A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90a

Mehta, Adi; Shervington, Leroy Alexander; Munje, Chinmay; Shervington, Amal

doi:10.3390/cancers3044228

Cited by 9 publications

(14 citation statements)

References 50 publications

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“…[ 276 ] HSP90 alpha has a role in tumor survival and progression and is highly expressed in GB while absent in normal tissue and cell lines and may be a target for cancer therapy taking into acount its potential role in tumor progression and in the antiapoptotic pathway. [ 186 ] The safety and efficacy of an autologous HSP complex-96 (HSPPC-96) vaccine for patients with recurrent GB has been evaluated in a phase II study in adult patients with resected recurrent GB. The HSPPC-96 vaccine was safe and concluded further study of efficacy for the treatment of recurrent GB was warranted.…”

Section: Glioblastomamentioning

confidence: 99%

The future of high-grade glioma: Where we are and where are we going

Rhun¹,

Taillibert²,

Chamberlain³

2015

Surg Neurol Int

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High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy.

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Section: Glioblastomamentioning

confidence: 99%

The future of high-grade glioma: Where we are and where are we going

Rhun¹,

Taillibert²,

Chamberlain³

2015

Surg Neurol Int

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“…The specific HSP90 inhibitor AUY922 plays a therapeutic role in the treatment of adrenocortical carcinoma and, therefore, HSP90 could qualify as a promising new target in adrenocortical carcinoma (Huang et al, 2014). Taking into account the role of HS90A in tumor progression, and the involvement of Akt kinase in cell signaling and the anti-apoptotic pathways in tumors, chemical and molecular double target treatment offers a novel therapeutic strategy (Mehta et al, 2011). In recent years, most researchers have concentrated on HSP90 inhibitor for breast cancer, acute myeloid leukemia, colorectal cancer, etc.…”

Section: Discussionmentioning

confidence: 99%

Potential role of heat-shock proteins in giant cell tumors

et al. 2015

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ABSTRACT. We investigated the differential expression protein profile of giant cell tumors (GCTs), which can be used to monitor the tumor's recurrence and metastasis, to provide preliminary results for further study. We also explored heat-shock protein (HSP) inhibitor that prevents tumors from recurring and migrating. A stable isotope-labeling strategy using isobaric tags for relative and absolute quantitation coupled with twodimensional liquid chromatography tandem mass spectrometry was used to separate and identify differentially expressed proteins. A total of 467 differentially expressed proteins were identified in GCT tissues. Up to 311 proteins were upregulated, whereas 156 proteins were downregulated in GCT tissues. Three of the differentially expressed HSPs, namely HP90A, HSPB1, and HSPB2, were upregulated. The differentially expressed proteins of GCT tissues will provide a scientific foundation for tumor prognosis, and for further studies exploring HSP inhibitor to prevent tumor recurrence and migration.

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“…The percent of viable cells was assessed using CellTiter-Glo ® luminescent cell viability assay (Promega) as described previously [ 6 ]. Briefly, U87-MG and SVGp12 cells were seeded at a density of 1000 cells / well in 96-well plates in triplicates 24 h prior to treatment with SCC and 17-AAG and the luminescent signal was recorded using Tecan GENios Pro ® (Tecan, Austria).…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…A standard protocol was followed for immunofluorescence described in depth in a previous publication [ 6 ]. The primary monoclonal antibody and FITC-conjugated secondary antibody were obtained from Cambridge Bioscience (UK).…”

Section: Immunofluorescencementioning

confidence: 99%

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Can RNAi‐mediated hsp90α knockdown in combination with 17‐AAG be a therapy for glioma?

et al. 2013

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Heat shock protein 90 promotes tumor progression and survival and has emerged as a vital therapeutic target. Previously we reported that the combinatorial treatment of 17AAG/sihsp90α significantly downregulated Hsp90α mRNA and protein levels in Glioblastoma Multiforme (GBM). Here we investigated the ability of cell penetrating peptide (Tat48–60 CPP)-mediated siRNA-induced hsp90α knockdown as a single agent and in combination with 17-allylamino-17-demethoxygeldanamycin (17-AAG) to induce tumor growth inhibition in GBM and whether it possessed therapeutic implications. GBM and non-tumorigenic cells exposed to siRNA and/or 17-AAG were subsequently assessed by qRT-PCR, immunofluorescence, FACS analysis, quantitative Akt, LDH leakage and cell viability assays. PAGE was performed for serum stability assessment. A combination of siRNA/17-AAG treatment significantly induced Hsp90α gene and protein knockdown by 95% and 98%, respectively, concomitant to 84% Akt kinase activity attenuation, induced cell cycle arrest and tumor-specific cytotoxicity by 88%. Efficient complex formation between CPP and siRNA exhibited improved serum stability of the siRNA with minimal intrinsic toxicity in vitro. The preliminary in vivo results showed that combination therapy induced hsp90α knockdown and attenuated Akt kinase activity in intracranial glioblastoma mouse models. The results imply that RNAi-mediated hsp90α knockdown increases 17-AAG treatment efficacy in GBM. In addition, the cytotoxic response observed was the consequence of downregulation of hsp90α gene expression, reduced Akt kinase activity and S-G2/M cell cycle arrest. These results are novel and highlight the ability of Tat to efficiently deliver siRNA in GBM and suggest that the dual inhibition of Hsp90 has therapeutic potentials.

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A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90a

Cited by 9 publications

References 50 publications

The future of high-grade glioma: Where we are and where are we going

The future of high-grade glioma: Where we are and where are we going

Potential role of heat-shock proteins in giant cell tumors

Can RNAi‐mediated hsp90α knockdown in combination with 17‐AAG be a therapy for glioma?

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