A novel breast cancer therapeutic strategy through Hsp90 inhibition and activation of the immune system
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA714405 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13960992_1.fastq.gz | Fastqsanger.gz | |||
| SRR13960992_2.fastq.gz | Fastqsanger.gz | |||
| SRR13960993_1.fastq.gz | Fastqsanger.gz | |||
| SRR13960993_2.fastq.gz | Fastqsanger.gz | |||
| SRR13960994_1.fastq.gz | Fastqsanger.gz |
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Project description:Low response rates and immune-related adverse events limit the impact of cancer immunotherapy. In the quest for improved clinical outcomes, preclinical studies have shown that combining immune checkpoint blockade therapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) with these inhibitors limited their clinical efficacy as monotherapies. We discovered that Enniatin A (EnnA) binds to the interface between the middle domains of the Hsp90 dimer and destabilizes Hsp90 client oncoproteins without inducing an HSR. We found that EnnA induces cancer cell immunogenic cell death in aggressive breast cancer models and exhibits superior anti-tumor activity compared to Hsp90 N-terminal inhibitors. Further, we show that EnnA reprograms the tumor microenvironment in syngeneic mouse models to promote CD8+ T cell-dependent anti-tumor activity mediated through the CX3CR1 signaling pathway. We propose that EnnA is a promising anti-tumor agent with a novel mechanism of action involving immunogenic cancer cell toxicity and the mobilization of CD8+ T cells into the tumor site.
2023-09-21 | GSE168875 | GEO
Project description:Purpose: The growth and survival of NF2-deficient cells are enhanced by the activation of multiple signaling pathways including ErbB2/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The ubiquitously expressed chaperone protein HSP90 is known to be essential for the stabilization of these signaling molecules. We aim to evaluate the effect of the HSP90 inhibition on the signaling pathways activated in NF2-related tumors. We tested the efficacy of the newly synthesized small molecule NXD30001 which was shown to be more potent in HSP90 inhibition in vitro and less toxic in vivo than already existing HSP90 inhibitors. Experimental Design: The anti-proliferative activity of NXD30001 was tested in NF2-deficient mouse cells in vitro, and its anti-tumor efficacy was verified in an NF2-deficient allograft model in vivo. The underlying molecular alteration in vitro and in vivo was further characterized by a global transcriptome approach. Results: NXD30001 was found to induce degradation of client proteins and to suppress proliferation in NF2-deficient cells in vitro and in vivo. Differential expression analysis further identified subsets of genes implicated in cell proliferation, survival, vascularization, and Schwann cell differentiation, whose expression were altered by NXD30001 treatment. Conclusions: NXD30001 is a potent HSP90 inhibitor showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo, and represents a promising option for novel NF2 therapies. Global RNA expression in NXD30001-treated and untreated matched NF2-deficiemt cultured cells (in vitro) and allograft tumors (in vivo) were compared by RNA-Seq.
2013-06-06 | E-GEOD-40187 | biostudies-arrayexpress
Project description:Purpose: The growth and survival of NF2-deficient cells are enhanced by the activation of multiple signaling pathways including ErbB2/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The ubiquitously expressed chaperone protein HSP90 is known to be essential for the stabilization of these signaling molecules. We aim to evaluate the effect of the HSP90 inhibition on the signaling pathways activated in NF2-related tumors. We tested the efficacy of the newly synthesized small molecule NXD30001 which was shown to be more potent in HSP90 inhibition in vitro and less toxic in vivo than already existing HSP90 inhibitors. Experimental Design: The anti-proliferative activity of NXD30001 was tested in NF2-deficient mouse cells in vitro, and its anti-tumor efficacy was verified in an NF2-deficient allograft model in vivo. The underlying molecular alteration in vitro and in vivo was further characterized by a global transcriptome approach. Results: NXD30001 was found to induce degradation of client proteins and to suppress proliferation in NF2-deficient cells in vitro and in vivo. Differential expression analysis further identified subsets of genes implicated in cell proliferation, survival, vascularization, and Schwann cell differentiation, whose expression were altered by NXD30001 treatment. Conclusions: NXD30001 is a potent HSP90 inhibitor showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo, and represents a promising option for novel NF2 therapies.
2013-06-06 | GSE40187 | GEO
Project description:Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination. There are 12 samples in total. There are three experimental replicate. Samples 1, 5 and 9 are control (C) (untreated PC3- prostate cancer cells). Samples 2, 6, and 10 are cells treated with Wee1 inhibitor II (W). Samples 3, 7, and 11 are treated with 17-AAG (A), (an Hsp90 inhibitor). Samples 4, 8, and 12 are treated with both Wee1 inhibitorII and 17-AAG (WA). Samples 5 was removed from our analysis due to weak signal.
2013-01-10 | E-GEOD-38972 | biostudies-arrayexpress
Project description:The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a unique role promoting the evolution of new heritable traits. To better understand how Hsp90 can affect mRNA translation we screened more than 1600 factors involved in mRNA regulation for physical interactions with Hsp90 in human cells. The mRNA binding protein CPEB2 strongly binds Hsp90 via its prion domain. In a yeast model, transient inhibition of Hsp90 resulted in persistent activation of a CPEB translation reporter even in the absence of exogenous CPEB that persisted for 30 generations after the inhibitor was removed. Ribosomal profiling revealed that some endogenous yeast mRNAs, including HAC1, show a persistent change in translation efficiency following transient Hsp90 inhibition. Thus, transient loss of Hsp90 function can promote a non-genetic inheritance of a translational state affecting specific mRNAs, introducing a new mechanism by which Hsp90 can promote phenotypic variation.
2020-08-11 | GSE153945 | GEO
Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas
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Project description:Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination.
2013-01-10 | GSE38972 | GEO
Project description:Exploring the Effect and Mechanisms of Telomerase Inhibition as A Novel Therapeutic Strategy for Glioma
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Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]
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Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]
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