Publications
75 results found
Cunnea P, Curry EW, Christie EL, et al., 2023, Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: implications for surgical and clinical outcomes, Cell Reports Medicine, Vol: 4, Pages: 1-20, ISSN: 2666-3791
Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.
Lythgoe M, Dama P, Frampton AE, et al., 2023, Immune modulation and the oral live biotherapeutic product, MRx0518, in treatment-naive patients with cancer: Updated safety data, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Krell J, Frost S, Negroni C, et al., 2023, Evaluation of THEO-260 as a novel oncolytic virus therapy for treating stromal rich tumours., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Yang Y, Li H, Fotopoulou C, et al., 2022, Toll-like receptor-targeted anti-tumor therapies: Advances and challenges, Frontiers in Immunology, Vol: 13, Pages: 1-37, ISSN: 1664-3224
Toll-like receptors (TLRs) are pattern recognition receptors, originally discovered to stimulate innate immune reactions against microbial infection. TLRs also play essential roles in bridging the innate and adaptive immune system, playing multiple roles in inflammation, autoimmune diseases, and cancer. Thanks to the immune stimulatory potential of TLRs, TLR-targeted strategies in cancer treatment have proved to be able to regulate the tumor microenvironment towards tumoricidal phenotypes. Quantities of pre-clinical studies and clinical trials using TLR-targeted strategies in treating cancer have been initiated, with some drugs already becoming part of standard care. Here we review the structure, ligand, signaling pathways, and expression of TLRs; we then provide an overview of the pre-clinical studies and an updated clinical trial watch targeting each TLR in cancer treatment; and finally, we discuss the challenges and prospects of TLR-targeted therapy.
Lythgoe M, Mullish B, Frampton A, et al., 2022, ORAL ADMINISTRATION OF MRX0518 IN TREATMENTNAIVE CANCER PATIENTS IS ASSOCIATED WITH COMPOSITIONAL TAXONOMIC AND METABOLOMIC CHANGES INDICATIVE OF ANTI-TUMORIGENIC EFFICACY, Publisher: BMJ PUBLISHING GROUP, Pages: A659-A659
Cunnea P, Gabra H, Stronach E, et al., 2022, 1h-pyrazolo[3,4-d]pyrimidine compounds useful for the treatment of platinum-resistant cancer, GB1918815.0
The invention relates to compounds of formula (I) and related compounds and their use in the treatment of cancer, especially platinum resistant cancer. The invention also provides a treatment comprising administration of a compound of formula (I) and a platinum containing drug.
Ghisoni E, Benedetti F, Cunnea P, et al., 2022, Integrated digital pathology and single-cell analysis identify the spatial and temporal evolution of immune cells networks in epithelial ovarian cancer, ESMO Gynaecological Cancers Congress, Publisher: ELSEVIER, Pages: S395-S395, ISSN: 0923-7534
Wulandari R, Nixon K, Rama N, et al., 2022, Characterisation of Proteomic heterogeneity following platinum therapy in High-grade Serous Ovarian Cancer, Publisher: WILEY, Pages: 40-41, ISSN: 1470-0328
Clark J, Fotopoulou C, Cunnea P, et al., 2022, Novel ex vivo models of epithelial ovarian cancer: the future of biomarker and therapeutic research, Frontiers in Oncology, Vol: 12, Pages: 1-17, ISSN: 2234-943X
Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types. Success in achieving cure in advanced EOC has however been limited, although significant prolongation of survival has been demonstrated. Development of novel research platforms is therefore necessary to address the rapidly advancing field of early diagnostics and therapeutics, whilst also acknowledging the significant tumour heterogeneity associated with EOC. Within available tumour models, patient-derived organoids (PDO) and explant tumour slices have demonstrated particular promise as novel ex vivo systems to model different cancer types including ovarian cancer. PDOs are organ specific 3D tumour cultures that can accurately represent the histology and genomics of their native tumour, as well as offer the possibility as models for pharmaceutical drug testing platforms, offering timing advantages and potential use as prospective personalised models to guide clinical decision-making. Such applications could maximise the benefit of drug treatments to patients on an individual level whilst minimising use of less effective, yet toxic, therapies. PDOs are likely to play a greater role in both academic research and drug development in the future and have the potential to revolutionise future patient treatment and clinical trial pathways. Similarly, ex vivo tumour slices or explants have also shown recent renewed promise in their ability to provide a fast, specific, platform for drug testing that accurately represents in vivo tumour response. Tumour explants retain tissue architecture, and thus incorporate the majority of tumour microenvironment making them an attractive
Prodromidou A, Phelps DL, Pergialiotis V, et al., 2022, Clinicopathological characteristics and survival outcomes of patients with large cell neuroendocrine carcinoma of the uterine cervix: A systematic review and meta-analysis, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 270, Pages: 212-220, ISSN: 0301-2115
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- Citations: 4
Fotopoulou C, Rockall A, Lu H, et al., 2021, Validation analysis of the novel imaging-based prognostic radiomic signature in patients undergoing primary surgery for advanced high-grade serous ovarian cancer (HGSOC), British Journal of Cancer, Vol: 126, Pages: 1047-1054, ISSN: 0007-0920
BackgroundPredictive models based on radiomics features are novel, highly promising approaches for gynaecological oncology. Here, we wish to assess the prognostic value of the newly discovered Radiomic Prognostic Vector (RPV) in an independent cohort of high-grade serous ovarian cancer (HGSOC) patients, treated within a Centre of Excellence, thus avoiding any bias in treatment quality.MethodsRPV was calculated using standardised algorithms following segmentation of routine preoperative imaging of patients (n = 323) who underwent upfront debulking surgery (01/2011-07/2018). RPV was correlated with operability, survival and adjusted for well-established prognostic factors (age, postoperative residual disease, stage), and compared to previous validation models.ResultsThe distribution of low, medium and high RPV scores was 54.2% (n = 175), 33.4% (n = 108) and 12.4% (n = 40) across the cohort, respectively. High RPV scores independently associated with significantly worse progression-free survival (PFS) (HR = 1.69; 95% CI:1.06–2.71; P = 0.038), even after adjusting for stage, age, performance status and residual disease. Moreover, lower RPV was significantly associated with total macroscopic tumour clearance (OR = 2.02; 95% CI:1.56–2.62; P = 0.00647).ConclusionsRPV was validated to independently identify those HGSOC patients who will not be operated tumour-free in an optimal setting, and those who will relapse early despite complete tumour clearance upfront. Further prospective, multicentre trials with a translational aspect are warranted for the incorporation of this radiomics approach into clinical routine.
Cunnea P, Fotopoulou C, Ploski J, et al., 2021, Changes in stem cell regulation and epithelial organisation during carcinogenesis and disease progression in gynaecological malignancies, Cancers, Vol: 13, ISSN: 2072-6694
Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches. This review revisits new findings on stemness and differentiation, considering main challenges and open questions. We focus on the role of stem cell niche and tumour microenvironment in early and metastatic stages of the disease progression and highlight the potential of patient-derived organoid models to study key events in tumour evolution, the appearance of resistance mechanisms, and as screening tools to enable personalisation of drug treatments.
Rinne N, Christie EL, Ardasheva A, et al., 2021, Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer, Cancer Drug Resistance, Vol: 4, Pages: 573-59514/04/2021, ISSN: 2578-532X
The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials.
Lu H, Cunnea P, Nixon K, et al., 2021, Discovery of a biomarker candidate for surgical stratification in high-grade serous ovarian cancer, British Journal of Cancer, Vol: 124, Pages: 1286-1293, ISSN: 0007-0920
Background: Maximal effort cytoreductive surgery is associated with improved outcomes in advanced high-grade serous ovarian cancer (HGSOC). However, despite complete gross resection (CGR), there is a percentage of patients who will relapse and die early. The aim of this study is to identify potential candidate biomarkers to help personalise surgical radicality.Methods: 136 advanced HGSOC cases who underwent CGR were identified from three public transcriptomic datasets. Candidate prognostic biomarkers were discovered in this cohort by Cox regression analysis, and further validated by targeted RNA-sequencing in HGSOC cases from Imperial College Healthcare NHS Trust (n = 59), and a public dataset. Gene set enrichment analysis was performed to understand the biological significance of the candidate biomarker.Results: We identified ALG5 as a prognostic biomarker for early tumour progression in advanced HGSOC despite CGR (HR = 2.42, 95% CI (1.57–3.75), p < 0.0001). The prognostic value of this new candidate biomarker was additionally confirmed in two independent datasets (HR = 1.60, 95% CI (1.03–2.49), p = 0.0368; HR = 3.08, 95% CI (1.07–8.81), p = 0.0365). Mechanistically, the oxidative phosphorylation was demonstrated as a potential biological pathway of ALG5-high expression in patients with early relapse (p < 0.001).Conclusion: ALG5 has been identified as an independent prognostic biomarker for poor prognosis in advanced HGSOC patients despite CGR. This sets a promising platform for biomarker combinations and further validations towards future personalised surgical care.
Hu Z, Cunnea P, Zhong Z, et al., 2021, The Oxford Classic links epithelial-to-mesenchymal transition to immunosuppression in poor prognosis ovarian cancers, Clinical Cancer Research, Vol: 27, Pages: 1570-1579, ISSN: 1078-0432
Purpose: Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier.Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs.Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors.Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.
Rinne N, Fotopoulou C, Cunnea P, 2021, TARGETING AKT AND DNA-PK AS A THERAPEUTIC STRATEGY IN PLATINUM RESISTANT HIGH-GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A231-A232, ISSN: 1048-891X
Ploski J, Burger-Ramos M, Yang Y, et al., 2021, PATIENT-DERIVED ORGANOIDS REFLECT INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A337-A338, ISSN: 1048-891X
Bartl T, Karacs J, Kreuzinger C, et al., 2021, Tumor Growth Rate Estimates Are Independently Predictive of Therapy Response and Survival in Recurrent High-Grade Serous Ovarian Cancer Patients, CANCERS, Vol: 13
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- Citations: 5
Cunnea P, Curry E, Christie E, et al., 2021, CHARACTERISATION OF INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A332-A333, ISSN: 1048-891X
Carvalho S, Dissanayake-Perera S, Demchenko N, et al., 2021, STUDY OF PARTICLE SIZE AND MORPHOLOGY FOR THE MULTIPLEXED DETECTION OF EPITHELIAL OVARIAN CANCER, Pages: 1609-1610
Ovarian cancer ranks globally as the 5th deadliest disease amongst women and the most lethal cancer of the reproductive system. Epithelial Ovarian Cancer (EOC) is the most prevalent and aggressive subtype of ovarian cancer. Herein we developed a lateral-flow immunoassay (LFIA) for the detection of two EOC biomarkers that have shown promise for EOC diagnosis. Monoclonal antibodies were conjugated to platinum nanoparticles (PtNPs) and gold nanoparticles (AuNPs) to provide a colorimetric readout. PtNPs showed better performance than AuNPs, being therefore employed for the development of the LFIA device, which has limits of detection (LOD) lower than the clinical cut-off limits for both biomarkers.
Cunnea P, Curry E, Christie E, et al., 2020, GENOMIC AND FUNCTIONAL CHARACTERISATION OF INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A98-A99, ISSN: 1048-891X
Rinne N, Yuan S, Fotopoulou C, et al., 2020, TARGETING AKT AND DNA-PK AS A THERAPEUTIC STRATEGY IN PLATINUM RESISTANT HIGH-GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A62-A62, ISSN: 1048-891X
Ploski J, Nixon K, Demchenko N, et al., 2020, NOVEL 3D MODEL SYSTEMS TO ASSESS HETEROGENEITY IN RESPONSE TO PLATINUM THERAPY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A99-A99, ISSN: 1048-891X
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- Citations: 1
Periyasamy M, Singh A, Gemma C, et al., 2020, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK directed activation of NF-κB, Oncogene, Vol: 15 December 2020, Pages: 1077-1090, ISSN: 0950-9232
The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-kB activity, with consequent recruitment of NF-kB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-kB pathways could promote cancer mutations and expedite chemoresistance.
Fotopoulou C, Rinne N, Ghirardi V, et al., 2020, Value of pre-existent bacterial colonization in patients with advanced/relapsed ovarian neoplasms undergoing cytoreductive surgery: a multicenter observational study (BONSAI), INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 30, Pages: 1562-1568, ISSN: 1048-891X
Johnson SC, Chakraborty S, Drosou A, et al., 2020, Inflammatory state of lymphatic vessels and miRNA profiles associated with relapse in ovarian cancer patients, PLoS One, Vol: 15, Pages: 1-23, ISSN: 1932-6203
Lymphogenic spread is associated with poor prognosis in epithelial ovarian cancer (EOC), yet little is known regarding roles of non-peri-tumoural lymphatic vessels (LVs) outside the tumour microenvironment that may impact relapse. The aim of this feasibility study was to assess whether inflammatory status of the LVs and/or changes in the miRNA profile of the LVs have potential prognostic and predictive value for overall outcome and risk of relapse. Samples of macroscopically normal human lymph LVs (n = 10) were isolated from the external iliac vessels draining the pelvic region of patients undergoing debulking surgery. This was followed by quantification of the inflammatory state (low, medium and high) and presence of cancer-infiltration of each LV using immunohistochemistry. LV miRNA expression profiling was also performed, and analysed in the context of high versus low inflammation, and cancer-infiltrated versus non-cancer-infiltrated. Results were correlated with clinical outcome data including relapse with an average follow-up time of 13.3 months. The presence of a high degree of inflammation correlated significantly with patient relapse (p = 0.033). Cancer-infiltrated LVs showed a moderate but non-significant association with relapse (p = 0.07). Differential miRNA profiles were identified in cancer-infiltrated LVs and those with high versus low inflammation. In particular, several members of the let-7 family were consistently down-regulated in highly inflamed LVs (>1.8-fold, p<0.05) compared to the less inflamed ones. Down-regulation of the let-7 family appears to be associated with inflammation, but whether inflammation contributes to or is an effect of cancer-infiltration requires further investigation.
Cunnea P, Curry E, Nixon K, et al., 2020, Phenotypic and genomic characterization of intratumoral heterogeneity in high-grade serous ovarian cancer., AACR Special Conference on Advances in Ovarian Cancer Research, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 42-42, ISSN: 1078-0432
Sabini C, Sorbi F, Cunnea P, et al., 2020, Ovarian cancer stem cells: ready for prime time?, ARCHIVES OF GYNECOLOGY AND OBSTETRICS, Vol: 301, Pages: 895-899, ISSN: 0932-0067
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- Citations: 7
Rinne N, Curry E, Fotopoulou C, et al., 2019, TARGETING AKT AND DNA-PK AS A THERAPEUTIC STRATEGY IN PLATINUM RESISTANT HIGH-GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A512-A513, ISSN: 1048-891X
Nixon K, Curry E, Wulandari R, et al., 2019, USE OF 3D ORGANOTYPIC MODELS TO ASSESS HETEROGENEITY IN RESPONSE TO PLATINUM THERAPY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A145-A145, ISSN: 1048-891X
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