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Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma

ABSTRACT: Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma

PROVIDER: PRJEB52647 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR9692764.fastq.gz	Fastqsanger.gz
	ERR9692765.fastq.gz	Fastqsanger.gz
	ERR9692766.fastq.gz	Fastqsanger.gz
	ERR9692767.fastq.gz	Fastqsanger.gz
	ERR9692768.fastq.gz	Fastqsanger.gz

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Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma

Project description:Comparing high grade glioma grown intracranially versus subcutaneously in fully immunocompetent rats

2023-12-31 | E-MTAB-11674 | biostudies-arrayexpress

Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma.

Project description:Radiotherapy can induce an immunological response. One limiting factor is side effects on normal tissue. Using FLASH radiotherapy, side effects could possibly be reduced. The efficacy of FLASH in relation to conventional radiotherapy (CONV-RT) has not been extensively explored in fully immunocompetent animals. Fully immunocompetent Fischer 344 rats were inoculated with NS1 glioblastoma cells subcutaneously or intracranially. Radiotherapy was delivered with FLASH or CONV-RT at 8 Gy × 2 (subcutaneous tumors) and 12.5 Gy × 2 (intracranial tumors). Cured animals were re-challenged in order to explore long-term anti-tumor immunity. Serum analytes and gene expression were explored. The majority of animals with subcutaneous tumors were cured when treated with FLASH or CONV-RT at 8 Gy × 2. Cured animals could reject tumor re-challenge. TIMP-1 in serum was reduced in animals treated with FLASH 8 Gy × 2 compared to control animals. Animals with intracranial tumors survived longer when treated with FLASH or CONV-RT at 12.5 Gy × 2, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.

| S-EPMC9296533 | biostudies-literature

Hypoxic tumors are sensitive to FLASH radiotherapy

Project description:Hypoxic tumors are sensitive to FLASH radiotherapy

| PRJNA926967 | ENA

Localized FLASH Radiotherapy Reduces Long-Term Skin and Muscle Damage While Preserving Systemic Homeostasis

Project description:Radiotherapy (RT) is a cornerstone treatment for nearly 50% of cancer patients, yet its efficacy remains limited by cumulative damage to healthy tissues over time. Delivering RT at ultra-high dose rates (FLASH-RT) represents a transformative strategy, as it appears to maintain tumor control, while sparing the surrounding normal tissue—a phenomenon termed FLASH effect. Here, we compared electron FLASH-RT and conventional RT (CONV-RT) on skin and muscle tissue of naïve mice assessing tissue integrity and gene expression. Bulk RNA sequencing revealed striking differences: FLASH induced minimal transcriptional disruption in skin and muscle, whereas CONV-RT triggered thousands of differentially expressed genes, including massive activation of fibrosis, inflammation, cell death-related pathways in skin, and broad dysregulation of genes linked to muscle function, remodeling and the unfolded protein response. Histological and ultrastructural analyses corroborated the findings, showing reduced immune infiltration in the skin and preserved tissue architecture both in skin and muscle following FLASH. In conclusion our study not only confirms the protective nature of FLASH but also provides novel mechanistic insights into the cascade linking local injury to systemic dysfunction under CONV-RT, reinforcing the translational potential of FLASH to expand the therapeutic window of radiotherapy.

2025-09-15 | GSE307570 | GEO

Hypoxic tumors are sensitive to FLASH radiotherapy

Project description:Purpose: Tumor hypoxia is a major cause of treatment resistance, especially to radiation therapy at conventional dose rate (CONV), and we wanted to assess whether hypoxia does alter tumor sensitivity to FLASH. Methods and materials: We engrafted several tumor types (glioblastoma [GBM], head and neck cancer, and lung adenocarcinoma) subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply via vascular clamping or carbogen breathing. We irradiated tumors using a single 20-Gy fraction at either CONV or FLASH, measured oxygen tension, monitored tumor growth, and sampled tumors for bulk RNAseq and pimonidazole analysis. Next, we inhibited glycolysis with trametinib in GBM tumors to enhance FLASH efficacy. Results: Using various subcutaneous tumor models, and in contrast to CONV, FLASH retained antitumor efficacy under acute hypoxia. These findings show that in addition to normal tissue sparing, FLASH could overcome hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNAseq profiling uncovered a FLASH-specific profile in human GBM that involved cell-cycle arrest, decreased ribosomal biogenesis, and a switch from oxidative phosphorylation to glycolysis. Glycolysis inhibition by trametinib enhanced FLASH efficacy in both normal and clamped conditions. Conclusions: These data provide new and specific insights showing the efficacy of FLASH in a radiation-resistant context, proving an additional benefit of FLASH over CONV.

2024-01-24 | GSE223607 | GEO

Sparing effects of FLASH irradiation in patient-derived lung tissue

Project description:This study aims to assess the effect of conventional radiotherapy compared to FLASH radiotherapy on healthy human lung tissue. FLASH radiotherapy, characterized by ultra-high dose rates, is hypothesized to spare healthy tissue from radiation-induced damage while maintaining efficacy against tumors. To achieve this goal and better characterize this sparing effect, bulk RNA sequencing analysis was conducted on 3 patients to study the molecular and cellular responses of lung tissue to both types of radiotherapy. The main objectives are to evaluate if FLASH radiotherapy effectively spares healthy lung tissue from radiation-induced damage and to understand the underlying molecular mechanisms behind this potential protective effect.

2025-09-08 | GSE263484 | GEO

Tissue-specific iron levels modulate lipid peroxidation and the FLASH radiotherapy effect

Project description:Tissue-specific iron levels modulate lipid peroxidation and the FLASH radiotherapy effect

| PRJNA1150908 | ENA

Localized FLASH Radiotherapy Reduces Long-Term Skin and Muscle Damage While Preserving Systemic Homeostasis

Project description:Localized FLASH Radiotherapy Reduces Long-Term Skin and Muscle Damage While Preserving Systemic Homeostasis

| PRJNA1322311 | ENA

IFN-M-NM-3-induced iNOS expression in regulatory macrophages prolongs allograft graft survival in fully immunocompetent recipients.

Project description:Mouse monocytes exposed to M-CSF and IFN-M-NM-3 were driven to a suppressor phenotype over a seven day culture period. The resulting regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarised macrophages and monocyte-derived DCs. M regs completely suppressed polyclonal T cell proliferation through an inducibile nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs were found to eliminate cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5x10^6 donor-strain M regs prior to transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c and C57BL/6-to-BALB/c strain combinations; this graft-protective effect was alloantigen-specific. M regs from Nos2-deficient mice did not prolong allograft survival, proving that M reg function in vivo is iNOS-mediated and dependent on living cells. Co-treatment with 1 mg/kg/day rapamycin for 10 days post-transplant markedly enhanced the effect of M regs. In untransplanted C57BL/6 recipients, M regs of BALB/c origin were detectable for up to 2 weeks post-infusion. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of tolerogenic macrophages, which resemble human M regs in their derivation, phenotype and in vitro functions. The dataset comprises 36 samples divided into twelve sample groups each representing a certain monocyte/macrophage subtype

2013-12-21 | E-GEOD-32690 | biostudies-arrayexpress

FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates

Project description:The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV) ionizing radiation (IR) dose-rate are not known. However, attenuated DNA damage and transient oxygen depletion are among a number of proposed models. Here, we tested whether FLASH-IR under physioxic (4% O2) and hypoxic conditions (≤2% O2) attenuates detection of genome-wide translocations relative to CONV dose rates and whether any differences identified revert under normoxic (21% O2) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), usingS. pyogenesandS. aureusCas9 “bait” DNA double strand breaks (DSBs), to measure differences in proximal deletions, inversions, and excision circles and their translocation to “prey” genome-wide DSBs generated by CONV (0.08-0.13Gy/s) and FLASH (1x102-5x106Gy/s) dose rates, under varying IR doses and oxygen tensions. Normoxic and physioxic IR exposure in HEK293T cells increased translocations at the cost of decreasing proximal repair but were indistinguishable between CONV and FLASH dose-rates. Although decreased numbers of translocations were recovered as cells transitioned to hypoxic (<2%) conditions, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in junction structures, which, for proximal repair, were increased in direct and short microhomologies. We conclude that irrespective of oxygen tension, FLASH IR dose rates produce translocations and junction structures at levels that are indistinguishable from CONV dose rates.

2023-03-29 | GSE227466 | GEO

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