Dataset Information

Ganetespib selectively sensitizes cancer cells for proximal and distal spread-out Bragg peak proton irradiation.

ABSTRACT:

Objective

Hypersensitivity towards proton versus photon irradiation was demonstrated in homologous recombination repair (HRR)-deficient cell lines. Hence, combined treatment concepts targeting HRR provide a rational for potential pharmaceutical exploitation. The HSP90 inhibitor ganetespib (STA-9090) downregulates a multitude of HRR-associated proteins and sensitizes for certain chemotherapeutics. Thus, the radiosensitizing effect of HSP90-inhibiting ganetespib was investigated for reference photon irradiation and proton irradiation at a proximal and distal position in a spread-out Bragg peak (SOBP).

Methods

A549 and FaDu cells were treated with low-dose (2 nM resp. 1 nM) ganetespib and irradiated with 200 kV photons. Proton irradiation was performed at a proximal and a distal position within a SOBP, with corresponding dose-averaged linear-energy transfer (LET_D) values of 2.1 and 4.5 keV/µm, respectively. Cellular survival data was fitted to the linear-quadratic model to calculate relative biological effectiveness (RBE) and the dose-modifying factor (DMF). Additionally, A549 cells were treated with increasing doses of ganetespib and investigated by flow cytometry, immunoblotting, and immunofluorescence microscopy to investigate cell cycle distribution, Rad51 protein levels, and γH2AX foci, respectively.

Results

Low-dosed ganetespib significantly sensitized both cancer cell lines exclusively for proton irradiation at both investigated LET_D, resulting in increased RBE values of 10-40%. In comparison to photon irradiation, the fraction of cells in S/G2/M phase was elevated in response to proton irradiation with 10 nM ganetespib consistently reducing this population. No changes in cell cycle distribution were detected in unirradiated cells by ganetespib alone. Protein levels of Rad51 are downregulated in irradiated A549 cells by 10 nM and also 2 nM ganetespib within 24 h. Immunofluorescence staining demonstrated similar induction and removal of γH2AX foci, irrespective of irradiation type or ganetespib administration.

Conclusion

Our findings illustrate a proton-specific sensitizing effect of low-dosed ganetespib in both employed cell lines and at both investigated SOBP positions. We provide additional experimental data on cellular response and a rational for future combinatorial approaches with proton radiotherapy.

SUBMITTER: Deycmar S

PROVIDER: S-EPMC8996402 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Ganetespib selectively sensitizes cancer cells for proximal and distal spread-out Bragg peak proton irradiation.

Deycmar Simon S Mara Elisabeth E Kerschbaum-Gruber Sylvia S Waller Verena V Georg Dietmar D Pruschy Martin M

Radiation oncology (London, England) 20220411 1

<h4>Objective</h4>Hypersensitivity towards proton versus photon irradiation was demonstrated in homologous recombination repair (HRR)-deficient cell lines. Hence, combined treatment concepts targeting HRR provide a rational for potential pharmaceutical exploitation. The HSP90 inhibitor ganetespib (STA-9090) downregulates a multitude of HRR-associated proteins and sensitizes for certain chemotherapeutics. Thus, the radiosensitizing effect of HSP90-inhibiting ganetespib was investigated for refere ...[more]

PMID: 35410422

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Project description:PurposeTo investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited.Methods and materialsHuman fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfraction period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism.ResultsSignificant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens.ConclusionsThe RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of fractionated proton therapy.

Project description:ObjectiveA favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model.Material/methodsRadiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment.ResultsComparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4).ConclusionFull dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Dataset Information

Ganetespib selectively sensitizes cancer cells for proximal and distal spread-out Bragg peak proton irradiation.

Objective

Methods

Results

Conclusion

Publications

Ganetespib selectively sensitizes cancer cells for proximal and distal spread-out Bragg peak proton irradiation.

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