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BACKGROUND: Ultra high dose rate (UHDR) radiotherapy using ridge filter is a new treatment modality known as conformal FLASH that, when optimized for dose, dose rate (DR), and linear energy transfer (LET), has the potential to reduce damage to healthy tissue without sacrificing tumor killing efficacy via the FLASH effect. PURPOSE: Clinical implementation of conformal FLASH proton therapy has been limited by quality assurance (QA) challenges, which include direct measurement of UHDR and LET. Voxel DR distributions and LET spectra at planning target margins are paramount to the DR/LET-related sparing of organs at risk. We hereby present a methodology to achieve experimental validation of these parameters. METHODS: Dose, DR, and LET were measured for a conformal FLASH treatment plan involving a 250-MeV proton beam and a 3D-printed ridge filter designed to uniformly irradiate a spherical target. We measured dose and DR simultaneously using a 4D multi-layer strip ionization chamber (MLSIC) under UHDR conditions. Additionally, we developed an "under-sample and recover (USRe)" technique for a high-resolution pixelated semiconductor detector, Timepix3, to avoid event pile-up and to correct measured LET at high-proton-flux locations without undesirable beam modifications. Confirmation of these measurements was done using a MatriXX PT detector and by Monte Carlo (MC) simulations. RESULTS: MC conformal FLASH computed doses had gamma passing rates of >95% (3 mm/3% criteria) when compared to MatriXX PT and MLSIC data. At the lateral margin, DR showed average agreement values within 0.3% of simulation at 100 Gy/s and fluctuations â¼10% at 15 Gy/s. LET spectra in the proximal, lateral, and distal margins had Bhattacharyya distances of <1.3%. CONCLUSION: Our measurements with the MLSIC and Timepix3 detectors shown that the DR distributions for UHDR scenarios and LET spectra using USRe are in agreement with simulations. These results demonstrate that the methodology presented here can be used effectively for the experimental validation and QA of FLASH treatment plans.
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Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.
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PURPOSE: The recently proposed Integrated Physical Optimization Intensity Modulated Proton Therapy (IPO-IMPT) framework allows simultaneous optimization of dose, dose rate, and linear energy transfer (LET) for ultra-high dose rate (FLASH) treatment planning. Finding solutions to IPO-IMPT is difficult because of computational intensiveness. Nevertheless, an inverse solution that simultaneously specifies the geometry of a sparse filter and weights of a proton intensity map is desirable for both clinical and preclinical applications. Such solutions can reduce effective biologic dose to organs at risk in patients with cancer as well as reduce the number of animal irradiations needed to derive extra biologic dose models in preclinical studies. METHODS AND MATERIALS: Unlike the initial forward heuristic, this inverse IPO-IMPT solution includes simultaneous optimization of sparse range compensation, sparse range modulation, and spot intensity. The daunting computational tasks vital to this endeavor were resolved iteratively with a distributed computing framework to enable Simultaneous Intensity and Energy Modulation and Compensation (SIEMAC). SIEMAC was demonstrated on a human patient with central lung cancer and a minipig. RESULTS: SIEMAC simultaneously improves maps of spot intensities and patient-field-specific sparse range compensators and range modulators. For the patient with lung cancer, at our maximum nozzle current of 300 nA, dose rate coverage above 100 Gy/s increased from 57% to 96% in the lung and from 93% to 100% in the heart, and LET coverage above 4 keV/µm dropped from 68% to 9% in the lung and from 26% to <1% in the heart. For a simple minipig plan, the full-width half-maximum of the dose, dose rate, and LET distributions decreased by 30%, 1.6%, and 57%, respectively, again with similar target dose coverage, thus reducing uncertainty in these quantities for preclinical studies. CONCLUSIONS: The inverse solution to IPO-IMPT demonstrated the capability to simultaneously modulate subspot proton energy and intensity distributions for clinical and preclinical studies.
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Algoritmos , Transferencia Lineal de Energía , Neoplasias Pulmonares , Órganos en Riesgo , Terapia de Protones , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada , Terapia de Protones/métodos , Humanos , Planificación de la Radioterapia Asistida por Computador/métodos , Animales , Neoplasias Pulmonares/radioterapia , Órganos en Riesgo/efectos de la radiación , Radioterapia de Intensidad Modulada/métodos , PorcinosRESUMEN
DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ. SIRT2 deacetylase activity governs cellular resistance to DSB-inducing agents and promotes NHEJ. SIRT2 furthermore interacts with and deacetylates DNA-PKcs in response to IR. SIRT2 deacetylase activity facilitates DNA-PKcs interaction with Ku and localization to DSBs and promotes DNA-PK activation and phosphorylation of downstream NHEJ substrates. Moreover, targeting SIRT2 with AGK2, a SIRT2-specific inhibitor, augments the efficacy of IR in cancer cells and tumors. Our findings define a regulatory step for DNA-PK activation by SIRT2-mediated deacetylation, elucidating a critical upstream signaling event initiating the repair of DSBs by NHEJ. Furthermore, our data suggest that SIRT2 inhibition may be a promising rationale-driven therapeutic strategy for increasing the effectiveness of radiation therapy.
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Roturas del ADN de Doble Cadena , Proteínas Quinasas , ADN/genética , ADN/metabolismo , Reparación del ADN por Unión de Extremidades , Reparación del ADN , Proteína Quinasa Activada por ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Autoantígeno Ku/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Quinasas/genética , Sirtuina 2/genética , Sirtuina 2/metabolismo , HumanosRESUMEN
Objective. The aim of this study was to investigate the feasibility of online monitoring of irradiation time (IRT) and scan time for FLASH proton radiotherapy using a pixelated semiconductor detector.Approach. Measurements of the time structure of FLASH irradiations were performed using fast, pixelated spectral detectors based on the Timepix3 (TPX3) chips with two architectures: AdvaPIX-TPX3 and Minipix-TPX3. The latter has a fraction of its sensor coated with a material to increase sensitivity to neutrons. With little or no dead time and an ability to resolve events that are closely spaced in time (tens of nanoseconds), both detectors can accurately determine IRTs as long as pulse pile-up is avoided. To avoid pulse pile-up, the detectors were placed well beyond the Bragg peak or at a large scattering angle. Prompt gamma rays and secondary neutrons were registered in the detectors' sensors and IRTs were calculated based on timestamps of the first charge carriers (beam-on) and the last charge carriers (beam-off). In addition, scan times inx,y, and diagonal directions were measured. The experiment was carried out for various setups: (i) a single spot, (ii) a small animal field, (iii) a patient field, and (iv) an experiment using an anthropomorphic phantom to demonstratein vivoonline monitoring of IRT. All measurements were compared to vendor log files.Main results. Differences between measurements and log files for a single spot, a small animal field, and a patient field were within 1%, 0.3% and 1%, respectively.In vivomonitoring of IRTs (95-270 ms) was accurate within 0.1% for AdvaPIX-TPX3 and within 6.1% for Minipix-TPX3. The scan times inx,y, and diagonal directions were 4.0, 3.4, and 4.0 ms, respectively.Significance. Overall, the AdvaPIX-TPX3 can measure FLASH IRTs within 1% accuracy, indicating that prompt gamma rays are a good surrogate for primary protons. The Minipix-TPX3 showed a somewhat higher discrepancy, likely due to the late arrival of thermal neutrons to the detector sensor and lower readout speed. The scan times (3.4 ± 0.05 ms) in the 60 mm distance ofy-direction were slightly less than (4.0 ± 0.06 ms) in the 24 mm distance ofx-direction, confirming the much faster scanning speed of the Y magnets than that of X. Diagonal scan speed was limited by the slower X magnets.
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Terapia de Protones , Radiometría , Radiometría/métodos , Rayos gamma , Terapia de Protones/métodos , Protones , NeutronesRESUMEN
Concerns over the health effects of space radiation exposure currently limit the duration of deep-space travel. Effective biological countermeasures could allow humanity to break this limit, facilitating human exploration and sustained presence on the Moon, Mars, or elsewhere in the Solar System. In this issue, we present a collection of 20 articles, each providing perspectives or data relevant to the implementation of a countermeasure discovery and development program. Topics include agency and drug developer perspectives, the prospects for repurposing of existing drugs or other agents, and the potential for adoption of new technologies, high-throughput screening, novel animal or microphysiological models, and alternative ground-based radiation sources. Long-term goals of a countermeasures program include reduction in the risk of radiation-exposure induced cancer death to an acceptable level and reduction in risks to the brain, cardiovascular system, and other organs.
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Exposición a la Radiación , Vuelo Espacial , Animales , Humanos , Exposición a la Radiación/efectos adversos , LunaRESUMEN
Implementation of a systematic program for galactic cosmic radiation (GCR) countermeasure discovery will require convenient access to ground-based space radiation analogs. The current gold standard approach for GCR simulation is to use a particle accelerator for sequential irradiation with ion beams representing different GCR components. This has limitations, particularly for studies of non-acute responses, strategies that require robotic instrumentation, or implementation of complex in vitro models that are emerging as alternatives to animal experimentation. Here we explore theoretical and practical issues relating to a different approach to provide a high-LET radiation field for space radiation countermeasure discovery, based on use of compact portable sources to generate neutron-induced charged particles. We present modeling studies showing that DD and DT neutron generators, as well as an AmBe radionuclide-based source, generate charged particles with a linear energy transfer (LET) distribution that, within a range of biological interest extending from about 10 to 200 keV/µm, resembles the LET distribution of reference GCR radiation fields experienced in a spacecraft or on the lunar surface. We also demonstrate the feasibility of using DD neutrons to induce 53BP1 DNA double-strand break repair foci in the HBEC3-KT line of human bronchial epithelial cells, which are widely used for studies of lung carcinogenesis. The neutron-induced foci are larger and more persistent than X ray-induced foci, consistent with the induction of complex, difficult-to-repair DNA damage characteristic of exposure to high-LET (>10 keV/µm) radiation. We discuss limitations of the neutron approach, including low fluence in the low LET range (<10 keV/µm) and the absence of certain long-range features of high charge and energy particle tracks. We present a concept for integration of a compact portable source with a multiplex microfluidic in vitro culture system, and we discuss a pathway for further validation of the use of compact portable sources for countermeasure discovery.
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Radiación Cósmica , Animales , Humanos , Transferencia Lineal de Energía , Radiación Ionizante , Reparación del ADN , Daño del ADNRESUMEN
Exosomes are extracellular vesicles that mediate transport of nucleic acids, proteins, and other molecules. Prior work has implicated exosomes in the transmission of radiation nontargeted effects. Here we investigate the ability of energetic heavy ions, representative of species found in galactic cosmic rays, to stimulate exosome release from human bronchial epithelial cells in vitro. Immortalized human bronchial epithelial cells (HBEC3-KT F25F) were irradiated with 1.0 Gy of high linear energy transfer (LET) 48Ti, 28Si, or 16O ions, or with 10 Gy of low-LET reference γ-rays, and extracellular vesicles were collected from conditioned media. Preparations were characterized by single particle tracking analysis, transmission electron microscopy, and immunoblotting for the exosomal marker, TSG101. Based on TSG101 levels, irradiation with high-LET ions, but not γ-rays, stimulated exosome release by about 4-fold, relative to mock-irradiated controls. The exosome-enriched vesicle preparations contained pro-inflammatory damage-associated molecular patterns, including HSP70 and calreticulin. Additionally, miRNA profiling was performed for vesicular RNAs using NanoString technology. The miRNA profile was skewed toward a small number of species that have previously been shown to be involved in cancer initiation and progression, including miR-1246, miR-1290, miR-23a, and miR-205. Additionally, a set of 24 miRNAs was defined as modestly over-represented in preparations from HZE ion-irradiated versus other cells. Gene set enrichment analysis based on the over-represented miRNAs showed highly significant association with nonsmall cell lung and other cancers.
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Exosomas/efectos de la radiación , Vesículas Extracelulares/efectos de la radiación , Radiación Ionizante , Calreticulina/metabolismo , Línea Celular Transformada , Células Epiteliales/efectos de la radiación , Vesículas Extracelulares/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Transferencia Lineal de Energía , MicroARNsRESUMEN
PURPOSE: To investigate the ability of radiation to stimulate exosome release from melanoma cells and to characterize the resulting exosome-containing vesicle preparations for their ability to promote a host antitumor immune response. MATERIALS AND METHODS: Cultured B16F10 murine melanoma cells or tumors were irradiated, and secreted extracellular vesicles were isolated and characterized. The exosome-containing vesicle preparations were injected into fresh tumors in syngeneic mice, and tumor growth and infiltrating T cells and natural killer (NK) cells were characterized. RESULTS: Irradiation stimulated exosome release from B16F10 murine melanoma cells. Exosome preparations from irradiated cell culture supernatants were biologically active, as demonstrated by uptake into recipient cells and by the ability to induce dendritic cell maturation and activation in vitro. Intratumoral injection significantly delayed tumor growth in vivo, whereas injection of similar preparations from non irradiated cells had no effect. The antitumor effect was correlated to an increase in interferon gamma-producing tumor-infiltrating NK cells. Pretreatment of the host mice with anti-NK cell antibodies abolished the effect, whereas pretreatment with anti-CD8+ T-cell antibodies did not. CONCLUSION: Exosomes from irradiated cells, or synthetic mimics, might provide an effective strategy for potentiation of NK cell-mediated host antitumor immunity.
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Exosomas/patología , Células Asesinas Naturales/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Femenino , Melanoma Experimental/radioterapia , Ratones , Ratones Endogámicos C57BLRESUMEN
Double-strand break (DSB) repair foci are important therapeutic targets. Here we describe platforms for delivery of macromolecules, nanomaterials and nanomedicines to repair foci. The strategy is based on the high affinity of the human 53BP1 protein for modified chromatin present at sites of DNA damage. As proof of concept, we created, expressed, and purified an engineered fragment of 53BP1 and coupled it to fluorescent streptavidin, a model cargo with no intrinsic affinity for repair foci. This binary complex was in turn coupled to the iron carrier protein, transferrin, which engages a high-affinity cell surface receptor. In a different version of the complex, transferrin was omitted and a protein transduction domain was incorporated directly into the primary structure of the 53BP1. These complexes were efficiently taken up into human osteosarcoma cells and synchronously released from endocytic vesicles by brief exposure to far-red light in the presence of the photosensitizer, disulfonated aluminum phthalocyanine. Upon release, the streptavidin cargo entered the nucleus and was recruited to repair foci. 53BP1-based platforms provide a method for targeted, temporally controlled delivery of macromolecular agents to sites of double-strand break repair. With the delivery platforms, we are capable to visualize, modify and redirect DSB repair pathways by coupling various nanomaterials to study machinery or manipulate for therapy purpose in the future.
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Roturas del ADN de Doble Cadena , Reparación del ADN , Portadores de Fármacos/química , Proteína 1 de Unión al Supresor Tumoral P53/química , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Citoplasma/metabolismo , Colorantes Fluorescentes/química , Humanos , Transporte de ProteínasRESUMEN
Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored. To address the functional consequences of NTHL1 overexpression, we employed transient overexpression. Both NTHL1 and a catalytically-dead NTHL1 (CATmut) induce DNA damage and genomic instability in non-transformed human bronchial epithelial cells (HBEC) when overexpressed. Strikingly, overexpression of either NTHL1 or CATmut causes replication stress signaling and a decrease in homologous recombination (HR). HBEC cells that overexpress NTHL1 or CATmut acquire the ability to grow in soft agar and exhibit loss of contact inhibition, suggesting that a mechanism independent of NTHL1 catalytic activity contributes to acquisition of cancer-related cellular phenotypes. We provide evidence that NTHL1 interacts with the multifunctional DNA repair protein XPG suggesting that interference with HR is a possible mechanism that contributes to acquisition of early cellular hallmarks of cancer.
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Transformación Celular Neoplásica , Desoxirribonucleasa (Dímero de Pirimidina)/metabolismo , Inestabilidad Genómica , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Línea Celular , Línea Celular Tumoral , Núcleo Celular/enzimología , Daño del ADN , Replicación del ADN , Desoxirribonucleasa (Dímero de Pirimidina)/genética , Células Epiteliales/enzimología , Humanos , Neoplasias Pulmonares/enzimología , Mutación , Mucosa Respiratoria/citología , Mucosa Respiratoria/enzimologíaRESUMEN
DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.
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Reparación del ADN por Unión de Extremidades , Recombinación Homóloga , Proteína 1 que Contiene Dominios SAM y HD/genética , Roturas del ADN de Doble Cadena , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Proteína 1 que Contiene Dominios SAM y HD/deficiencia , Proteína 1 que Contiene Dominios SAM y HD/metabolismo , TransfecciónRESUMEN
The tandem RNA recognition motif protein, NONO, was previously identified as a candidate DNA double-strand break (DSB) repair factor in a biochemical screen for proteins with end-joining stimulatory activity. Subsequent work showed that NONO and its binding partner, SFPQ, have many of the properties expected for bona fide repair factors in cell-based assays. Their contribution to the DNA damage response in intact tissue in vivo has not, however, been demonstrated. Here we compare DNA damage sensitivity in the testes of wild-type mice versus mice bearing a null allele of the NONO homologue (Nono gt). In wild-type mice, NONO protein was present in Sertoli, peritubular myoid, and interstitial cells, with an increase in expression following induction of DNA damage. As expected for the product of an X-linked gene, NONO was not detected in germ cells. The Nono gt/0 mice had at most a mild testis developmental phenotype in the absence of genotoxic stress. However, following irradiation at sublethal, 2-4 Gy doses, Nono gt/0 mice displayed a number of indicators of radiosensitivity as compared to their wild-type counterparts. These included higher levels of persistent DSB repair foci, increased numbers of apoptotic cells in the seminiferous tubules, and partial degeneration of the blood-testis barrier. There was also an almost complete loss of germ cells at later times following irradiation, evidently arising as an indirect effect reflecting loss of stromal support. Results demonstrate a role for NONO protein in protection against direct and indirect biological effects of ionizing radiation in the whole animal.
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Roturas del ADN de Doble Cadena , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Tolerancia a Radiación , Testículo/metabolismo , Animales , ADN/metabolismo , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Noqueados , Proteínas de Unión al ARN , Radiación Ionizante , Regulación hacia ArribaRESUMEN
A complex of two related mammalian proteins, SFPQ and NONO, promotes DNA double-strand break repair via the canonical nonhomologous end joining (c-NHEJ) pathway. However, its mechanism of action is not fully understood. Here we describe an improved SFPQâ¢NONO-dependent in vitro end joining assay. We use this system to demonstrate that the SFPQâ¢NONO complex substitutes in vitro for the core c-NHEJ factor, XLF. Results are consistent with a model where SFPQâ¢NONO promotes sequence-independent pairing of DNA substrates, albeit in a way that differs in detail from XLF. Although SFPQâ¢NONO and XLF function redundantly in vitro, shRNA-mediated knockdown experiments indicate that NONO and XLF are both required for efficient end joining and radioresistance in cell-based assays. In addition, knockdown of NONO sensitizes cells to the interstrand crosslinking agent, cisplatin, whereas knockdown of XLF does not, and indeed suppresses the effect of NONO deficiency. These findings suggest that each protein has one or more unique activities, in addition to the DNA pairing revealed in vitro, that contribute to DNA repair in the more complex cellular milieu. The SFPQâ¢NONO complex contains an RNA binding domain, and prior work has demonstrated diverse roles in RNA metabolism. It is thus plausible that the additional repair function of NONO, revealed in cell-based assays, could involve RNA interaction.
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Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Enzimas Reparadoras del ADN/metabolismo , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Proteínas Asociadas a Matriz Nuclear/metabolismo , Factores de Transcripción de Octámeros/metabolismo , Factor de Empalme Asociado a PTB/metabolismo , Proteínas de Unión al ARN/metabolismo , Línea Celular , Supervivencia Celular/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Epistasis Genética , Humanos , Proteínas Asociadas a Matriz Nuclear/química , Proteínas Asociadas a Matriz Nuclear/genética , Factores de Transcripción de Octámeros/química , Factores de Transcripción de Octámeros/genética , Factor de Empalme Asociado a PTB/química , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genéticaRESUMEN
Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis. Exposure to the heavy ion component of cosmic rays triggers a multitude of cellular changes, depending on the rate of exposure, the type of damage incurred and individual susceptibility. Heterogeneity in dose, dose rate, radiation quality, energy and particle flux contribute to the complexity of risk assessment. To unravel the impact of each of these factors, it is critical to identify sensitive biomarkers that can serve as inputs for robust modeling of individual risk of cancer or other long-term health consequences of exposure. Limitations in sensitivity of biomarkers to dose and dose rate, and the complexity of longitudinal monitoring, are some of the factors that increase uncertainties in the output from risk prediction models. Here, we critically evaluate candidate early and late biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions. Some of the biomarkers we have reviewed include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations and inflammation. Other biomarkers discussed, often assayed for at longer points post exposure, include mutations, chromosome aberrations, reactive oxygen species and telomere length changes. We discuss the relationship of biomarkers to different potential cell fates, including proliferation, apoptosis, senescence, and loss of stemness, which can propagate genomic instability and alter tissue composition and the underlying mRNA signatures that contribute to cell fate decisions. Our goal is to highlight factors that are important in choosing biomarkers and to evaluate the potential for biomarkers to inform models of post exposure cancer risk. Because cellular stress response pathways to space radiation and environmental carcinogens share common nodes, biomarker-driven risk models may be broadly applicable for estimating risks for other carcinogens.