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Protein Kinase C Epsilon Overexpression Is Associated With Poor Patient Outcomes in AML and Promotes Daunorubicin Resistance Through p-Glycoprotein-Mediated Drug Efflux (2022)
Journal Article
Nicholson, R., Menezes, A., Azevedo, A., Leckenby, A., Davies, S., Seedhouse, C., …Darley, R. L. (2022). Protein Kinase C Epsilon Overexpression Is Associated With Poor Patient Outcomes in AML and Promotes Daunorubicin Resistance Through p-Glycoprotein-Mediated Drug Efflux. Frontiers in Oncology, 12, Article 840046. https://doi.org/10.3389/fonc.2022.840046

The protein kinase C (PKC) family of serine/threonine kinases are pleiotropic signaling regulators and are implicated in hematopoietic signaling and development. Only one isoform however, PKCϵ, has oncogenic properties in solid cancers where it is as... Read More about Protein Kinase C Epsilon Overexpression Is Associated With Poor Patient Outcomes in AML and Promotes Daunorubicin Resistance Through p-Glycoprotein-Mediated Drug Efflux.

A same‐day assay predicts apoptotic response to combined BCL‐2 and MCL‐1 BH3‐mimetic targeting in multiple myeloma cells (2020)
Journal Article
Grundy, M., Al‐Kaisi, F., Cull, J., Williams, C., Smith, D., & Seedhouse, C. H. (2021). A same‐day assay predicts apoptotic response to combined BCL‐2 and MCL‐1 BH3‐mimetic targeting in multiple myeloma cells. eJHaem, 2(1), 40-47. https://doi.org/10.1002/jha2.133

Recent advances in treatment options for multiple myeloma (MM) have positive impact on patient survival. However, there is a short fall of rapid and reliable assays that can predict patient response to novel agents. The anti-apoptotic proteins B-cell... Read More about A same‐day assay predicts apoptotic response to combined BCL‐2 and MCL‐1 BH3‐mimetic targeting in multiple myeloma cells.

Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia (2020)
Journal Article
Bailey, G. D., Doolan, L., Baskar, A., Smith, L. C., & Seedhouse, C. H. (2020). Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia. Scientific Reports, 10, Article 17695. https://doi.org/10.1038/s41598-020-73782-x

Nucleophosmin is commonly both over-expressed and mutated in acute myeloid leukemia (AML). NPM1 mutations are always heterozygous. In addition, NPM1 has a number of different splice variants with the major variant encoded by exons 1–9 and 11–12 (NPM1... Read More about Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia.

Frequent loss of BTG1 activity and impaired interactions with the Caf1 subunit of the Ccr4–Not deadenylase in non-Hodgkin lymphoma (2020)
Journal Article
Almasmoum, H., Airhihen, B., Seedhouse, C., & Winkler, G. S. (2020). Frequent loss of BTG1 activity and impaired interactions with the Caf1 subunit of the Ccr4–Not deadenylase in non-Hodgkin lymphoma. Leukemia & Lymphoma, 62(2), 281-290. https://doi.org/10.1080/10428194.2020.1827243

© 2020 Informa UK Limited, trading as Taylor & Francis Group. Mutations in the highly similar genes B-cell translocation gene 1 (BTG1) and BTG2 are identified in approximately 10–15% of non-Hodgkin lymphoma cases, which may suggest a direct involve... Read More about Frequent loss of BTG1 activity and impaired interactions with the Caf1 subunit of the Ccr4–Not deadenylase in non-Hodgkin lymphoma.

The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun (2020)
Journal Article
Alhuthali, H. M., Bradshaw, T. D., Lim, K. H., Kam, T. S., & Seedhouse, C. H. (2020). The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun. BMC Cancer, 20, Article 629. https://doi.org/10.1186/s12885-020-07119-2

© 2020 The Author(s). Background: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanis... Read More about The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun.

Increased FLYWCH1 Expression is Negatively Correlated with Wnt/β-catenin Target Gene Expression in Acute Myeloid Leukemia Cells (2019)
Journal Article
Almars, A., Chondrou, P. S., Onyido, E. K., Almozyan, S., Seedhouse, C., Babaei-Jadidi, R., & Nateri, A. S. (2019). Increased FLYWCH1 Expression is Negatively Correlated with Wnt/β-catenin Target Gene Expression in Acute Myeloid Leukemia Cells. International Journal of Molecular Sciences, 20(11), Article 2739. https://doi.org/10.3390/ijms20112739

Acute myeloid leukaemia (AML) is a heterogeneous clonal malignancy of hematopoietic progenitor cells. The Wnt pathway and its downstream targets are tightly regulated by β-catenin. We recently discovered a new protein, FLYWCH1, which can directly bin... Read More about Increased FLYWCH1 Expression is Negatively Correlated with Wnt/β-catenin Target Gene Expression in Acute Myeloid Leukemia Cells.

Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells (2018)
Journal Article
Grundy, M., Balakrishnan, S., Fox, M., Seedhouse, C., & Russell, N. (2018). Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget, 9, Article 102. https://doi.org/10.18632/oncotarget.26540

Acute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL... Read More about Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells.

Quantitative assessment of the sensitivity of dormant AML cells to the BAD mimetics ABT-199 and ABT-737 (2018)
Journal Article
Yu, N., Seedhouse, C., Russell, N., & Pallis, M. (2018). Quantitative assessment of the sensitivity of dormant AML cells to the BAD mimetics ABT-199 and ABT-737. Leukemia & Lymphoma, 59(10), 2447-2453. https://doi.org/10.1080/10428194.2018.1434884

Cells from patients with acute myeloid leukaemia (AML) that remain dormant and protected by stromal cells may escape effects of chemotherapy. We modelled dormancy in vitro and investigated the ability of Bcl-2 inhibitors ABT-199 and ABT-737 to overco... Read More about Quantitative assessment of the sensitivity of dormant AML cells to the BAD mimetics ABT-199 and ABT-737.

Predicting effective pro-apoptotic antileukaemic drug combinations using cooperative dynamic BH3 profiling (2018)
Journal Article
Grundy, M., Seedhouse, C., Jones, T., Elmi, L., Hall, M., Graham, A., …Pallis, M. (2018). Predicting effective pro-apoptotic antileukaemic drug combinations using cooperative dynamic BH3 profiling. PLoS ONE, 13(1), Article e0190682. https://doi.org/10.1371/journal.pone.0190682

The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-le... Read More about Predicting effective pro-apoptotic antileukaemic drug combinations using cooperative dynamic BH3 profiling.

Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer (2017)
Journal Article
Shafiee, M. N., Mongan, N. P., Seedhouse, C., Chapman, C., Deen, S., Abu, J., & Atiomo, W. (2017). Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer. Acta Obstetricia et Gynecologica Scandinavica, 96(5), 556-562. https://doi.org/10.1111/aogs.13106

Introduction: Women with polycystic ovary syndrome (PCOS) have a 3-fold higher risk of endometrial cancer (EC). Insulin resistance and hyperlipidaemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to inves... Read More about Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer.

Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells (2016)
Journal Article
Pallis, M., Burrows, F., Ryan, J., Grundy, M., Seedhouse, C., Abdul-Aziz, A., …Russell, N. (2016). Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. Oncotarget, 8(10), https://doi.org/10.18632/oncotarget.8742

Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have appl... Read More about Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells.

Up-regulation of genes involved in the Insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link Polycystic Ovarian Syndrome and endometrial cancer (2016)
Journal Article
Shafiee, M. N., Seedhouse, C., Mongan, N., Chapman, C., Deen, S., Abu, J., & Atiomo, W. (2016). Up-regulation of genes involved in the Insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link Polycystic Ovarian Syndrome and endometrial cancer. Molecular and Cellular Endocrinology, 424, 94-101. https://doi.org/10.1016/j.mce.2016.01.019

BACKGROUND Endometrial cancer (EC) is the most common gynaecological cancer amongst women in the UK. Although previous studies have found that women with polycystic ovary syndrome (PCOS) have at least a three-fold increase in endometrial cancer (E... Read More about Up-regulation of genes involved in the Insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link Polycystic Ovarian Syndrome and endometrial cancer.

Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy (2014)
Journal Article
Albarakati, N., Abdel-Fatah, T. M., Doherty, R., Russell, R., Agarwal, D., Moseley, P., …Madhusudan, S. (2015). Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy. Molecular Oncology, 9(1), 204-217. https://doi.org/10.1016/j.molonc.2014.08.001

BRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1‐BER deficient cells by blockade of ATM and DNA‐PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1... Read More about Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy.

Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy (2014)
Journal Article

Phosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease... Read More about Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy.

Efficacy of RNA polymerase II inhibitors in targeting dormant leukaemia cells (2013)
Journal Article
Pallis, M., Burrows, F., Whittall, A., Boddy, N., Seedhouse, C., & Russell, N. (2013). Efficacy of RNA polymerase II inhibitors in targeting dormant leukaemia cells. BMC Pharmacology and Toxicology, 14(June), Article 11. https://doi.org/10.1186/2050-6511-14-32

Background Dormant cells are characterised by low RNA synthesis. In contrast, cancer cells can be addicted to high RNA synthesis, including synthesis of survival molecules. We hypothesised that dormant cancer cells, already low in RNA, might be sens... Read More about Efficacy of RNA polymerase II inhibitors in targeting dormant leukaemia cells.

Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells (2013)
Journal Article
Sultana, R., Abdel-Fatah, T., Perry, C., Moseley, P., Albarakti, N., Mohan, V., …Madhusudan, S. (2013). Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. PLoS ONE, 8(2), Article e57098. https://doi.org/10.1371/journal.pone.0057098

Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in sin... Read More about Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.

Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in acute Myeloid Leukaemia (2012)
Journal Article
Jawad, M., Yu, N., Seedhouse, C., Tandon, K., Russell, N. H., & Pallis, M. (2012). Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in acute Myeloid Leukaemia. BMC Cancer, https://doi.org/10.1186/1471-2407-12-431

Background The CD34+CD38- subset of AML cells is enriched for resistance to current chemotherapeutic agents and considered to contribute to disease progression and relapse in Acute Myeloid Leukaemia (AML) patients following initial treatment. Met... Read More about Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in acute Myeloid Leukaemia.

The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells (2012)
Journal Article
Pallis, M., Abdul-Aziz, A., Burrows, F., Seedhouse, C., Grundy, M., & Russell, N. (2012). The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells. British Journal of Haematology, 159(2), 191-203. https://doi.org/10.1111/bjh.12018

The novel multi-kinase inhibitor TG02 has selectivity against cell cycle and transcriptional cyclin dependent kinases (CDKs) as well as fms-like tyrosine kinase receptor-3 (FLT3). Inhibition of transcriptional CDKs preferentially depletes short-lived... Read More about The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells.