Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90

Ernst, Anne; Hennel, Roman; Krombach, Julia; Kapfhammer, Heidi; Brix, Nikko; Zuchtriegel, Gabriele; Uhl, Bernd; Reichel, Christoph; Frey, Benjamin; Gaipl, Udo S.; Winssinger, Nicolas; Shirasawa, Senji; Sasazuki, Takehiko; Sperandio, Markus; Belka, Claus; Lauber, Kirsten

doi:10.3389/fonc.2020.01668

Cited by 6 publications

(4 citation statements)

References 94 publications

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“…The HSP90 inhibitor NW457 ( epi -pochoxime F) was previously described ( 27 – 31 ). For in vitro experiments, a 10 mM stock solution was prepared in DMSO (Sigma-Aldrich, Taufkirchen, Germany) and was further diluted to 100 µM with DMSO before final concentrations were adjusted in cell culture medium.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were seeded into Ibidi µ-slides supplemented with culture inserts (both from Ibidi) and allowed to adhere overnight. Cells were treated with 30 nM NW457 or DMSO for 24 h, irradiated at 3 Gy, and live-cell imaging was performed for 12 h. Images were captured in intervals of 3 min, and cell migration was analyzed using the manual tracking plugin tool (ImageJ) as previously described ( 31 , 34 ). Migration was quantified in form of colonized area (four regions of interest per condition in three independent experiments) and accumulated distance per cell over time (at least 25 randomly picked cells per condition).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

et al. 2021

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Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with per se limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells in vitro. In vivo, HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising in vitro results the in vivo efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

et al. 2021

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“…Astonishingly, the specific immune response may also be subject to secondary interferences. In this regard it could be shown that HSP90 inhibitors strongly increase immune priming of tumor cells after irradiation [84].…”

Section: Radiation Biology On the Move Advances In Radiation Biology-mentioning

confidence: 99%

X-change symposium: status and future of modern radiation oncology—from technology to biology

et al. 2021

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Future radiation oncology encompasses a broad spectrum of topics ranging from modern clinical trial design to treatment and imaging technology and biology. In more detail, the application of hybrid MRI devices in modern image-guided radiotherapy; the emerging field of radiomics; the role of molecular imaging using positron emission tomography and its integration into clinical routine; radiation biology with its future perspectives, the role of molecular signatures in prognostic modelling; as well as special treatment modalities such as brachytherapy or proton beam therapy are areas of rapid development. More clinically, radiation oncology will certainly find an important role in the management of oligometastasis. The treatment spectrum will also be widened by the rational integration of modern systemic targeted or immune therapies into multimodal treatment strategies. All these developments will require a concise rethinking of clinical trial design. This article reviews the current status and the potential developments in the field of radiation oncology as discussed by a panel of European and international experts sharing their vision during the “X-Change” symposium, held in July 2019 in Munich (Germany).

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“…As HSP90 stabilises numerous crucial proteins in tumor growth, it has the capacity to be a promising biomarker for diagnosis and prognosis and may be of therapeutic value for monitoring various cancers (Kryeziu et al, 2019). HSP90 is also a potential target for anti-cancer treatment, e.g., HSP90 inhibitors have become popular candidates for anti-cancer therapy (Ernst et al, 2020). Studies have indicated that HSP90 may be positively involved in the development of HCC and may provide a potential biomarker for monitoring advanced HCC (Qin et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a point-of-use device used for autoantibody analysis and its potential for following microcystin leucine-arginine exposure

Ma,

Loscher,

Parle-McDermott

et al. 2024

Front. Sens.

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Introduction: Globally, the need for measuring exposure to algal toxins has become urgent due to ever-increasing reports of contamination in sea and freshwater, in shellfish and fish stocks and in aerosols.Methods: To address this issue, we evaluated the potential of determining autoantibodies to a panel of biomarkers known to be elevated following exposure to the hepatotoxin microcystin leucine-arginine. The presence of autoantibodies, specific to four selected stress-response, metabolomic and chaperone biomarkers, namely, Heat shock protein 1, Triosephosphate isomerase, Peroxiredoxin 1 and Peroxiredoxin 2 was employed in screening 371 serum samples from microcystin-exposed individuals in Tanzania. In addition, the capacity of the LightDeck fluorescence-based detector, a point-of-use device, to monitor these autoantibody responses in comparison to enzyme-linked immunosorbent assay was evaluated.Results: By using the determination of autoantibodies to this novel panel of biomarkers an altered response was observed following microcystin exposure, with levels generally upregulated. The presence of elevated levels of microcystin leucine-arginine in water, as well as in food sources in Tanzania, may potentially have significant health effects on the population.Discussion: This novel biomarker panel may have potential for the detection of microcystin leucine-arginine exposure as well as various microcystin exposure-associated cancers (e.g., hepatocellular cancer and colorectal cancer). In addition, the utilisation of the LightDeck point-of-use device proved successful for the rapid analysis of this biomarker panel.

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Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90

Cited by 6 publications

References 94 publications

Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

X-change symposium: status and future of modern radiation oncology—from technology to biology

Evaluation of a point-of-use device used for autoantibody analysis and its potential for following microcystin leucine-arginine exposure

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