Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy

Makinde, Adeola Y.; Eke, Iris; Aryankalayil, Molykutty J.; Ahmed, Mansoor M.; Coleman, C. Norman

doi:10.1016/j.semradonc.2016.07.001

Cited by 7 publications

(6 citation statements)

References 62 publications

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“…On the contrary, in E0771 cells, 6 Gy radiation increased the percentage of PD-L1-positive TMPs, an effect that was not observed after 2 Gy irradiation. These differential effects might be explained by differences in stress response mechanisms and activation of transcription machinery in the distinct cell types [37,38]. Importantly, we demonstrate that these effects can modulate cytotoxic T-cell activity in distant organs such as the spleen, and therefore can systemically promote immune escape.…”

Section: Discussionmentioning

confidence: 78%

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Timaner¹,

Kotsofruk²,

Raviv³

et al. 2019

Oncogene

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Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)-extracellular vesicles shed from tumor cells-following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 78%

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Timaner¹,

Kotsofruk²,

Raviv³

et al. 2019

Oncogene

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“…Our finding suggests that this benefit might be further increased when combined with a targeted therapy against Nek1. Second, in line with preclinical evidence that fractionated radiation can induce an extensive array of targetable molecules [35], Nek1 inhibition may be combined with additional targeting strategies against transcription factors, immune and inflammatory responses and tumor cell stemness [36]. Finally, enrichment of cells in G2 by fractionated irradiation may represent a more general approach to increase the therapeutic efficacy of HR-specific therapeutics such as small molecule inhibitors of Rad51 [37,38].…”

Section: Discussionmentioning

confidence: 96%

Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1

Freund

Hehlgans

Martin

et al. 2020

Cells

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NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.

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“…Our ongoing observations from the inducible changes demonstrate that there are more changes early after radiation from MF compared with SD (12,16,21,38); however, at 2 months, the pattern is reversed with cells that survived SD showing more changes. These data will be the subject of future reports.…”

Section: Phosphoproteomic Upregulation Of Akt and Mtor And Increasedmentioning

confidence: 88%

“…Ongoing work to characterize and utilize the potential tumor adaptation includes detailed studies of phosphoproteomics, metabolomics, DNA repair, and epigenetic changes, as well as further in vivo studies (16,34,12,56). Long-term studies of tumors postirradiation conducted with Citrin at NCI demonstrate long-term upregulation of integrins in PC3 tumors (38).…”

Section: Metabolic Adaptations After Radiationmentioning

confidence: 99%

Radiation-induced Adaptive Response: New Potential for Cancer Treatment

Coleman

Eke

Makinde

et al. 2020

Clinical Cancer Research

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◥Radiotherapy is highly effective due to its ability to physically focus the treatment to target the tumor while sparing normal tissue and its ability to be combined with systemic therapy. This systemic therapy can be utilized before radiotherapy as an adjuvant or induction treatment, during radiotherapy as a radiation "sensitizer," or following radiotherapy as a part of combined modality therapy. As part of a unique concept of using radiation as "focused biology," we investigated how tumors and normal tissues adapt to clinically relevant multifraction (MF) and single-dose (SD) radiation to observe whether the adaptations can induce susceptibility to cell killing by available drugs or by immune enhancement. We identified an adaptation occurring after MF (3 Â 2 Gy) that induced cell killing when AKT-mTOR inhibitors were delivered following cessation of radiotherapy. In addition, we identified inducible changes in integrin expression 2 months following cessation of radiotherapy that differ between MF (1 Gy Â 10) and SD (10 Gy) that remain targetable compared with preradiotherapy. Adaptation is reflected across different "omics" studies, and thus the range of possible molecular targets is not only broad but also time, dose, and schedule dependent. While much remains to be studied about the radiation adaptive response, radiation should be characterized by its molecular perturbations in addition to physical dose. Consideration of the adaptive effects should result in the design of a tailored radiotherapy treatment plan that accounts for specific molecular changes to be targeted as part of precision multimodality cancer treatment.

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Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy

Cited by 7 publications

References 62 publications

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1

Radiation-induced Adaptive Response: New Potential for Cancer Treatment

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