-
1دورية أكاديمية
المؤلفون: Spiliopoulou, Pavlina, Kazmi, Farasat, Aroldi, Francesca, Holmes, Thomas, Thompson, David, Griffiths, Lucinda, Qi, Cathy, Parkes, Matthew, Lord, Simon, Veal, Gareth J., Harrison, David J., Coyle, Vicky M., Graham, Jill, Jeffry Evans, Thomas R., Blagden, Sarah P.
الوصف: Purpose: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/323722/2/323722.pdfTest; Spiliopoulou, P. et al. (2024) A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301). Journal of Experimental and Clinical Cancer Research , 43(1), 100. (doi:10.1186/s13046-024-03010-1 ) (PMID:38566164) (PMCID:PMC10986017)
-
2دورية أكاديمية
الوصف: Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (Treg) cells (CD4+CD25+FOXP3+). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on Treg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (Teff/Treg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of Treg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target Treg cells.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/320446/1/320446.pdfTest; Spiliopoulou, P. , Kaur, P., Hammett, T., Di Conza, G. and Lahn, M. (2024) Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers. Cancer Drug Resistance , 7, 2. (doi:10.20517/cdr.2023.46 ) (PMID:38318526) (PMCID:PMC10838381)
-
3دورية أكاديمية
الوصف: The therapeutic landscape of malignant melanoma has been radically reformed in recent years, with novel treatments emerging in both the field of cancer immunotherapy and signalling pathway inhibition. Large-scale tumour genomic characterization has accurately classified malignant melanoma into four different genomic subtypes so far. Despite this, only somatic mutations in BRAF oncogene, as assessed in tumour biopsies, has so far become a validated predictive biomarker of treatment with small molecule inhibitors. The biology of tumour evolution and heterogeneity has uncovered the current limitations associated with decoding genomic drivers based only on a single-site tumour biopsy. There is an urgent need to develop minimally invasive biomarkers that accurately reflect the real-time evolution of melanoma and that allow for streamlined collection, analysis, and interpretation. These will enable us to face challenges with tumour tissue attainment and process and will fulfil the vision of utilizing “liquid biopsy” to guide clinical decisions, in a manner akin to how it is used in the management of haematological malignancies. In this review, we will summarize the most recent published evidence on the role of minimally invasive biomarkers in melanoma, commenting on their future potential to lead to practice-changing discoveries.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/312902/1/312902.pdfTest; Spiliopoulou, P. , Lopes, C. D. H. and Spreafico, A. (2024) Promising and minimally invasive biomarkers: targeting melanoma. Cells , 13(1), 19. (doi:10.3390/cells13010019 ) (PMID:38201222) (PMCID:PMC10777980)
-
4رسالة جامعية
المؤلفون: Spiliopoulou, Pavlina
مصطلحات موضوعية: 616.99
الوصف: Despite ample clinical evidence that prognosis of patients with advanced ovarian cancer is critically dependent on the anti-tumour immune response, cancer immunotherapy treatments have failed to achieve a meaningful survival benefit for many patients. A need to potentiate the host’s immune response against ovarian cancer cells is therefore imperative. Ovarian cancer cells manage to evade immune responses by altering the epigenome in a way that it can modulate all steps of the immune cycle. This includes antigen presentation, lymphocyte priming, activation and trafficking, as well as cytotoxic lymphocyte effector functions. DNA methylation and histone deacetylation were the two mechanisms initially identified to play a crucial role in immune evasion, with histone methylation being an important emerging pathway too. In this PhD project, I initially sought to discover novel epigenetic mechanisms involved in the immune process in a Trp53-/- murine model of ovarian cancer by undertaking a medium-throughput screening with a library of novel epigenetic probes. G9a and EZH2 histone lysine methyltransferases emerged as mechanisms implicated in the release of lymphocyte chemotactic chemokines, such as CXCL9, CXCL10 and CXCL11. By using a novel dual inhibitor and with a combination of cellular, transcriptional and chromatin accessibility assays, I observed that simultaneous inhibition of G9a and EZH2 modulated the tumour immune microenvironment. I observed a transcriptional upregulation of immune pathways, coupled with cellular changes that represented a favourable immune profile intratumorally. The cellular changes included modulation of CD8+ lymphocyte phenotype, an increase in the presence of Natural Killer cells and an increase in expression of CXCR3, the receptor for CXCL9-11 chemokines. Moreover, these alterations in the immune microenvironment were accompanied by a modest therapeutic effect. The results of this thesis highlight the importance of inhibiting G9a/EZH2 in Trp53-/- ovarian cancer.
-
5دورية أكاديمية
الوصف: Immune checkpoint inhibitors (ICIs) have emerged as a novel class of anti-neoplastic agent in oncology. Their integration into practice has been accompanied by "immune-related adverse events" (irAEs) wherein off-target immune responses damage healthy tissues. Severe irAEs can cause irreversible organ dysfunction and death. Despite this, little is known about factors which predispose certain patients to develop irAEs or which precipitate their onset. Here, we report a case of a patient with melanoma who completed adjuvant immunotherapy, underwent elective hip replacement, and developed a rare rheumatologic irAE (remitting seronegative symmetrical synovitis with pitting edema) post-operatively. Mechanistically, we hypothesize that surgery contributed to irAE pathogenesis as a sensitizing event in which self-antigens were presented to an immune system with diminished peripheral tolerance in the context of recent ICI administration. This case highlights a need for future correlative analyses, investigating whether iatrogenic interventions such as surgery might be associated with irAE development.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/315864/1/315864.pdfTest; Janse van Rensburg, H. J., Spiliopoulou, P. , Makhzoum, A. and Healy, B. D. (2023) Remitting seronegative symmetrical synovitis with pitting edema: a case report of an immune-related adverse event following surgery. Case Reports in Oncology , 16(1), pp. 662-669. (doi:10.1159/000532004 ) (PMID:37933314) (PMCID:PMC10625819)
-
6دورية أكاديمية
المؤلفون: Lee, Cha Len, O'Kane, Grainne M., Mason, Warren P., Zhang, Wen-Jiang, Spiliopoulou, Pavlina, Hansen, Aaron R., Grant, Robert C., Knox, Jennifer J., Stockley, Tracy L., Zadeh, Gelareh, Chen, Eric X.
الوصف: Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients. Results were validated in cohorts of CCA and clear cell renal cell carcinoma (ccRCC) patients. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for IDHmt glioma patients, while circulating rRS was elevated in IDHmt CCA patients. There were overlap distributions of circulating R2HG and total 2HG (t2HG) in both IDHmt and wild-type (IDHwt) CCA patients, while there was minimal overlap in rRS values between IDHmt and IDHwt CCA patients. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in IDHmt CCA patients compare to IDHwt CCA patients. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/314673/1/314673.pdfTest; Lee, C. L. et al. (2023) Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential biomarker for isocitrate dehydrogenase (IDH1/2) mutant cholangiocarcinoma. Molecular Cancer Therapeutics , (doi:10.1158/1535-7163.mct-23-0460 ) (PMID:38015561) (Early Online Publication)
-
7دورية أكاديمية
المؤلفون: Genta, Sofia, Lajkosz, Katherine, Yee, Noelle R., Spiliopoulou, Pavlina, Heirali, Alya, Hansen, Aaron R., Siu, Lillian L., Saibil, Sam, Stayner, Lee-Anne, Yanekina, Maryia, Sauder, Maxwell B., Keshavarzi, Sareh, Salawu, Abdulazeez, Vornicova, Olga, Butler, Marcus O., Bedard, Philippe L., Razak, Albiruni R. Abdul, Rottapel, Robert, Chruscinski, Andrzej, Coburn, Bryan, Spreafico, Anna
الوصف: Background: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb). Methods: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal–Wallis test. MFI 500 was used as threshold to define autoAb reactivity. Results: A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p < 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009). Conclusions: Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311).
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/315156/1/315156.pdfTest; Genta, S. et al. (2023) Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT). Journal of Experimental and Clinical Cancer Research , 42(1), 276. (doi:10.1186/s13046-023-02851-6 ) (PMID:37865776) (PMCID:PMC10589949)
-
8دورية أكاديمية
المؤلفون: Spiliopoulou, Pavlina, Vornicova, Olga, Genta, Sofia, Spreafico, Anna
الوصف: Recent advances in treating cutaneous melanoma have resulted in impressive patient survival gains. Refinement of disease staging and accurate patient risk classification have significantly improved our prognostic knowledge and ability to accurately stratify treatment. Undoubtedly, the most important step towards optimizing patient outcomes has been the advent of cancer immunotherapy, in the form of immune checkpoint inhibition (ICI). Immunotherapy has established its cardinal role in the management of both early and late-stage melanoma. Through leveraging outcomes in melanoma, immunotherapy has also extended its benefit to other types of skin cancers. In this review, we endeavor to summarize the current role of immunotherapy in melanoma and non-melanoma skin cancers, highlight the most pertinent immunotherapy-related molecular biomarkers, and lastly, shed light on future research directions.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/309079/1/309079.pdfTest; Spiliopoulou, P. , Vornicova, O., Genta, S. and Spreafico, A. (2023) Shaping the future of immunotherapy targets and biomarkers in melanoma and non-melanoma cutaneous cancers. International Journal of Molecular Sciences , 24(2), 1294. (doi:10.3390/ijms24021294 ) (PMID:36674809) (PMCID:PMC9862040)
-
9دورية أكاديمية
المؤلفون: Spiliopoulou, Pavlina, Janse van Rensburg, Helena J., Avery, Lisa, Kulasingam, Vathany, Razak, Albiruni, Bedard, Philippe, Hansen, Aaron, Chruscinski, Andrzej, Wang, Ben, Kulikova, Maria, Chen, Rachel, Speers, Vanessa, Nguyen, Alisa, Lee, Jasmine, Coburn, Bryan, Spreafico, Anna, Siu, Lillian L.
الوصف: Despite more than 2 years having elapsed since the onset of SARS-CoV-2 pandemic, a level of hesitation around increased SARS-CoV-2 vaccine toxicity in cancer patients receiving immunotherapy (IO) remains. This hesitation stems from the idea that IO agents could elicit an overwhelming immune stimulation post vaccination and therefore increase the risk of vaccine-related toxicity. The aim of our study was to explore serological responses to SARS-CoV-2 vaccination in patients treated with IO and describe the level of immune stimulation using parameters such as blood cytokines, autoantibody levels and immune related adverse events (irAEs) post vaccination. Fifty-one evaluable patients were enrolled in this longitudinal study. Absolute levels and neutralization potential of anti-SARS-CoV-2 antibodies were not significantly different in the IO group compared to non-IO. Chemotherapy adversely affected seroconversion when compared to IO and/or targeted treatment. Following vaccination, the prevalence of grade ≥2 irAEs in patients treated with IO was not higher than the usual reported IO toxicity. We report, for the first time, that anti-SARS-CoV-2 vaccination, elicited the generation of five autoantibodies. The significantly increased autoantibodies were IgM autoantibodies against beta-2 glycoprotein (p = 0.02), myeloperoxidase (p = 0.03), nucleosome (p = 0.041), SPLUNC2 (p < 0.001) and IgG autoantibody against Myosin Heavy Chain 6 (MYH6) (p < 0.001). Overall, comprehensive analysis of a small cohort showed that co-administration of SARS-CoV-2 vaccine and IO is not associated with increased irAEs. Nevertheless, the detection of autoantibodies post anti-SARS-CoV-2 vaccination warrants further investigation (NCT03702309).
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/309078/1/309078.pdfTest; Spiliopoulou, P. et al. (2023) Longitudinal efficacy and toxicity of SARS-CoV-2 vaccination in cancer patients treated with immunotherapy. Cell Death and Disease , 14(1), 49. (doi:10.1038/s41419-022-05548-4 ) (PMID:36670100) (PMCID:PMC9853486)
-
10دورية أكاديمية
المؤلفون: Mittal, Abhenil, Al-Ezzi, Esmail, Li, Xuan, Moloney, Brian, Wilson, Brooke, Spiliopoulou, Pavlina, Sridhar, Srikala, Fallah-Rad, Nazanin, Chung, Peter, James Hamilton, Robert, O’malley, Martin, Hansen, Aaron R.
الوصف: Background: Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. Methods: Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan–Meier method (log-rank). Results: Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8–27.7) vs. 13.9 m (7.9–21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4–48.9) vs. 12.1 m (8.8–27.7), p = 0.01]. Conclusion: In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.
وصف الملف: text
العلاقة: https://eprints.gla.ac.uk/309061/1/309061.pdfTest; Mittal, A. et al. (2023) The role of cytoreductive nephrectomy and systemic therapy in the management of tumour thrombus in patients with metastatic renal cell carcinoma. British Journal of Cancer , 128(10), pp. 1888-1896. (doi:10.1038/s41416-023-02166-5 ) (PMID:36859686) (PMCID:PMC10147707)
