Search Results (310)

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

Cancer is a major threat to human health, and radiotherapy is a key treatment method. However, its effectiveness is often limited by tumor radioresistance. The PI3K/AKT/mTOR signaling pathway is commonly dysregulated in cancers and plays a significant role in radioresistance, though its exact mechanisms remain unclear. This review discusses how this pathway regulates tumor radioresistance and highlights recent progress in the development of related inhibitors in preclinical and clinical studies. These findings aim to guide clinical treatment strategies and provide new approaches to overcoming radioresistance. Full article

Radiotherapy (RT) continues to be a fundamental component in the management of non-small cell lung cancer (NSCLC). Nevertheless, some NSCLC patients do not attain optimal therapeutic outcomes due to the emergence of radioresistance. Improving the effectiveness of RT in NSCLC necessitates a thorough comprehension of the mechanisms that lead to radioresistance. This review delineates various potential mechanisms of radioresistance in NSCLC, encompassing augmented DNA damage repair, cell cycle dysregulation, cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), tumor hypoxia, an immunosuppressive tumor microenvironment (TME), dysregulation of cell death pathways, metabolic reprogramming, exosome-mediated signaling, genetic mutations, aberrant activation of signaling pathways, and epigenetic modifications. In addition, this study explores various novel strategies aimed at enhancing the radiosensitivity of NSCLC and provides a concise overview of potential biomarkers predictive of RT response, which may contribute to the development of innovative combination therapies to address radioresistance and improve patient outcomes. Full article

Multidrug resistance (MDR) represents a major obstacle to successful chemotherapy and, due to overlapping defense mechanisms, such as enhanced DNA repair and the evasion of apoptosis, can also be associated with radioresistance. In this study, we investigated whether MDR breast cancer cells (MCF-7/CMF) exhibit reduced susceptibility to radiation-induced DNA fragmentation compared to their non-resistant parental counterpart (MCF-7). Using a nucleosome-based ELISA, we quantified the chromatin fragmentation in MCF-7 and MCF-7/CMF cells following their exposure to four radiopharmaceuticals: [^99mTc]pertechnetate, [¹³¹I]NaI (sodium iodide), [¹²⁵I]NaI, and the DNA-incorporating compound [¹²⁵I]iododeoxyuridine ([¹²⁵I]IdU). Each radioactive preparation was assessed across a range of activity concentrations, using a two-way ANOVA. For [^99mTc]pertechnetate and [¹³¹I]NaI, significantly higher DNA fragmentation was observed in the sensitive cell line, whereas [¹²⁵I]NaI showed no significant difference between the two phenotypes. In contrast to the other radiopharmaceuticals, [¹²⁵I]IdU induced greater fragmentation in resistant cells. This finding was supported by the statistical analysis (a 63.7% increase) and visualized in the corresponding dose–response plots. These results highlight the critical role of the intranuclear enrichment of Auger emitters and support further development of radiopharmaceuticals in accordance with this principle. Our data suggest that radiotoxicity is governed not by linear energy transfer (LET) alone, but, fundamentally, by the spatial proximity of the radionuclide to the DNA. Targeting tumor cell DNA with precision radiotherapeutics may, therefore, offer a rational strategy to overcome MDR in breast cancer. Full article

Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, and potential progression to fibrosis and secondary malignancy. Emerging evidence identifies the epithelial kinase doublecortin-like kinase 1 (DCLK1)—highly expressed in GI tuft cells and cancer stem-like cells—as a master regulator of post-IR responses. DCLK1 integrates DNA repair (via p53/ATM), and survival signaling (via NF-κB, TGF-β, and MAPK) to promote epithelial regeneration, yet these same mechanisms contribute to therapy resistance and oncogenesis. DCLK1 further modulates the immune microenvironment by skewing macrophages toward an immunosuppressive M2 phenotype, enhancing tissue remodeling, angiogenesis, and immune evasion. Preclinical studies demonstrate that DCLK1 inhibition sensitizes tumors to radiotherapy while preserving mucosal repair. Therapeutic strategies targeting DCLK1, alongside radioprotective agents, immunomodulators, and senolytics, may enhance regeneration, limit fibrosis, and eradicate therapy-resistant cancer stem cells. This review highlights DCLK1’s dual role in regeneration and tumorigenesis and evaluates its potential as a therapeutic target and biomarker in IR-induced GI damage. Full article

Purpose: The development of acquired resistance to arginine deprivation therapy (ADT) is a major barrier to its efficacy. This study aimed to elucidate the possible mechanisms underlying the resistance to ADT. Methods: We applied repeated ADT and established a subline SAS-R9 of the human head and neck squamous cell carcinoma (HNSCC) cells semi-resistant to arginine (Arg) deprivation in vitro. This subline was compared to the parental SAS cell lines for its relative clonogenic proliferation, aggregation, adhesion, and migration capacities. The transcriptomic changes were assessed by RNA sequencing. Signaling pathway alterations were confirmed by RT-PCR and Western blotting. Relative cell radioresistance was analyzed by radiobiological clonogenic survival assay. DNA double-strand break (DSB) repair was assessed by γH2A.X foci analysis. Results: SAS-R9 cells showed higher survival in response to ADT and radiotherapy, elevated clonogenic proliferation rate, cell–cell aggregation, and cell–matrix adhesion, along with increased epithelial–mesenchymal transition (EMT) markers and enhanced DNA DSB repair, potentially related to a more aggressive and therapy-resistant phenotype. Conclusions: While acute ADT has radiosensitizing potential, this new study suggests that long-term, repeated ADT is associated with cell selection and reprogramming, resulting in resistance to radiotherapy-induced DNA damage and higher tumor cell aggressiveness. Full article

Radiotherapy resistance represents a critical aspect of cancer treatment, and molecular characterization is needed to explore the pathways and mechanisms involved. DNA repair, hypoxia, metabolic reprogramming, apoptosis, tumor microenvironment modulation, and activation of cancer stem cells are the primary mechanisms that regulate radioresistance, and understanding their complex interactions is essential for planning the correct therapeutic strategy. Proteomics has emerged as a key approach in precision medicine to study tumor heterogeneity and treatment response in cancer patients. The integration of mass spectrometry-based techniques with bioinformatics has enabled high-throughput, quantitative analyses to identify biomarkers, pathways, and new potential therapeutic targets. This review highlights recent advances in proteomic technologies and their application in identifying biomarkers predictive of radiosensitivity and radioresistance in different tumors, including head and neck, breast, lung, and prostate cancers. Sample variability, data interpretation, and the translation of findings into clinical practice remain challenging elements of proteomics. However, technological advancements support its application in a wide range of topics, allowing a comprehensive approach to radiobiology, which helps overcome radiation resistance. Ultimately, incorporating proteomics into the radiotherapy workflow offers significant potential for enhancing treatment efficacy, minimizing toxicity, and guiding precision oncology strategies. Full article

Prostate cancer cell lines are particularly clinically homogenous, mostly representing metastatic states rather than localized disease. While there has been significant work in the development of additional models, few have been created without oncogenic transformation. We derived a primary prostate cancer cell line from a patient with localized Gleason 7 prostate cancer—designated CaB34—which spontaneously immortalized. We leveraged CaB34 to generate a paired radioresistant subline, CaB34-CF, using a clinically relevant fractionated radiotherapy schedule. These two paired cell lines were investigated extensively to determine their molecular characteristics and therapy responses. Both CaB34 and CaB34-CF express prostate-specific markers, including KRT18, NKX3.1, and AMACR. Multi-omic analyses using RNAseq and shotgun proteomics identified NNMT as the most significantly dysregulated component in CaB34-CF. A bioinformatic analysis determined that NNMT was more abundant within prostate tumors compared to benign prostate, suggesting a role in tumor progression. Knockdown studies of NNMT demonstrated significant radiosensitization of CaB34-CF cells, which was largely a result of increased radiation-induced cellular senescence. Growth as 3D organoids was significantly higher in the CaB34-CF line, and demonstrated a less structured pattern of expression of cytokeratin markers. Radiosensitization with NNMT siRNA was recapitulated in a 3D organoid clonogenic assay in CaB34-CF cells. Our research provides a paired primary model of treatment-naïve and radioresistant disease to address mechanisms of therapy resistance, while expanding the repertoire of localized prostate cancer cell lines for the research community. In addition, our findings present NNMT as a potential therapeutic target for sensitization of radioresistant disease. Full article

Background/Objectives: In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), the overall prognosis is poor, and systemic treatment options remain limited. While precision therapy approaches have revolutionized treatment strategies in several tumor types, molecularly informed therapies in R/M HNSCC are rare, primarily due to the low number of actionable genetic alterations identified through next-generation sequencing (NGS) panels. There is an urgent need to establish precision therapy approaches in R/M HNSCC using innovative predictive testing. Methods: We report the case of a 43-year-old patient with recurrent oral cancer who was extensively pretreated and comprehensively characterized using both descriptive and functional testing. Results: NGS revealed no targetable alterations. A tumor tissue slice radiosensitivity assay suggested radioresistance, arguing against re-irradiation. Kinome profiling identified upregulated Src-family kinases (SFK), and SFK inhibition reduced kinase activity in vitro. Most notably, mRNA analysis demonstrated high Trop-2 overexpression, confirmed by immunohistochemistry (3+ in 100% of tumor cells). Following six cycles of the Trop-2-directed antibody–drug conjugate Sacituzumab govitecan (SG), the patient had an impressive clinical response. Conclusions: Tumor characterization beyond genetic profiling can identify novel treatment options in therapy-refractory HNSCC. This is the first report of “real-world” data on promising antitumor efficacy of SG in a heavily pretreated oral cancer patient with Trop-2 overexpression. Consistent with the findings of the Basket TROPiCS-03 study, SG appears to be a promising novel therapy option for R/M HNSCC after failure of immunotherapy and chemotherapy, particularly in patients with Trop-2 overexpression. Full article

Cervical cancer is the fourth most prevalent cancer among women globally. Protein concentrations of Large Tumor Suppressor Kinase-1 (LATS1) and Nuclear Factor Kappa-B (NF-κB) have been identified as prospective biomarkers of radioresistance in cervical cancer. This preliminary study aimed to investigate the effectiveness of LATS1 and NF-κB levels as a biomarker for radioresistance and evaluate their response to radiation in cervical cancer patients. A comprehensive cross-sectional study was conducted involving 114 subjects diagnosed with advanced stages cervical cancer (stage IIIB and IVA) who underwent definitive radiotherapy. The concentrations of LATS1 and NF-κB were measured using ELISA from biopsy samples taken prior to the initiation of radiotherapy. This study’s finding included 114 subjects, with a median age of 53 years. A total of 85 (74.5%) subjects had stage IIIB, while 29 (25.4%) subjects had stage IVA. The cut-offs for LATS1 and NF-κB were 0.02765 ng/mg and 192.42 pg/mg, respectively. Subjects with a higher expression of LATS1 were found to be unresponsive to radiation therapy (p ≤ 0.001; AUC = 32.7%), and subjects with a lower expression of NF-κB were found to be unresponsive to radiation therapy (p = 0.009; AUC = 61%). This study suggests that elevated LATS1 expression may inversely predict radioresistance, while NF-κB expression shows a weak correlation with resistance to radiation therapy. Full article

Quantitative phosphoproteomics enables the comprehensive analysis of signaling pathways driven by overexpressed cancer receptors, revealing the molecular mechanisms that underpin tumor progression and therapy resistance. The glycoprotein L1 cell adhesion molecule (L1CAM) is overexpressed in high-grade serous ovarian carcinoma (HGSOC) and plays a crucial role in carcinogenesis by regulating cancer stem cell properties. Here, CRISPR–Cas9-mediated knockout of L1CAM in ovarian cancer OVCAR8 and OVCAR4 cells significantly impaired anchor-independent growth in soft agar assays and reduced clonogenic survival following external beam irradiation. In vivo, L1CAM knockout decreased cancer stem cell frequency and significantly decreased tumorigenicity. To uncover L1CAM-regulated signaling networks, we employed quantitative phosphoproteomics and proteomics. Bioinformatics analyses and validation studies revealed L1CAM-associated pathways that contribute to radioresistance through DNA repair processes and mammalian target or rapamycin complex 1 (mTORC1)-mediated signaling. In conclusion, our study established a link between L1CAM-dependent tumorigenesis and radioresistance, both hallmarks of cancer stemness, with phosphorylation of key proteins involved in DNA damage response. This study further emphasizes the value of quantitative phosphoproteomics in cancer research, showcasing its ability to enhance understanding of cancer progression and therapy resistance. Full article

Radiation therapy is a medical treatment that uses high doses of radiation to kill or damage cancer cells. It works by damaging the DNA within the cancer cells, ultimately causing cell death. Radiotherapy can be used as a primary treatment, adjuvant treatment in combination with surgery or chemotherapy or palliative treatment to relieve symptoms in advanced cancer stages. Radiation therapy is constantly improving in order to enhance the effect on cancer cells and reduce the side effects on healthy tissues. Our results clearly demonstrate that proton therapy and, even more, carbon ion therapy appear as promising alternatives to overcome the radioresistance of various tumors thanks to less dependency on oxygen and a better ability to kill cancer stem cells. Interestingly, hadrons also retain the advantages of radiosensitization approaches. These data confirm the great ability of hadrons to spare healthy tissue near the tumor via various mechanisms (reduced lymphopenia, bystander effect, etc.). Technology and machine improvements such as image-guided radiotherapy or particle therapies can improve treatment quality and efficacy (dose deposition and biological effect) in tumors while increasingly sparing healthy tissues. Radiation biology can help to understand how cancer cells resist radiation (hypoxia, DNA repair mechanisms, stem cell status, cell cycle position, etc.), how normal tissues may display sensitivity to radiation and how radiation effects can be increased with either radiosensitizers or accelerated particles. All these research topics are under investigation within the ARCHADE research community in France. By focusing on these areas, radiotherapy can become more effective, targeted and safe, enhancing the overall treatment experience and outcomes for cancer patients. Our goal is to provide biological evidence of the therapeutic advantages of hadrontherapy, according to the tumor characteristics. This article aims to give an updated view of our research in radiation biology within the frame of the French “ARCHADE association” and new perspectives on research and treatment with the C400 multi-ions accelerator prototype. Full article

FLASH radiation therapy is an emerging technique that provides several advantages over conventional radiotherapy. By delivering ultra-high dose rate radiation, the damage to healthy tissues surrounding the treatment area is minimized, treatment time is reduced and treatment outcomes of radioresistant tumors are improved. Despite its promising potential, FLASH radiation therapy remains relatively understudied, particularly in the field of dosimetry. Polymer gel dosimetry is a promising technique for verifying FLASH radiation therapy because it enables volumetric dose distribution measurements with high spatial accuracy. This study investigates the applicability of two commonly used polymer gel dosimeters, nPAG and NIBMAGAT, enhanced with nanoparticles, in ultra-high dose rate radiation therapy. The results indicate that NIBMAGAT gel, enriched with Ag nanoparticles, outperforms nPAG. NIBMAGAT gel exhibits less saturation at high doses, maintains dose rate independence and offers comparable sensitivity to nPAG formulation. Full article

Hypoxic cells exhibit radioresistance, which is associated with poor prognosis in cancer patients. Understanding the molecular mechanisms underlying radioresistance in hypoxic tumor cells is crucial for improving radiotherapy efficacy. In this study, we examined the role of FDX1 in regulating cellular responses to severe hypoxia in glioblastoma cell lines T98G and A172. We found that FDX1 expression was upregulated under severe hypoxia, and its knockdown reduced the hypoxia-induced activation of key radioresistance factors and cellular survival mechanisms, including ATM, DNA-PKcs, Akt, and EGFR. FDX1 knockdown also sensitized T98G cells to radiation under severe hypoxia. Furthermore, FDX1 was found to regulate HIF-1α protein level, while HIF-1α did not regulate FDX1 expression. These results suggest that FDX1 may be a novel therapeutic target to overcome radioresistance in glioblastoma under severe hypoxia. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10–15% of initial breast cancer diagnosis, due to its aggressive nature, it carries a worse prognosis in comparison to its hormone receptor-positive counterparts. Despite significant advancements in the screening, diagnosis, and treatment of breast cancer, TNBC remains an important public health burden. Following treatment with chemotherapy, surgery, and radiation, over 40% of TNBC patients experience relapse within 3 years and achieve the least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) is pivotal in TNBC initiation, progression, immune evasion, treatment resistance, and tumor prognosis. TME is a complex network that consists of immune cells, non-immune cells, and soluble factors located in the region adjacent to the tumor that modulates the therapeutic response differentially between hormone receptor-positive breast cancer and TNBC. While the mechanisms underlying the radiation resistance of TNBC remain unclear, the immunosuppressive TME of TNBC has been implicated in chemotherapeutic resistance. Radiation therapy (RT) is known to alter the TME; however, immune changes elicited by radiation are poorly characterized to date, and whether these immune changes contribute to radiation resistance remains unknown. This review delves into the distinct characteristics of the TNBC TME, explores how RT influences TME dynamics, and examines mechanisms underlying tumor radiosensitization, radioresistance, and immune responses. Full article