The Impact of Radiation on the Tumor Microenvironment: Effect of Dose and Fractionation Schedules

Arnold, K.; Flynn, Nicole; Raben, Adam; Romak, Lindsay B.; Yan, Yu; Dicker, Adam P.; Mourtada, Firas; Sims‐Mourtada, Jennifer

doi:10.1177/1179064418761639

Cited by 129 publications

(141 citation statements)

References 179 publications

(264 reference statements)

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“…In clinical practice, fractionated radiation regimens are commonly used for the treatment of multiple solid tumor types. The duration of radiation therapy with curative intent usually extends several weeks of therapy and applies fractionated doses of 1.8-2.0 Gy, for a total dose of approximately 50-70 Gy, depending on the tumor type and location (27). Therefore, we applied a 6-week radiotherapy regimen (5 days on, 2 days off) with 2 Gy fractions to subcutaneously implanted mouse xenograft tumors and investigated the effect of different doses of M3814 together with IR (Fig.…”

Section: M3814 Strongly Potentiates Ir Efficacy In Xenograft Models Omentioning

confidence: 99%

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models

Zenke

Zimmermann

Sirrenberg

et al. 2020

Molecular Cancer Therapeutics

115

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Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.

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Section: M3814 Strongly Potentiates Ir Efficacy In Xenograft Models Omentioning

confidence: 99%

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models

Zenke

Zimmermann

Sirrenberg

et al. 2020

Molecular Cancer Therapeutics

115

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“…Our approach regarding the method by which the radiation was induced has important clinical relevance as patients receiving BM transplant therapy commonly undergo whole-body irradiation [59]. Furthermore, although the radiation dose used in our study is enough to induce long-term cognitive impairments in rodents, radiation doses used in human patients against abnormal cell growth in the brain are significantly larger and depend on tumour size and recipient age [60,61]. In cases where whole-body irradiation is required, patients are typically exposed to several regiments of 10 Gy spaced out over multiple days [62].…”

Section: Discussionmentioning

confidence: 99%

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors

Wlodarek

Cao

Alibhai

et al. 2020

J Neuroinflammation

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Background: Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy.Methods: Here we implanted hematopoietic stem cells (HSCs) from young or old (2-or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution.Results: Regardless of donor age, GFP + cells homed to the brain of old recipients and expressed the macrophage/ microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP + /Iba1 + cells from young and old donors were differentially polarized to an anti-and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively. Conclusion: Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.

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“…Metabolic alterations may be pro-tumorigenic, promoting glioma initiation and progression (21)(22)(23)(24). RT-induced metabolic changes in GBM depend on tumor volume, location, and dose-time regime of RT-administration, all of which can vary treatment response (8,(25)(26)(27)(28)(29). While differential metabolism of glioma tumor cells can be targeted to regress tumor growth, understanding the impact of radiation-induced metabolic alterations in GBM microenvironment can provide new avenues to maximize long term benefits of RT in GBM care.…”

Section: Introductionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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The Impact of Radiation on the Tumor Microenvironment: Effect of Dose and Fractionation Schedules

Cited by 129 publications

References 179 publications

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

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