Articoli di riviste: "Radiosensitisation of tumours"

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Diaz Miqueli, A., J. Rolff, M. Lemm, I. Fichtner, R. Perez e E. Montero. "Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies". British Journal of Cancer 100, n. 6 (marzo 2009): 950–58. http://dx.doi.org/10.1038/sj.bjc.6604943.

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Hong, Cho R., Chantal D. Buckley, Way W. Wong, Praju V. Anekal, Benjamin D. Dickson, Gib Bogle, Kevin O. Hicks, Michael P. Hay e William R. Wilson. "Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648". Radiotherapy and Oncology 166 (gennaio 2022): 162–70. http://dx.doi.org/10.1016/j.radonc.2021.11.027.

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Vinchon-Petit, Sandrine, Delphine Jarnet, Archibald Paillard, Jean-Pierre Benoit, Emmanuel Garcion e Philippe Menei. "In vivo evaluation of intracellular drug-nanocarriers infused into intracranial tumours by convection-enhanced delivery: distribution and radiosensitisation efficacy". Journal of Neuro-Oncology 97, n. 2 (22 settembre 2009): 195–205. http://dx.doi.org/10.1007/s11060-009-0012-4.

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Vitti, Eirini Terpsi, Andrzej Kacperek e Jason L. Parsons. "Targeting DNA Double-Strand Break Repair Enhances Radiosensitivity of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma to Photons and Protons". Cancers 12, n. 6 (7 giugno 2020): 1490. http://dx.doi.org/10.3390/cancers12061490.

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The response of head and neck squamous cell carcinoma (HNSCC) to radiotherapy depends on human papillomavirus type 16 (HPV) status, and where improved outcome and survival is observed in HPV-positive disease. However, strategies to further radiosensitise the tumours, particularly relatively radioresistant HPV-negative HNSCC, are actively being sought. The impact of targeting the major protein kinases involved in the signaling of DNA double-strand break (DSB) repair, namely ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and the catalytic subunit of DNA-dependent protein kinase (DNA-Pkcs), on the radiosensitisation of HNSCC cells was examined. The response to both conventional photon radiotherapy, but also proton beam therapy, was analysed by clonogenic assays and 3D spheroid growth. We observed that inhibition of ATM, ATR, and particularly DNA-Pkcs, caused a significant reduction in HNSCC cell survival post-irradiation with both photons and protons, with less of an impact on the most radiosensitive HPV-positive cell line. The inhibition of DNA-Pkcs and, to a lesser extent ATM, in combination with radiation was also more effective at inhibiting the growth of 3D spheroids derived from relatively radioresistant HPV-negative HNSCC. Similar effects of the inhibitors were observed comparing photon and proton irradiation, demonstrating the potential for targeting DSB repair as an effective combination treatment for HNSCC.

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Rominiyi, Ola, Katie Myers, Natividad Gomez-Roman, Nikita Lad, Dawoud Dar, David Jellinek, Anthony Chalmers et al. "RDNA-12. THE FANCONI ANAEMIA (FA) PATHWAY AND GLIOBLASTOMA: A NEW FOUNDATION FOR DNA DAMAGE RESPONSE TARGETED COMBINATIONS". Neuro-Oncology 21, Supplement_6 (novembre 2019): vi209. http://dx.doi.org/10.1093/neuonc/noz175.871.

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Abstract Treatment resistance in glioblastoma is underpinned by highly interconnected DNA damage response (DDR) processes. The FA-pathway is a fundamental DDR process required for the resolution of replication fork impeding lesions, and we have previously shown that it is inactive in normal brain, but is re-activated in glioblastoma, providing a cancer-specific target for combination DDR therapies. Here, we find that elevated FA-pathway gene expression in gliomas is associated with poor survival (-17.1% 5-year OS, p< 0.0001, n=329–REMBRANT). Furthermore, patient-derived glioblastoma stem cell (GSC) populations, which drive therapeutic resistance, display high FA-pathway expression relative to paired bulk tumour cell populations (mean 2.3-fold higher across genes, p=0.0073). We further show that inhibition of a single DDR process (FA-pathway, PARP, ATR or ATM) increases the susceptibility of glioblastoma cell lines and patient-derived GSCs to current adjuvant therapy. Importantly, clinically approved PARP inhibitor (PARPi) monotherapy stimulates robust FANCD2 mono-ubiquitination, supporting a role of FA-pathway activation in response to current DDR-targeted therapy. In clinically-relevant 3D GSC models, simultaneous inhibition of the FA-pathway (FAPi) and PARP or ATR enhanced temozolomide sensitisation compared to a single DDR inhibitor (DDRi). Furthermore, combined FAPi+PARPi consistently conferred radiosensitisation whilst combined FAPi+ATRi led to a profoundly radiosensitising effect; e.g. sensitizer enhancement ratio (SER0.37) of 3.23 (3.03–3.49, 95% CI). Furthermore, comparison of α/β ratio enhancement suggests dual-DDRi strategies fundamentally alter the response of GSCs, whilst single cell gel electrophoresis & immunofluorescence studies suggest FA-pathway based DDRi combinations profoundly delay the resolution of IR-induced DNA strand breaks at 6 hours post-treatment, with increased persistent DNA double strand breaks at 24 hours. In conclusion, simultaneously targeting the FA-pathway and interconnected DDR processes represents an appealing therapeutic strategy. Additionally, constitutive lack of FA pathway function in some tumours, could serve as a novel predictive biomarker for patient response to PARPi and ATRi currently in clinical trials.

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Brunner, T. "SP-0194: Tumour-specific radiosensitisation by ATR inhibitors". Radiotherapy and Oncology 119 (aprile 2016): S90. http://dx.doi.org/10.1016/s0167-8140(16)31443-8.

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Middleton, Fiona, John Pollard e Nicola Curtin. "The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation". Cancers 10, n. 8 (20 agosto 2018): 275. http://dx.doi.org/10.3390/cancers10080275.

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Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival. The cytotoxicity of VE-821 alone and its ability to potentiate radiation and gemcitabine cytotoxicity was determined in isogenic and unmatched p53 wild-type (wt) and null/mutant cells, as well as immortalised nonmalignant MCF10 (immortalised non-neoplastic) cells, by colony-forming assay. The effect on cell cycle checkpoints was determined by flow cytometry. The isogenic p53 defective cells were not more sensitive to VE-821 alone. Defective p53 consistently conferred greater chemo- and radiosensitisation, particularly at high dose levels in isogenic cells but not unmatched cells. VE-821 did not sensitise MCF10 cells. We conclude that p53 status is just one factor contributing to chemo- and radiosensitisation by ATR inhibition, the lack of chemo- or radiosensitisation in the noncancerous cells suggests an element of tumour-specificity that warrants further investigation. The greater sensitisation at high-dose irradiation suggests that ATR inhibitors may be most effective with hypofractionated radiotherapy.

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Antrobus, Jennifer, e Jason L. Parsons. "Histone Deacetylases and Their Potential as Targets to Enhance Tumour Radiosensitisation". Radiation 2, n. 1 (18 marzo 2022): 149–67. http://dx.doi.org/10.3390/radiation2010011.

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In mammalian cells, genomic DNA is packaged with histone proteins and condensed into chromatin. To gain access to the DNA, chromatin remodelling is required that is enhanced through histone post-translational modifications, which subsequently stimulate processes including DNA repair and transcription. Histone acetylation is one of the most well understood modifications and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes play critical roles in normal cellular functioning, and the dysregulation of HDAC expression in particular has been linked with the development of a number of different cancer types. Conversely, tumour cell killing following radiotherapy is triggered through DNA damage and HDACs can help co-ordinate the cellular DNA damage response which promotes radioresistance. Consequently, HDAC inhibitors have been investigated as potential radiosensitizers in vitro and in vivo to improve the efficacy or radiotherapy in specific tumour types. In this review, we provide an up-to-date summary of HDACs and their cellular functions, including in DNA damage repair. We also review evidence demonstrating that HDAC inhibitors can effectively enhance tumour radiosensitisation, and which therefore show potential for translation into the clinic for cancer patient benefit.

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Yi, S., P. Zhou, L. J. Chang e J. Hendry. "221 Radiosensitisation of tumour cells by the HIV-1 TAT protein". Radiotherapy and Oncology 78 (marzo 2006): S78. http://dx.doi.org/10.1016/s0167-8140(06)80698-5.

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Dehghankelishadi, Pouya, Michelle F. Maritz, Nicole Dmochowska, Parisa Badiee, Edward Cheah, Ivan Kempson, Ross I. Berbeco e Benjamin Thierry. "Formulation of simvastatin within high density lipoprotein enables potent tumour radiosensitisation". Journal of Controlled Release 346 (giugno 2022): 98–109. http://dx.doi.org/10.1016/j.jconrel.2022.04.017.

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Rojas, A., P. Largen, H. Johns, M. R. L. Stratford e M. F. Dennis. "75 Dependence of radiosensitisation on irradiating at the time of peak nicotinamide tumour concentration". Radiotherapy and Oncology 40 (gennaio 1996): S21. http://dx.doi.org/10.1016/s0167-8140(96)80082-x.

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Wood, PJ, e DG Hirst. "Cinnarizine and flunarizine improve the tumour radiosensitisation induced by erythrocyte transfusion in anaemic mice". British Journal of Cancer 60, n. 1 (luglio 1989): 36–40. http://dx.doi.org/10.1038/bjc.1989.215.

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Hawkes, Eliza A., Kate Manos, Geoff Chong, Jodie Palmer, Michael MacManus, Colm Keane, Andrew Scott et al. "Phase I Dose Escalation Study of Radiotherapy and Durvalumab (MEDI4736) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): The RaDD Study". Blood 134, Supplement_1 (13 novembre 2019): 5328. http://dx.doi.org/10.1182/blood-2019-122635.

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Background: Although ~60% of patients with DLBCL are cured with frontline therapy, outcomes for those with relapsed/refractory disease remain poor. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade and inhibit host anti-tumour immune responses. PD1/PDL1 expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for PDL1 inhibition (PD-L1i) in DLBCL. Though single agent PD1i yields a disappointing ORR of 10-30% in heavily pre-treated DLBCL, some responses are durable.1 Radiotherapy (RT) is an established mechanism of stimulating anti-tumour immunity via increased circulating tumour antigen, immunogenic cell death and T-cell recruitment and activation in the tumour microenvironment. Synergy between concomitant immune checkpoint inhibition (ICI) and RT has been demonstrated in preclinical studies2 and solid tumours; a recent study in non-small cell lung cancer demonstrated an ORR of 36% with pembrolizumab + RT compared with 18% with pembrolizumab alone.3 RT hypofractionation appears critical to the abscopal effect when used with ICI,4 and concurrent RT and PD-L1i is more successful than sequential treatment.5 RT to multiple sites may broaden the spectrum of tumour antigen released and overcome clonal variation between disease sites; a dose-response relationship between RT and antigen release has yet to be established. This phase I study aims to determine the safety profile of escalating dose and number of sites of RT in combination with Durvalumab (MEDI4736), an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL, including primary refractory DLBCL and transformed follicular lymphoma. Study Design and Methods: RaDD (NCT03610061) includes eligible pts who have received ≥1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplantation (SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic SCT or chronic steroid use are excluded. Treatment comprises external beam RT to target site(s) daily for 5 days (Fig 1). Durvalumab 1500mg IV commences on day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The primary endpoint is the toxicity, drug pharmacokinetics, maximum tolerated dose (MTD) and recommended phase two dose (RP2D) of simultaneous RT plus durvalumab. Secondary endpoints are response rates; progression free survival; and overall survival. An exploratory PET substudy will employ novel tracers to characterise the local and systemic immune response via assessment of the biodistribution of durvalumab (with 89Zr-Durvalumab) and CD8+ T cells (with 89Zr -Df-IAB22M2C). Biomarker sample collection is synchronised with PET response assessment. A comprehensive translational substudy will apply high throughput technologies to tissue and sequential blood samples to characterise the tumour-immune system interaction and correlate novel host, tumour and tumour microenvironment factors with treatment responses and toxicity. Findings may inform the RP2D. RT dose and site escalation will proceed according to a 3+3 design with 5 dose levels (cohorts 1-5, Fig 2). The dose limiting toxicity assessment window is the first 28 days. Projected enrolment for determination of MTD and RP2D is 6-30 pts pending toxicity. Recruitment will continue to a total of 36 pts to allow for secondary endpoint analysis. 5 pts have been enrolled to date. Acknowledgements: Victorian Cancer Agency (funding), Astra Zeneca (durvalumab and funding), Celgene (funding), Imaginab (89Zr -Df-IAB22M2C) References: 1. Ansell SM et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation. J Clin Oncol. 2. Deng L et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 3. Theelen W et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer. JAMA oncology. 4. Golden EB et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 5. Sharabi AB et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncology. Disclosures Hawkes: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau; Astra Zeneca: Research Funding; Merck KgA: Research Funding; Mundi pharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Manos:Janssen: Honoraria; Novo Nordisk Pharmaceuticals: Other: Travel. Chong:Merck Serono: Research Funding; Hutchison Medipharma: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Bayer: Research Funding; BMS: Research Funding. MacManus:National Health and Medical Research Council Australia: Research Funding. Keane:MSD: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BMS: Research Funding; Roche: Consultancy, Other: Travel Grant. Scott:Cancer Council Victoria: Research Funding; Cancer Australia: Research Funding; Avipep: Consultancy; IBA: Consultancy; Paracrine Therapeutics: Equity Ownership, Patents & Royalties; Life Science Pharmaceuticals: Equity Ownership; NHMRC: Research Funding; Abbvie: Consultancy, Patents & Royalties; Cure Brain Cancer: Research Funding; Medimmune: Consultancy; Humanigen: Patents & Royalties. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Lee:Australian Nuclear Science and Technology Organisation: Membership on an entity's Board of Directors or advisory committees. Koldej:NanoString Technologies: Other: Travel grant. OffLabel Disclosure: Durvalumab is an anti-PD-L1 monoclonal antibody.

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Rojas, A., RJ Hodgkiss, MRL Stratford, MF Dennis e H. Johns. "Pharmacokinetics of varying doses of nicotinamide and tumour radiosensitisation with carbogen and nicotinamide: clinical considerations". British Journal of Cancer 68, n. 6 (dicembre 1993): 1115–21. http://dx.doi.org/10.1038/bjc.1993.490.

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Hébert, Etienne M., Pierre-Jean Debouttière, Martin Lepage, Léon Sanche e Darel J. Hunting. "Preferential tumour accumulation of gold nanoparticles, visualised by magnetic resonance imaging: Radiosensitisation studies in vivo and in vitro". International Journal of Radiation Biology 86, n. 8 (29 giugno 2010): 692–700. http://dx.doi.org/10.3109/09553001003746067.

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Rothkamm, Kai, Sabrina Christiansen, Thorsten Rieckmann, Michael Horn, Thorsten Frenzel, Alexandra Brinker, Udo Schumacher, Alexander Stein, Cordula Petersen e Susanne Burdak-Rothkamm. "Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays". Cancer Letters 493 (novembre 2020): 179–88. http://dx.doi.org/10.1016/j.canlet.2020.08.038.

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Wanigasooriya, Kasun, Robert Tyler, Joao D. Barros-Silva, Yashashwi Sinha, Tariq Ismail e Andrew D. Beggs. "Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors". Cancers 12, n. 5 (18 maggio 2020): 1278. http://dx.doi.org/10.3390/cancers12051278.

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Abstract (sommario):

Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.

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Fabbrizi, Maria Rita, Catherine M. Nickson, Rachel J. Carter, Jonathan R. Hughes, Andrzej Kacperek, Mark A. Hill e Jason L. Parsons. "USP9X Inhibition Enhances Radiosensitisation of Head and Neck Cancer Cells in Response to High-LET Radiation by Destabilising Centrosome Proteins". Medical Sciences Forum 3, n. 1 (29 gennaio 2021): 2. http://dx.doi.org/10.3390/iecc2021-09211.

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Ionising radiation (IR) is widely used in cancer treatment as it induces vast DNA damage, ultimately leading to tumour cell death. The mechanisms involved in X-ray-induced cell death have been deeply studied, while little is known about the impact of IR of higher linear energy transfer (LET) on cell biology and the critical enzymes and mechanisms that are responsive to this. We recently performed a focused small interfering RNA (siRNA) screen to identify proteins involved in cell survival in response to high-LET α-particles and protons, versus low-LET X-rays and protons. From this screening, we validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using siRNA leads to a significantly decreased survival of cells after exposure to high-LET radiation, whilst no effect was observed after low-LET radiation (protons and X-rays) treatment. We consequently investigated the mechanism through which this occurs and found that USP9X inhibition does not interfere with DNA damage (double-strand breaks and complex DNA damage) repair post-irradiation, nor does it induce apoptosis, autophagy or senescence. Instead, we observed that USP9X depletion destabilises key centrosome proteins (CEP55 and CEP131), causing centrosome amplification and, ultimately, cell death in response to high-LET protons.

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Na, J., R. Laney e C. Hanemann. "P18.04.A Cay10603, HDAC6 inhibitor, enhances radiosensitivity in meningioma via supressing the nuclear beta-catenin accumulation". Neuro-Oncology 24, Supplement_2 (1 settembre 2022): ii94—ii95. http://dx.doi.org/10.1093/neuonc/noac174.331.

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Abstract Background Meningioma is the most frequent primary central nervous system tumour (PCNST) which account ca 36% of all PCNST. Due to the lack of efficient chemotherapy for meningioma, radiotherapy often become a first-line treatment especially when the tumour is not operable. Radiotherapy plays a crucial role in local control but its efficacy is restricted by radioresistance and by normal tissue radiation tolerance. Therefore, developing and evaluating potential radiosensitisers to enhance therapeutic efficacy are needed.Histone deacetylase (HDACs) expression is generally increased in many cancer types and regulate the expression of numerous proteins involved in tumorigenesis. Targeting HDAC using HDAC inhibitor (HDACi) represent promising radiosensitisers that affect various biological processes, such as cell survival, apoptosis, and DNA repair. Material and Methods We investigated whether pre-treatment with the hydroxamate-based HDAC6 inhibitor, Cay10603, impacts radiation-induced DNA double-strand break (DSB) induction, cell survival, cell cycle arrest, and cell death using immunocytochemistry, clonogenic assay, and flow cytometry in meningioma cell lines. Low concentration (100 nM) of Cay10603 was treated 24 hr prior to high energy x-ray irradiation (2 Gy) by a medical linear accelerator (LINAC). To investigate the nuclear localisation of beta-catenin, subcellular fractionation and Western Blotting were conducted. Results We found that tumour cells survival was synergistically decreased after combination treatment of Cay10603 and radiation. Combination therapy induced DNA damage with activation of histone gH2AX and increased G2/M arrest compared to drug or radiation alone. Both apoptotic and necrotic cell death were increased after combination therapy. To focus on the mechanisms of action of HDAC6 inhibition followed by radiation, we further investigated nuclear localisation of beta-catenin levels. The results showed the both beta-catenin and c-myc expression in the nucleus was suppressed after combination therapy. Conclusion In meningioma cells, radiotherapy in combination with HDAC6 inhibitor reduces the nuclear localisation of beta-catenin and synergistically decreases cell survival. Our findings demonstrate a potential therapeutic strategy of Cay10603 to improve the radiosensitisation for meningioma cells.

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Then, Chee Kin, Salome Paillas, Xuedan Wang, Mariya Misheva, James McCullagh, Kevin R. Foster e Anne E. Kiltie. "Abstract 6060: Can the gut microbiota both radiosensitize tumors and spare normal tissue toxicity". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 6060. http://dx.doi.org/10.1158/1538-7445.am2022-6060.

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Abstract Background: New non-toxic radiosensitizers are needed in the treatment of muscle-invasive bladder cancer because elderly patients are vulnerable to chemotherapy-related toxicity of currently available radiosensitizers. Our previous study showed that high fiber diets sensitized RT112 xenografts to ionizing radiation (IR) by modifying the gut microbiome and this phenotype was positively correlated with B.acidifaciens (BA) abundance. It is noted that gut microbiota can enhance anti-tumoral responses, so we hypothesise that gut microbiota including BA may radiosensitize tumors via secretion of metabolites and immunomodulation. Methods: UPPL1591 mouse bladder cancer cell line flank xenografts were implanted into C57BL/6 mice (an immune-competent setting) at the same time as starting low (0.2% cellulose) and high fiber (5% psyllium, 5% psyllium plus 10% resistant starch/10% inulin) diets for their lifetime (N=30). 16S rRNA sequencing, IC-MS, IHC and the Nanostring platform were used for gut microbiota, untargeted metabolomics, and local tumor immunity analyses. For normal tissue toxicity studies, mice received 10-14 Gy IR (N=84). We used an intestinal crypt assay and FACS analysis of spleen to assess acute normal effects in small intestine and systemic immunity. Cell viability, clonogenic assay and Western blotting were used to validate the cytotoxic and radiosensitizing effects of bacterial supernatants on RT112 human bladder cancer cells (N=3). Results: Psyllium plus either resistant starch (RS, p=0.007) or inulin (p<0.001) significantly decreased tumors size. Psyllium plus inulin raised inosine-producing bacteria (p<0.001) and faecal inosine levels (p<0.001) which has been shown to enhance immunotherapy efficacy. Increased systemic (p=0.189) and local (p=0.024) anti-tumoral T cell responses were observed in the psyllium plus inulin group. Furthermore, the two diets mitigated the radiation injury from 14 Gy in intestinal crypt assays (p=0.011) and increased systemic immunity, with higher populations of B (p=0.024), cytotoxic T (p=0.019) and helper T (p<0.001) cells. Psyllium plus RS or inulin significantly increased caecal size (p<0.001), implying higher fermentation levels. We previously found inulin can enhance the relative abundance of BA. The supernatants of co-cultures of BA and F.praunitzii (FP, butyrate-producer) conferred greater cytotoxity than BA alone (p<0.001) or co-cultures of Bifidobacterium and FP (p<0.001), and also increased histone acetylation levels. Bacterial supernatants of BA increased DNA damage with 5Gy IR (p<0.05) and radiosensitivity of bladder tumour cells (p=0.008 at 8Gy). Conclusions: B.acidifaciens is a potential radiosensitiser with enhanced efficacy in combination with butyrate-producing bacteria. Our in vivo experiments suggest a role for inosine and cytotoxic T cells generated by the gut microbiota in radiosensitisation of bladder tumors. Citation Format: Chee Kin Then, Salome Paillas, Xuedan Wang, Mariya Misheva, James McCullagh, Kevin R. Foster, Anne E. Kiltie. Can the gut microbiota both radiosensitize tumors and spare normal tissue toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6060.

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Thirion, P. "A randomised phase II trial assessing the impact of the addition of gefitinib to the combination of radiotherapy and short-term maximal androgen blockage in high-risk localised prostate cancer: Safety evaluation". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 14613. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14613.

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14613 Background: Given the in-vitro evidence of potential increase in tumour radiosensitisation and hormonal deprivation-related tumour growth inhibiting effect by the addition of EGFR inhibitors, a randomised unblinded phase II trial was initiated to evaluate the impact of the addition of gefitinib to a combination of radiotherapy (RT) and maximal androgen blockage (MAB) in patients (pts) with high-risk localised prostate cancer. Methods: Eligible pts had biopsy proven localised prostate carcinoma Gleason score ≥7 and/or cT3 stage and/or initial PSA ≥ 20; without nodal and distant metastases. All pts were treated by 8 months MAB using LH-RH agonist (Zoladex 3.6 mg/month) and peripheral anti-androgen (Casodex 50 mg/day), and localised Conformal RT (Prostate + Seminal Vesicles, 75.6 Gy/42 daily fractions), initiated after 4 months of MAB. Pts were randomised to receive or not gefitinib 250 mg/day concomitantly for 8 months. The planned accrual was 98 pts. The end-points were ASTRO defined PSA-relapse-free survival at 18 months and toxicity. A safety evaluation was performed mid 2005. Results: 20 pts (10 per arm) were included from 10/2003 to 02/2005. No significant difference in RT or MAB-related toxicity was seen between the 2 arms. The addition of gefitinib significantly increased the frequency and intensity of reversible skin toxicity events (Rash-CTC grade 3–4: 4 pts Vs O pts, p = 0.04), with a trend for reversible transaminase enzymes elevation (TEE) (CTC grade 3–4: 2 pts Vs 0 pts). No treatment interruption was reported in the control arm. In the experimental arm, 3 pts completed treatment, 3 pts had a temporary (<10 days) gefitinib discontinuation (reversible asthenia and skin rash) and 4 pts had a permanent gefitinib discontinuation for reversible CTC grade 3 toxicity (skin rash: 2 pts, TEE: 2 pts). Conclusions: Gefitinib-related toxicity led to treatment discontinuation in 4 out of 10 patients. The trial is under review. This trial was supported by AstraZeneca. No significant financial relationships to disclose.

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Playle, L. C., D. J. Hicks, D. Qualtrough e C. Paraskeva. "Abrogation of the radiation-induced G2 checkpoint by the staurosporine derivative UCN-01 is associated with radiosensitisation in a subset of colorectal tumour cell lines". British Journal of Cancer 87, n. 3 (luglio 2002): 352–58. http://dx.doi.org/10.1038/sj.bjc.6600492.

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Dholaria, Hetal, Jessica Buck, Hilary Hii, Brooke Carline, Jacob Bryne, Mani Kuchibhotla, Jessica Lawler et al. "MODL-19. Exploiting DNA damage response inhibitors to enhance radiation efficacy in medulloblastoma models". Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i173. http://dx.doi.org/10.1093/neuonc/noac079.642.

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Abstract Despite treatment intensification, survival for certain high-risk subgroups of medulloblastoma (MB) such as p53 mutant SHH (SHHa) and MYC amplified Group 3 (Gr3) have remained dismal. Recently, the use of Carboplatin as radiosensitiser with craniospinal irradiation (CSI) has shown survival benefit in children with Gr3 MB. However, there is an ongoing need to discover newer, non-chemo radiosensitisers which have minimal toxicity and unequivocal benefit in high-risk MB. Radiation is a potent inducer of DNA damage in cancer cells. CHK1/2, ATR, and WEE1 kinases are critical regulators of the DNA damage response (DDR). We hypothesised that inhibition of these kinases may enhance radiation-induced cytotoxicity in MB. We utilised small-animal radiotherapy platform to deliver CSI to MB-tumour-bearing mice that closely mimic clinical settings. Here we demonstrate systematic preclinical evaluation of DDR inhibitors (DDRi) as radiosensitiser in MB models. In vitro treatment of Gr3 MB cell lines with either CHK1/2 inhibitor (CHKi, Prexasertib, AZD7762), ATR inhibitor (ATRi, AZD6738), or WEE1 inhibitor (WEE1i, AZD1775) along with radiation ceased post-radiation cell cycle arrest, prohibiting DNA repair, and increasing apoptosis. The combination also reduced the colony-forming ability of MB cells post-irradiation. In vivo, CSI and DDRi, each induced modest apoptosis in orthotopically-implanted high-risk MB mice. When these models were treated with CHKi+CSI, ATRi+CSI or WEE1i+CSI, the effect was cumulative. Importantly, addition of DDRi to CSI significantly prolonged the survival of MB-bearing mice compared to CSI alone. Here we also explored strategy of “vertical blockade” by simultaneous use of CHKi and WEE1i which when combined with CSI also prolonged survival in MB-bearing mice. Additionally, we evaluated various regimens to best deliver these novel agents with CSI, maximising effect and minimising toxicity. Our study opens up new realms of radiosensitisation with the use of DDRi in paediatric medulloblastoma and provides robust preclinical evidence for clinical translation.

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Hamunyela, Roswita, Antonio Serafin, Mogammad Hamid, Sechaba Maleka, Daniel Achel e John Akudugu. "A Cocktail of Specific Inhibitors of HER-2, PI3K, and mTOR Radiosensitises Human Breast Cancer Cells". Journal of Cancer Biology and Therapeutics 1, n. 1 (3 giugno 2015). http://dx.doi.org/10.18314/gjct.v1i1.33.

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Abstract (sommario):

Intrinsic tumour radioresistance limits the benefit of radiotherapy. Targeted treatment modalities that are singly effective for triple-negative breast cancer are lacking, partly due to paucity of relevant targets as they are devoidof the human epidermal growth factor receptor 2 (HER-2), progesterone receptor (PR), and oestrogen receptor (ER); or to resistance to single-target therapies as a consequence of cellular heterogeneity. Concomitant targeting of cell signaling entities other than HER-2, PR and ER may sensitise triple-negative tumours to radiotherapy. In this study, we investigated the effect of an HER-2 inhibitor (TAK-165) and a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) (NVP-BEZ235) in three human breast cancer cell lines. The potential of simultaneous inhibition of HER-2, PI3K and mTOR with a cocktail of the specific inhibitors TAK-165 and NVP-BEZ235, to radiosensitise human breast cancer cells in vitro was examined using the colony forming assay. Combined inhibition of HER-2, PI3K, and mTOR resulted in significant radiosensitisation in all cell lines, independent of HER-2, ER, or PR status. Radiosensitisation was more prominent in ER- and PR-negative cells expressing higher levels of epidermal growth factor receptor (EGFR). These data suggest that a cocktail of TAK-165 and NVP-BEZ235 could potentially be effective in the treatment of triple-negative breast cancer.

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Inder, S., M. Bates, N. Ni Labhrai, N. McDermott, J. Schneider, G. Erdmann, T. Jamerson et al. "Multiplex profiling identifies clinically relevant signalling proteins in an isogenic prostate cancer model of radioresistance". Scientific Reports 9, n. 1 (22 novembre 2019). http://dx.doi.org/10.1038/s41598-019-53799-7.

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AbstractThe exact biological mechanism governing the radioresistant phenotype of prostate tumours at a high risk of recurrence despite the delivery of advanced radiotherapy protocols remains unclear. This study analysed the protein expression profiles of a previously generated isogenic 22Rv1 prostate cancer model of radioresistance using DigiWest multiplex protein profiling for a selection of 90 signalling proteins. Comparative analysis of the profiles identified a substantial change in the expression of 43 proteins. Differential PARP-1, AR, p53, Notch-3 and YB-1 protein levels were independently validated using Western Blotting. Pharmacological targeting of these proteins was associated with a mild but significant radiosensitisation effect at 4Gy. This study supports the clinical relevance of isogenic in vitro models of radioresistance and clarifies the molecular radiation response of prostate cancer cells.

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Hamid, Mogammad, John Akudugu, Roswita Hamunyela e Antonio Serafin. "Inhibition of PI3K and mTOR Sensitises Oestrogen Receptor Positive Human Breast Cancer Cells to a Large Fraction of Radiation Dose". Journal of Cancer Biology and Therapeutics 2, n. 1 (31 dicembre 2016). http://dx.doi.org/10.18314/gjct.v2i1.74.

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Resistance to radiotherapy has been attributed to the expression of proteins pertinent to cancer cell survival. Treatment approaches that can effectively target these proteins, to possibly augment the effect of radiotherapy, are lacking. This is partly due to the heterogeneity in cellular expression of potential targetproteins like human epidermal growth factor receptor 2 (HER-2), progesterone receptor (PR), and oestrogen receptor (ER). Such heterogeneity can result in an inability to adequately target all cells, and thus treatment failure. Hypofractionated radiotherapy has become a common clinical practice, and developing approachesthat can enhance the effect of this regimen may prove beneficial to cancer management. In this study, an inhibitor of HER-2 (TAK-165) and a dual inhibitor of phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) (NVP-BEZ235) were tested for their radiomodulatory effects, at 6 Gy, in three humanbreast cell lines (MDA-MB-231, MCF-7, MCF-12A) with low expression of HER-2, and different expression levels of ER and PR. Pre-treatment with TAK-165 or a cocktail of TAK-165 and NVP-BEZ235 yielded a modest or no radiosensitisation in all cell lines. NVP-BEZ235 treatment resulted in a significant radiosensitisation of theER and PR overexpressing cells (MCF-7), but not in the ER and PR negative cells (MDA-MB-231 and MCF-12A). These results strongly suggest that inhibition of PI3K and mTOR in ER-positive tumours might sensitise them to hypofractionated radiotherapy, and that triple-negative cancers may not benefit from this regimen.

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Brüningk, Sarah C., Peter Ziegenhein, Ian Rivens, Uwe Oelfke e Gail ter Haar. "A cellular automaton model for spheroid response to radiation and hyperthermia treatments". Scientific Reports 9, n. 1 (27 novembre 2019). http://dx.doi.org/10.1038/s41598-019-54117-x.

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AbstractThermo-radiosensitisation is a promising approach for treatment of radio-resistant tumours such as those containing hypoxic subregions. Response prediction and treatment planning should account for tumour response heterogeneity, e.g. due to microenvironmental factors, and quantification of the biological effects induced. 3D tumour spheroids provide a physiological in vitro model of tumour response and a systems oncology framework for simulating spheroid response to radiation and hyperthermia is presented. Using a cellular automaton model, 3D oxygen diffusion, delivery of radiation and/or hyperthermia were simulated for many ($${\bf{1}}{{\bf{0}}}^{{\bf{4}}}{\boldsymbol{-}}{\bf{1}}{{\bf{0}}}^{{\bf{7}}}$$104−107) individual cells forming a spheroid. The iterative oxygen diffusion model was compared to an analytical oxygenation model and simulations were calibrated and validated against experimental data for irradiated (0–10 Gy) and/or heated (0–240 CEM43) HCT116 spheroids. Despite comparable clonogenic survival, spheroid growth differed significantly following radiation or hyperthermia. This dynamic response was described well by the simulation ($${{\bf{R}}}^{{\bf{2}}}$$R2 > 0.85). Heat-induced cell death was implemented as a fast, proliferation-independent process, allowing reoxygenation and repopulation, whereas radiation was modelled as proliferation-dependent mitotic catastrophe. This framework stands out both through its experimental validation and its novel ability to predict spheroid response to multimodality treatment. It provides a good description of response where biological dose-weighting based on clonogenic survival alone was insufficient.

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Hamunyela, Roswita, Mogammad Hamid, Antonio Serafin e John Akudugu. "Combined Inhibition of PI3K, mTOR and Bcl-2 Significantly Radiosensitises Progesterone and Oestrogen Receptor Negative Breast Cancer Cells". Journal of Cancer Biology and Therapeutics 2, n. 1 (31 agosto 2017). http://dx.doi.org/10.18314/gjct.v2i1.138.

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Patients with triple-negative breast cancers (TNBC) constitute about one-fifth of all breast cancer patients. TNBC is an aggressive and heterogeneous disease entity in comparison with other types of breast cancer and, therefore, tends to be resistant to existing treatment regimens, such as, targeted and hormone therapies. There is evidence to suggest that proliferative and survival pathways of triple-negative tumours are still poorly understood, which could be the reason for the observed treatment resistance. Novel treatment approaches are, therefore, needed to overcome the challenges in the treatment of triple-negative breast cancers. Three human breast cell lines (MDAMB- 231, MCF-7 and MCF-12A) were pre-treated ith inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and the pro-survival gene (Bcl-2), and their radiosensitivities were evaluated using the clonogenic cell survival assay. Inhibition of PI3K, mTOR, and Bcl-2 with a cocktail of small molecule inhibitors NVP-BEZ235 and ABT-263 resulted in a 4- to 14-fold radiosensitisation of human breast cell lines with features similar to those of triple-negative cancers. These findings suggest that inhibition of I3K, mTOR, and Bcl-2 can significantly enhance the sensitivity of breast cells devoid of progesterone and oestrogen receptor expression. This approach may have therapeutic potential for breast cancer management.

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Russell, Emily, Victoria Dunne, Ben Russell, Hibaaq Mohamud, Mihaela Ghita, Stephen J. McMahon, Karl T. Butterworth, Giuseppe Schettino, Conor K. McGarry e Kevin M. Prise. "Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells". Radiation Oncology 16, n. 1 (12 giugno 2021). http://dx.doi.org/10.1186/s13014-021-01829-y.

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Abstract Purpose The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. Methods SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. Results The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 μg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05). Conclusions SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

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"1007 poster p53 status of tumour cells has no effect on radiosensitisation by gemcitabine in vitro". Radiotherapy and Oncology 73 (ottobre 2004): S424. http://dx.doi.org/10.1016/s0167-8140(04)82874-3.

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Bennie, Lindsey A., Jie Feng, Christopher Emmerson, Wendy B. Hyland, Kyle B. Matchett, Helen O. McCarthy e Jonathan A. Coulter. "Formulating RALA/Au nanocomplexes to enhance nanoparticle internalisation efficiency, sensitising prostate tumour models to radiation treatment". Journal of Nanobiotechnology 19, n. 1 (19 settembre 2021). http://dx.doi.org/10.1186/s12951-021-01019-8.

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Abstract Background Gold nanoparticles (AuNP) are effective radiosensitisers, however, successful clinical translation has been impeded by short systemic circulation times and poor internalisation efficiency. This work examines the potential of RALA, a short amphipathic peptide, to enhance the uptake efficiency of negatively charged AuNPs in tumour cells, detailing the subsequent impact of AuNP internalisation on tumour cell radiation sensitivity. Results RALA/Au nanoparticles were formed by optimising the ratio of RALA to citrate capped AuNPs, with assembly occurring through electrostatic interactions. Physical nanoparticle characteristics were determined by UV–vis spectroscopy and dynamic light scattering. Nano-complexes successfully formed at w:w ratios > 20:1 (20 µg RALA:1 µg AuNP) yielding positively charged nanoparticles, sized < 110 nm with PDI values < 0.52. ICP-MS demonstrated that RALA enhanced AuNP internalisation by more than threefold in both PC-3 and DU145 prostate cancer cell models, without causing significant toxicity. Importantly, all RALA-AuNP formulations significantly increased prostate cancer cell radiosensitivity. This effect was greatest using the 25:1 RALA-AuNP formulation, producing a dose enhancement effect (DEF) of 1.54 in PC3 cells. Using clinical radiation energies (6 MV) RALA-AuNP also significantly augmented radiation sensitivity. Mechanistic studies support RALA-AuNP nuclear accumulation resulting in increased DNA damage yields. Conclusions This is the first study to demonstrate meaningful radiosensitisation using low microgram AuNP treatment concentrations. This effect was achieved using RALA, providing functional evidence to support our previous imaging study indicating RALA-AuNP nuclear accumulation. Graphic abstract

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Rominiyi, O., A. Vanderlinden, K. Myers, N. Gomez-Roman, D. Dar, V. Bagga, DA Jellinek et al. "O2: TOWARDS A LIVING BIOBANK OF SURGICALLY-RELEVANT 3-DIMENSIONAL GLIOBLASTOMA STEM CELL MODELS TO EVALUATE NOVEL THERAPEUTICS AND INTERROGATE INTRATUMOURAL HETEROGENEITY". British Journal of Surgery 108, Supplement_1 (1 marzo 2021). http://dx.doi.org/10.1093/bjs/znab117.002.

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Abstract Introduction Glioblastoma is the most common cancer arising within the brain. Despite surgery, followed by DNA-damaging chemoradiotherapy, average survival remains between 12-15 months. Unacceptable survival rates underline the need to develop preclinical research models which recapitulate features underpinning therapeutic resistance in patients, such as intratumoural heterogeneity and treatment resistant glioblastoma stem cell (GSC) subpopulations which demonstrate elevated DNA damage response (DDR) activity. Method Tumour specimens from patients were used to generate 2D and 3D scaffold-based GSC models, with a range of preclinical survival and molecular assays used to interrogate cancer biology and assess therapeutic responses. Result We have developed a ‘living biobank’ of 20+ ex-vivo GSC models which reflect key clinicopathological diversity. These models include residual disease models based on careful macrodissection of rare en-blocpartial lobectomy specimens to liberate parallel GSC lines from the tumour core and adjacent infiltrated brain, to represent cells typically left behind after surgery. Therapeutic strategies targeting fundamental DDR processes demonstrate preclinical efficacy, for example dual inhibition of ATR and the FA DNA damage repair pathways elicits profound radiosensitisation (sensitiser enhancement ratio of 3.23 (3.03-3.49, 95%-CI)) with evidence of delayed DNA damage repair on single-cell gel electrophoresis. Finally, characterisation of our surgically-relevant resected and residual models reveals numerous divergent properties including elevated stem cell marker expression in residual models (p=0.0021), which may partially explain treatment resistance in disease left behind after surgery. Conclusion Our living biobank represents a useful resource for preclinical glioblastoma research and demonstrates the value of partnership between surgeons and laboratory-based scientists. Take-home message Our living biobank represents a useful resource for preclinical glioblastoma research and demonstrates the value of partnership between surgeons and laboratory-based scientists.

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de Haan, R., E. van Werkhoven, M. M. van den Heuvel, H. M. U. Peulen, G. S. Sonke, P. Elkhuizen, M. W. M. van den Brekel et al. "Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib". BMC Cancer 19, n. 1 (10 settembre 2019). http://dx.doi.org/10.1186/s12885-019-6121-3.

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Abstract Background Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited. Methods Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses. Discussion We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity. Trial registration ClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).

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