obligate parasites and those worms in which the free-living stage in the environment is enclosed within a resistant egg, possess a GA-binding Hsp-90. We analysed Hsp-90 sequences from fifteen nematode species to determine whether nematode hsp-90s have undergone adaptive evolution that influences GA-binding. Our data provide evidence of rapid diversifying selection in the evolution of the hsp-90 gene along three separate lineages, and identified a number of residues showing significant evidence of adaptive evolution. However, we were unable to prove that the selection observed is correlated with the ability to bind geldanamycin or not.ConclusionHsp-90 is a multi-functional protein and the rapid evolution of the hsp-90 gene presumably correlates with other key cellular functions. Factors other than primary amino acid sequence may influence the ability of Hsp-90 to bind to geldanamycin.

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Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy.

Project description:The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product DeltaF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in DeltaF508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of DeltaF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on DeltaF508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects DeltaF508 CFTR trafficking by inhibiting Hop expression, and that combination therapies--using differing mechanisms of action--may have additive benefits in treating CF.

| S-EPMC2895117 | biostudies-literature

Homo sapiens

Project description:Antitumor Activity and Molecular Effects of the Novel Hsp 90 Inhibitor, IPI-504, in Pancreatic Cancer

| PRJNA113811 | ENA

Gene expression analysis of prostate cancer cells treated with fatty acid synthase (FASN) inhibitor IPI-9119

Project description:Alterations in gene expression following fatty acid synthase inhibtion were evaluated in androgen sensitive LNCaP cells and castration resistant 22Rv1 and LNCaP-95 cells. Cell were exposed to 2 concentrations (0.1 and 0.5 uM) of FASN inhibitor IPI-9119 or DMSO for 6 days.

2019-01-17 | GSE114016 | GEO

HSP90, a potential common therapeutic target for suppressing skin injury caused by exposure to chemically diverse classes of blistering agents

Project description:Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence, developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES) respectively, we defined a common underlying mechanism of toxic action by these distinct classes of vesicants. Murine skin exposure to these chemicals causes skin inflammation and tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells and appearance of apoptotic epidermal and dermal cells. RNAseq analysis identified ~346 inflammatory genes that were commonly altered by both PAO and CEES along with identification of cytokine signaling activation as top canonical pathway. Activation of several of these inflammatory genes and pathways are associated with phosphorylation-dependent activation of heat shock protein 90 (pHSP90). Topical treatment with known HSP90 inhibitors, SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuates these chemical-induced skin damage (reduction in overall skin injury and clinical scores). In addition, highly upregulated inflammatory genes Saa3, Cxcl1, Ccl7, IL-6, Nlrp3, Csf3, Chil3 etc. by both PAO and CEES, significantly diminished by the treatment with these HSP90 inhibitors. These drugs not only reduced PAO or CEES-induced pHSP90 expression but also its client proteins NLRP3, pP38 and expression of their targeted inflammatory genes. These data confirm a critical role of HSP90 as a shared underlying molecular signaling of toxicity by these two distinct vesicants and provide effective and novel medical countermeasure to suppress vesicants pathogenesis.

2024-02-14 | GSE230382 | GEO

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