المؤلفون: Peter Hoskin, Marina Lee, Denise Dunkley, Mary Danh, Robin Wickens, Geoff Saunders, Josh Northey, Simon Crabb, Vicky McFarlane, Azmat Sadozye, Rachel Cooper, Tony Mathew, Kate Haslett, Kim Reeves, Rachel Reed, Kamilla Bigos, Kaye J. Williams, Emily Rowling, Ananya Choudhury, Sonia Dancer, Deb Smith, Gareth Griffiths

المصدر: BMC Cancer, Vol 24, Iss 1, Pp 1-10 (2024)

مصطلحات موضوعية: Cervical cancer, Tolinapant, Chemoradiotherapy, Cisplatin, Phase I, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). Methods CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. Discussion If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. Trial registrations EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2407Test

الوصول الحر: https://doaj.org/article/f7ea589d3ca34f57b9365cb0b9d214d5Test

المؤلفون: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Wei Zhang, Vishaka Gopalan, Sorayut Chattrakarn, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Daniel J. Wilcock, Michael P. Smith, Kleita Sergiou, Brian A. Telfer, Dervla T. Isaac, Chang Liu, Nicholas R. Perl, Kerrie Marie, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. L. Hurlstone

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-21 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/93f86ebcf5e046d68cb9b2272850303fTest

المؤلفون: Emma R. Biglin, Adam H. Aitkenhead, Gareth J. Price, Amy L. Chadwick, Elham Santina, Kaye J. Williams, Karen J. Kirkby

المصدر: Scientific Reports, Vol 12, Iss 1, Pp 1-13 (2022)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Preclinical radiation research lacks standardized dosimetry procedures that provide traceability to a primary standard. Consequently, ensuring accuracy and reproducibility between studies is challenging. Using 3D printed murine phantoms we undertook a dosimetry audit of Xstrahl Small Animal Radiation Research Platforms (SARRPs) installed at 7 UK centres. The geometrically realistic phantom accommodated alanine pellets and Gafchromic EBT3 film for simultaneous measurement of the dose delivered and the dose distribution within a 2D plane, respectively. Two irradiation scenarios were developed: (1) a 10 × 10 mm2 static field targeting the pelvis, and (2) a 5 × 5 mm2 90° arc targeting the brain. For static fields, the absolute difference between the planned dose and alanine measurement across all centres was 4.1 ± 4.3% (mean ± standard deviation), with an overall range of − 2.3 to 10.5%. For arc fields, the difference was − 1.2% ± 6.1%, with a range of − 13.1 to 7.7%. EBT3 dose measurements were greater than alanine by 2.0 ± 2.5% and 3.5 ± 6.0% (mean ± standard deviation) for the static and arc fields, respectively. 2D dose distributions showed discrepancies to the planned dose at the field edges. The audit demonstrates that further work on preclinical radiotherapy quality assurance processes is merited.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/837936469b87449c8bfd74544c4248a6Test

المؤلفون: Becky A. S. Bibby, Niluja Thiruthaneeswaran, Lingjian Yang, Ronnie R. Pereira, Elisabet More, Darragh G. McArt, Paul O’Reilly, Robert G. Bristow, Kaye J. Williams, Ananya Choudhury, Catharine M. L. West

المصدر: BMC Urology, Vol 21, Iss 1, Pp 1-11 (2021)

مصطلحات موضوعية: Diseases of the genitourinary system. Urology, RC870-923

الوصف: Abstract Background The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer. Methods Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia. Results Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells. Conclusion Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2490Test

الوصول الحر: https://doaj.org/article/dc9fc4ab567343f7a4756b4ec9e09d1bTest

المؤلفون: Maria Likhatcheva, Roben G. Gieling, James A. L. Brown, Constantinos Demonacos, Kaye J. Williams

المصدر: Frontiers in Cell and Developmental Biology, Vol 9 (2021)

مصطلحات موضوعية: Ataxia Telangiectasia Mutated (ATM), hypoxia, SUV39H1, Tip60, MDM2, Biology (General), QH301-705.5

الوصف: The effects of genotoxic stress can be mediated by activation of the Ataxia Telangiectasia Mutated (ATM) kinase, under both DNA damage-dependent (including ionizing radiation), and independent (including hypoxic stress) conditions. ATM activation is complex, and primarily mediated by the lysine acetyltransferase Tip60. Epigenetic changes can regulate this Tip60-dependent activation of ATM, requiring the interaction of Tip60 with tri-methylated histone 3 lysine 9 (H3K9me3). Under hypoxic stress, the role of Tip60 in DNA damage-independent ATM activation is unknown. However, epigenetic changes dependent on the methyltransferase Suv39H1, which generates H3K9me3, have been implicated. Our results demonstrate severe hypoxic stress (0.1% oxygen) caused ATM auto-phosphorylation and activation (pS1981), H3K9me3, and elevated both Suv39H1 and Tip60 protein levels in FTC133 and HCT116 cell lines. Exploring the mechanism of ATM activation under these hypoxic conditions, siRNA-mediated Suv39H1 depletion prevented H3K9me3 induction, and Tip60 inhibition (by TH1834) blocked ATM auto-phosphorylation. While MDM2 (Mouse double minute 2) can target Suv39H1 for degradation, it can be blocked by sirtuin-1 (Sirt1). Under severe hypoxia MDM2 protein levels were unchanged, and Sirt1 levels depleted. SiRNA-mediated depletion of MDM2 revealed MDM2 dependent regulation of Suv39H1 protein stability under these conditions. We describe a novel molecular circuit regulating the heterochromatic state (H3K9me3 positive) under severe hypoxic conditions, showing that severe hypoxia-induced ATM activation maintains H3K9me3 levels by downregulating MDM2 and preventing MDM2-mediated degradation of Suv39H1. This novel mechanism is a potential anti-cancer therapeutic opportunity, which if exploited could target the hypoxic tumor cells known to drive both tumor progression and treatment resistance.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fcell.2021.720194/fullTest; https://doaj.org/toc/2296-634XTest

الوصول الحر: https://doaj.org/article/c0666bb8a86b4bdd9b41099d7119f8abTest

المؤلفون: Emma R. Biglin, Gareth J. Price, Amy L. Chadwick, Adam H. Aitkenhead, Kaye J. Williams, Karen J. Kirkby

المصدر: Radiation Oncology, Vol 14, Iss 1, Pp 1-10 (2019)

مصطلحات موضوعية: Radiotherapy, Tissue-equivalent, Dosimetry, Phantoms, 3D printing, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Preclinical radiotherapy studies using small animals are an indispensable step in the pathway from in vitro experiments to clinical implementation. As radiotherapy techniques advance in the clinic, it is important that preclinical models evolve to keep in line with these developments. The use of orthotopic tumour sites, the development of tissue-equivalent mice phantoms and the recent introduction of image-guided small animal radiation research platforms has enabled similar precision treatments to be delivered in the laboratory. These technological developments, however, are hindered by a lack of corresponding dosimetry standards and poor reporting of methodologies. Without robust and well documented preclinical radiotherapy quality assurance processes, it is not possible to ensure the accuracy and repeatability of dose measurements between laboratories. As a consequence current RT-based preclinical models are at risk of becoming irrelevant. In this review we explore current standardization initiatives, focusing in particular on recent developments in small animal irradiation equipment, 3D printing technology to create customisable tissue-equivalent dosimetry phantoms and combining these phantoms with commonly used detectors.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13014-019-1343-8Test; https://doaj.org/toc/1748-717XTest

الوصول الحر: https://doaj.org/article/f446a7dfc65f4a6790c49cdf71d6849cTest

المؤلفون: Paul David Tar, Neil A. Thacker, Muhammad Babur, Grazyna Lipowska-Bhalla, Susan Cheung, Ross A. Little, Kaye J. Williams, James P. B. O’Connor

المصدر: Cancers, Vol 14, Iss 9, p 2159 (2022)

مصطلحات موضوعية: cancer, imaging, modelling, statistics, machine learning, diffusion weighted MRI, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Imaging biomarkers are used in therapy development to identify and quantify therapeutic response. In oncology, use of MRI, PET and other imaging methods can be complicated by spatially complex and heterogeneous tumor micro-environments, non-Gaussian data and small sample sizes. Linear Poisson Modelling (LPM) enables analysis of complex data that is quantitative and can operate in small data domains. We performed experiments in 5 mouse models to evaluate the ability of LPM to identify responding tumor habitats across a range of radiation and targeted drug therapies. We tested if LPM could identify differential biological response rates. We calculated the theoretical sample size constraints for applying LPM to new data. We then performed a co-clinical trial using small data to test if LPM could detect multiple therapeutics with both improved power and reduced animal numbers compared to conventional t-test approaches. Our data showed that LPM greatly increased the amount of information extracted from diffusion-weighted imaging, compared to cohort t-tests. LPM distinguished biological response rates between Calu6 tumors treated with 3 different therapies and between Calu6 tumors and 4 other xenograft models treated with radiotherapy. A simulated co-clinical trial using real data detected high precision per-tumor treatment effects in as few as 3 mice per cohort, with p-values as low as 1 in 10,000. These findings provide a route to simultaneously improve the information derived from preclinical imaging while reducing and refining the use of animals in cancer research.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/14/9/2159Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/1ea88080121c4b8c98aa204d6d9a7b6dTest

المؤلفون: Natalie Burrows, Muhammad Babur, Julia Resch, Kaye J. Williams, Georg Brabant

المصدر: Journal of Thyroid Research, Vol 2011 (2011)

مصطلحات موضوعية: Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2042-0072Test

الوصول الحر: https://doaj.org/article/7c3a1b0a9fb34f3a86433f8cb39ae888Test

المؤلفون: Ian J. Stratford, Susan E. Critchlow, Paul D. Smith, Kaye J. Williams, Brian A. Telfer, Kathryn G. Blount, Filippos Michopoulos, Amy L. Chadwick, Becky M. Bola

الوصف: This file shows the aerobic and anoxic toxicity of AZD3965.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2310b6caa33dbfec3004ae7b7846fb5cTest
https://doi.org/10.1158/1535-7163.22502373.v1Test

المؤلفون: Kaye J. Williams, Ian Wilson, Duncan Hiscock, Caroline Dive, Adam McMahon, Gavin Brown, Cassandra Hodgkinson, Kathryn Simpson, Muhammad Babur, Alison Smigova, Marc Radigois, Jamil Gregory, Duncan Forster, Christopher J. Morrow, Roben G. Gieling, Natalie Burrows, Christopher Cawthorne

الوصف: PDF file - 65 KB, Acute dosing with GDC-0941 leads to an increase in apoptotic signaling in in sensitive tumors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::708657f7214f04cb186176d4644e0ee6Test
https://doi.org/10.1158/1535-7163.22499062Test