Can supervise: YES
Pateetin, P, Pisitkun, T, McGowan, E & Boonyaratanakornkit, V 2020, 'Differential quantitative proteomics reveals key proteins related to phenotypic changes of breast cancer cells expressing progesterone receptor A', Journal of Steroid Biochemistry and Molecular Biology, vol. 198.View/Download from: Publisher's site
© 2019 Progesterone receptor isoforms A and B exert different biological effects in breast cancer cells. Alteration of PRA/PRB ratio is often observed during breast cancer progression. High PRA/PRB ratios in breast cancer patients are associated with resistance to chemotherapy and poor prognosis. While it is well accepted that PRA and PRB regulate different sets of genes, how the expression of PRA and PRB alters breast cancer proteomes has not been fully investigated. To directly investigate the effects of PR isoform expression on the breast cancer proteome, both in the presence and absence of progestin, PRA and PRB were independently stably expressed in T47DC42 PR-null breast cancer cells using a doxycycline (Dox)-regulated promoter. Dox induction dose-dependently increased PRA and PRB expression. Dox-induced PRA and PRB showed normal receptor localization and were transcriptionally active. Differential quantitative proteomic analysis by stable isotope dimethyl labeling was performed to quantitatively examine how PR isoforms altered global breast cancer proteomes. Cells expressing PRA in the absence of progestin were enriched in proteins involved in the TCA cycle and enriched in proteins involved in glycolysis in the presence of progestin, whilst cells expressing PRB in the absence and presence progestin were significantly enriched in proteins involved in the cell cycle and cell apoptosis pathways. This proteomic data revealed a link between PR isoform expression and alteration in cell metabolism, cell proliferation, and apoptosis. The enrichment of proteins involved in the glycolytic pathway in breast cancer cells expressing PRA is consistent with stem cell-like properties, previously reported in PRA-rich breast cancer cells. Moreover, compared to liganded PRB, liganded PRA differentially upregulated proteins involved in chromatin remodeling, such as linker histone H1.2. Silencing H1.2 gene expression suppressed PRA-mediated cell proliferation and promoted G2/M...
Sukocheva, OA, Lukina, E, McGowan, E & Bishayee, A 2020, 'Sphingolipids as mediators of inflammation and novel therapeutic target in inflammatory bowel disease', Advances in Protein Chemistry and Structural Biology, vol. 120, pp. 123-158.View/Download from: Publisher's site
© 2020 Elsevier Inc. Morbidity of inflammatory gastrointestinal (GI) diseases continues to grow resulting in worsen quality of life and increased burden on public medical systems. Complex and heterogenous illnesses, inflammatory bowel diseases (IBDs) encompass several inflammation -associated pathologies including Crohn's disease and ulcerative colitis. IBD is often initiated by a complex interplay between host genetic and environmental factors, lifestyle and diet, and intestinal bacterial components. IBD inflammatory signature was linked to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) signaling pathway that is currently targeted by IBD therapies. Sphingolipid signaling was identified as one of the key mediators and regulators of pro-inflammatory conditions, and, specifically, TNF-α related signaling. All GI tissues and circulating immune/blood cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinases (SphK1 and SphK2) that generate sphingosine-1-phosphate (S1P), a bioactive lipid and ligand for five G-protein coupled membrane S1P receptors (S1PRs). Numerous normal and pathogenic inflammatory responses are mediated by SphK/S1P/S1PRs signaling axis including lymphocyte trafficking and activation of cytokine signaling machinery. SphK1/S1P/S1PRs axis has recently been defined as a target for the treatment of GI diseases including IBD/colitis. Several SphK1 inhibitors and S1PRs antagonists have been developed as novel anti-inflammatory agents. In this review, we discuss the mechanisms of SphK/S1P signaling in inflammation-linked GI disorders. The potential role of SphK/S1PRs inhibitors in the prevention and treatment of IBD/colitis is critically evaluated.
Zhong, H-J, Sun, H-H, Xue, L-F, McGowan, EM & Chen, Y 2019, 'Differential hepatic features presenting in Wilson disease-associated cirrhosis and hepatitis B-associated cirrhosis.', World journal of gastroenterology, vol. 25, no. 3, pp. 378-387.View/Download from: Publisher's site
BACKGROUND:Cirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features. AIM:To delineate the liver features between WD-associated cirrhosis and hepatitis B-associated cirrhosis in the Chinese population. METHODS:In this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups. RESULTS:No inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WD-associated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.3...
Lin, Y, An, H, Yin, H, Chen, S & McGowan, E 2019, '37P - Chemokine receptor CCR2b expressing anti-Tn-MUC1 CAR-T cells enhanced anti-breast cancer activity', Annals of Oncology, vol. 30, no. Supplement 11, pp. xi12-xi12.View/Download from: Publisher's site
Background: Enhanced anti-tumour activity is required for eradication of solid tumours by CART cells. One possibility of enhancing anti-tumour activity is by programming CART cells to express chemokine receptors that match chemokines produced either by the tumours or tumour-associated cells, thereby improving the infiltrating capacity of the CART cells. In this study, we engineered CCR2b expressing anti-Tn-MUC1 CAR T cells for the treatment of breast cancer.
Methods: Anti-Tn-MUC1-CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. CCR2b expressing anti-Tn-MUC1 CAR T cells were prepared using PLV-CAR-5E5-CCR2b lentivirus. The susceptibility of MCF-7 cells to either anti-MUC1 CART or CCR2b expressing anti-MUC1 CART cell-mediated lysis was assessed using in vitro killing assays. For cytolytic analysis, CART-cells were cocultured 10:1 (effector:target) ratio with MCF-7 cells. The effects of CCR2b expressing CART cells on anti-tumour activity and infiltration were also assessed in an in vivo murine xenograft model.
Results: Activated T cells co-modified with both CCR2b and anti-MUC1-CAR had greater anti-tumour activity both in vivo and in vitro. When the effector / target cell ratio was 10, the killing rates of CART and CART-CCR2b were 56.9% and 83.9%, respectively. Tumour size was significantly smaller (P < 0.001) in the CAR-CCR2b group compared to the CAR alone group. At day 7 post-injection of CART cells, the infiltrated T cells was significantly increased (~2 folds) in the CAR-CCR2b group compared with the CART only group.
Conclusions: Our data demonstrated that the anti-tumour activity of the CCR2b expressing anti-Tn-MUC1 CART cells is 1.5 times more potent than CART cells without CCR2b. Augmentation of tumour suppression was also demonstrated in vivo in a murine xenograft model. These pre-clinical results show translational potential to the clinic for tr...
Lin, Y, He, P, Hu, P, Chen, H, Chen, Y & McGowan, E 2019, 'Low level of centromere-associated protein E promotes growth of hepatocellular carcinoma and is associated with adverse clinical features.', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 30 Suppl 4, pp. iv9-iv9.View/Download from: Publisher's site
Bhullar, KS, Lagarón, NO, McGowan, EM, Parmar, I, Jha, A, Hubbard, BP & Rupasinghe, HPV 2018, 'Kinase-targeted cancer therapies: Progress, challenges and future directions', Molecular Cancer, vol. 17, no. 1.View/Download from: Publisher's site
© 2018 The Author(s). The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
Boonyaratanakornkit, V, Hamilton, N, Márquez-Garbán, DC, Pateetin, P, McGowan, EM & Pietras, RJ 2018, 'Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer', Molecular and Cellular Endocrinology, vol. 466, pp. 51-72.View/Download from: Publisher's site
© 2017 Elsevier B.V. Estrogen and progesterone play essential roles in the development and progression of breast cancer. Over 70% of breast cancers express estrogen receptors (ER) and progesterone receptors (PR), emphasizing the need for better understanding of ER and PR signaling. ER and PR are traditionally viewed as transcription factors that directly bind DNA to regulate gene networks. In addition to nuclear signaling, ER and PR mediate hormone-induced, rapid extranuclear signaling at the cell membrane or in the cytoplasm which triggers downstream signaling to regulate rapid or extended cellular responses. Specialized membrane and cytoplasmic proteins may also initiate hormone-induced extranuclear signaling. Rapid extranuclear signaling converges with its nuclear counterpart to amplify ER/PR transcription and specify gene regulatory networks. This review summarizes current understanding and updates on ER and PR extranuclear signaling. Further investigation of ER/PR extranuclear signaling may lead to development of novel targeted therapeutics for breast cancer management.
Moulder, D, Hatoum, D, Tay, E, Lin, Y & McGowan, E 2018, 'The Roles of p53 in Mitochondrial Dynamics andCancer Metabolism: The Pendulum between Survivaland Death in Breast Cancer?', Cancers, vol. 10, no. 189, pp. 1-22.View/Download from: Publisher's site
Abstract: Cancer research has been heavily geared towards genomic events in the development
and progression of cancer. In contrast, metabolic regulation, such as aberrant metabolism in
cancer, is poorly understood. Alteration in cellular metabolism was once regarded simply as a
consequence of cancer rather than as playing a primary role in cancer promotion and maintenance.
Resurgence of cancer metabolism research has identified critical metabolic reprogramming events
within biosynthetic and bioenergetic pathways needed to fulfill the requirements of cancer cell growth
and maintenance. The tumor suppressor protein p53 is emerging as a key regulator of metabolic
processes and metabolic reprogramming in cancer cells—balancing the pendulum between cell death
and survival. This review provides an overview of the classical and emerging non-classical tumor
suppressor roles of p53 in regulating mitochondrial dynamics: mitochondrial engagement in cell
death processes in the prevention of cancer. On the other hand, we discuss p53 as a key metabolic
switch in cellular function and survival. The focus is then on the conceivable roles of p53 in breast
cancer metabolism. Understanding the metabolic functions of p53 within breast cancer metabolism
will, in due course, reveal critical metabolic hotspots that cancers advantageously re-engineer for
sustenance. Illustration of these events will pave the way for finding novel therapeutics that target
cancer metabolism and serve to overcome the breast cancer burden.
Hatoum, D, Yagoub, D, Ahadi, A, Nassif, NT & McGowan, EM 2017, 'Annexin/S100A protein family regulation through p14ARF-p53 activation: A role in cell survival and predicting treatment outcomes in breast cancer', PLoS ONE, vol. 12, no. 1.View/Download from: Publisher's site
© 2017 Hatoum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The annexin family and S100A associated proteins are important regulators of diverse calcium- dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.
Udommethaporn, S, Tencomnao, T, McGowan, EM & Boonyaratanakornkit, V 2016, 'Assessment of anti-TNF-α activities in keratinocytes expressing inducible TNF- α: A novel tool for anti-TNF-α drug screening', PLoS ONE, vol. 11, no. 7.View/Download from: Publisher's site
© 2016 Udommethaporn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine important in normal and pathological biological processes. Newly synthesized pro-TNF-α is expressed on the plasma membrane and cleaved to release soluble TNF-α protein: both are biologically active. Secreted TNF-α signals through TNF receptors and the membrane-bound TNF-α acts by cell contact-dependent signaling. Anti-TNF-α antibodies have been used effectively for treatment of chronic inflammation, however with adverse side effects. Thus, there is a need for new anti-TNF-α small molecule compounds. Anti-TNF-α activity assays involve treatment of keratinocytes with exogenous TNF-α before or after anti-TNF-α incubation. However, this model fails to address the dual signaling of TNF-α. Here we describe a Doxycycline (Dox)-inducible TNF-α (HaCaT-TNF-α) expression system in keratinocytes. Using this in-vitro model, we show cell inhibition and induced expression of pro-inflammatory cytokines and markers, including IL-1β, IL-6, IL-8, NF-êB1, and KRT-16, similar to cells treated with exogenous TNF-α. Sufficient secreted TNF-α produced also activated IL-1β and IL-8 expression in wt HaCaT cells. Importantly, stimulated expression of IL-1β and IL-8 in HaCaT-TNF-α were blocked by Quercetin, a flavanol shown to possess anti-TNF-α activities. This novel in vitro cell model provides an efficient tool to investigate the dual signaling of TNF-α. Importantly, this model provides an effective, fast, and simple screening for compounds with anti-TNF-α activities for chronic inflammatory disease therapies.
Hatoum, D & McGowan, EM 2015, 'Recent Advances in the Use of Metformin: Can Treating Diabetes Prevent Breast Cancer?', BioMed Research International, vol. 2015, pp. 1-13.View/Download from: Publisher's site
Haass, NK, Nassif, N & McGowan, EM 2015, 'Switching the Sphingolipid Rheostat in the Treatment of Diabetes and Cancer Comorbidity from a Problem to an Advantage', BIOMED RESEARCH INTERNATIONAL.View/Download from: Publisher's site
Yagoub, D, Wilkins, MR, Lay, AJ, Kaczorowski, DC, Hatoum, D, Bajan, S, Hutvagner, G, Lai, JH, Wu, W, Martiniello-Wilks, R, Xia, P & McGowan, EM 2014, 'Sphingosine Kinase 1 Isoform-Specific Interactions in Breast Cancer', MOLECULAR ENDOCRINOLOGY, vol. 28, no. 11, pp. 1899-1915.View/Download from: Publisher's site
Jackson, E, Righi, L, McGowan, E & Sapino, A 2011, '1104 POSTER Sphingosine Kinase 1 Correlates With a Neuroendocrine Phenotype in Breast Cancer in Vivo and in Vitro', European Journal of Cancer, vol. 47, pp. S125-S125.View/Download from: Publisher's site
McGowan, EM, Alling, N, Jackson, E, Yagoub, D, Haass, NK, Allen, J & Martiniello-Wilks, R 2011, 'Evaluation Of Cell Cycle Arrest In Estrogen Responsive MCF-7 Breast Cancer Cells: Pitfalls Of The MTS Assay', PLoS ONE, vol. 6, no. 6, pp. 0-0.View/Download from: Publisher's site
Endocrine resistance is a major problem with anti-estrogen treatments and how to overcome resistance is a major concern in the clinic. Reliable measurement of cell viability, proliferation, growth inhibition and death is important in screening for drug t
McGowan, E, Alling, N, Shephard, R, Yagoub, D, Tran, N & Xia, P 2010, 'Abstract P1-04-03: A Role for Cyclin D1 in Neoplastic Transformation in MCF-7 Breast Cancer Cells Post p14ARF-p53 Induced Senescence', Poster Session Abstracts.View/Download from: Publisher's site
Martin, JL, Lin, MZ, McGowan, EM & Baxter, RC 2009, 'Potentiation of Growth Factor Signaling by Insulin-like Growth Factor-binding Protein-3 in Breast Epithelial Cells Requires Sphingosine Kinase Activity', JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, no. 38, pp. 25542-25552.View/Download from: Publisher's site
Zhang, N, Wu, Z-M, McGowan, E, Shi, J, Hong, Z-B, Ding, C-W, Xia, P & Di, W 2009, 'Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: Therapeutic potential for ovarian cancer', CANCER SCIENCE, vol. 100, no. 12, pp. 2459-2464.View/Download from: Publisher's site
Boonyaratanakornkit, V, McGowan, E, Sherman, L, Mancini, MA, Cheskis, BJ & Edwards, DP 2007, 'The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle', MOLECULAR ENDOCRINOLOGY, vol. 21, no. 2, pp. 359-375.View/Download from: Publisher's site
McGowan, EM, Russell, AJ, Boonyaratanakornkit, V, Saunders, DN, Lehrbach, GM, Sergio, CM, Musgrove, EA, Edwards, DP & Sutherland, RL 2007, 'Progestins reinitiate cell cycle progression in antiestrogen-arrested breast cancer cells through the B-Isoform of progesterone receptor', CANCER RESEARCH, vol. 67, no. 18, pp. 8942-8951.View/Download from: Publisher's site
McGowan, EM, Saad, S, Bendall, LJ, Bradstock, KF & Clarke, CL 2004, 'Effect of progesterone receptor A predominance on breast cancer cell migration into bone marrow fibroblasts', BREAST CANCER RESEARCH AND TREATMENT, vol. 83, no. 3, pp. 211-220.View/Download from: Publisher's site
McGowan, EM, Weinberger, RP, Graham, JD, Hill, HD, Hughes, JAI, O'Neill, GM & Clarke, CL 2003, 'Cytoskeletal responsiveness to progestins is dependent on progesterione receptor A levels', JOURNAL OF MOLECULAR ENDOCRINOLOGY, vol. 31, no. 2, pp. 241-253.View/Download from: Publisher's site
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 2000, 'Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma', HUMAN REPRODUCTION, vol. 15, pp. 48-56.View/Download from: Publisher's site
Saad, SR, Bendall, LJ, McGowan, EM, Gottlieb, DJ, Clarke, CL & Bradstock, KF 2000, 'Effects of progesterone on the migration of breast cancer cells within bone marrow stroma.', MOLECULAR BIOLOGY OF THE CELL, vol. 11, pp. 82A-82A.
McGowan, EM & Clarke, CL 1999, 'Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells', Molecular Endocrinology, vol. 13, no. 10, pp. 1657-1671.View/Download from: Publisher's site
The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, which differ in the N-terminal region and exhibit different activities in vitro, with PRA demonstrating dominant negative inhibitory effects on the activity of PRB and other nuclear receptors. PRA and PRB are expressed in target tissues at comparable levels although cells expressing a predominance of one isoform can be identified. In breast cancers, PRA is expressed at high levels in some tumors, and this may be associated with features of poorer prognosis. To investigate the role of PRA overexpression in PR-positive target cells, the effect of PRA induction on cell proliferation and expression of endogenous progestin-sensitive genes, SOX4 and fatty acid synthetase (FAS), was examined using PR-positive T-47D cell lines, which express a pre-dominance of PRB, in which PRA could be increased 2- to 20-fold over basal levels. No effect of PRA induction was noted on cell proliferation, but marked changes in morphology, consistent with loss of adherent properties, were observed. Increases up to 4-fold in the relative PRA levels augmented progestin induction of SOX4 mRNA expression, and RU486 treatment revealed a progestin agonist effect. There was no consistent effect of PRA induction on progestin-mediated increases in FAS mRNA levels under these conditions. Clones with PRA:PRB ratios greater than 15 were associated with diminished progestin responses on both SOX4 and FAS mRNA expression. These data show that PRA overexpression is associated with alteration in adhesive properties in breast cancer cells and effects on endogenous progestin targets that were dependent on the cellular ratio of PRA:PRB. The results of this study are consistent with the view that PRA expression can fluctuate within a broad range in target cells without influencing the nature of progestin action on downstream targets, but that overexpression of PRA, such as is seen in a proportion of breast cancers, may be associat...
McGowan, EM & Clarke, CL 1999, 'Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells', MOLECULAR ENDOCRINOLOGY, vol. 13, no. 10, pp. 1657-1671.View/Download from: Publisher's site
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 1999, 'Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle', JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 84, no. 8, pp. 2963-2971.View/Download from: Publisher's site
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 1999, 'Colocalization of Progesterone Receptors A and B by Dual Immunofluorescent Histochemistry in Human Endometrium during the Menstrual Cycle1', The Journal of Clinical Endocrinology & Metabolism, vol. 84, no. 8, pp. 2963-2971.View/Download from: Publisher's site
Graham, JD, Roman, SD, McGowan, E, Sutherland, RL & Clarke, CL 1995, 'Preferential stimulation of human progesterone receptor B expression by estrogen in T-47D human breast cancer cells', JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 51, pp. 30693-30700.View/Download from: Publisher's site
Lin, Y, Chen, S, Shupeng, Z, An, H, Yin, H & McGowan, E 2019, 'Phase 1 clinical trial of PD-1 knockout anti-MUC1 CAR-T cells in the treatment of patients with non-small cell lung cancer', Annals of Oncology, ESMO Immuno-oncology Congress 2019, Oxford University Press (OUP), Geneva.View/Download from: Publisher's site
Background: Little has been done on assessing the safety and efficacy of programmed death-1 (PD-1) knockout (KO) engineered CART cells in cancer patients. Here we designed a clinical trial to evaluate the safety of PD-1 KO engineered anti-MUC1 CART cells for the treatment of patients with advanced non-small cell lung cancer (NSCLC). The primary endpoint was to evaluate the safety of the new treatment.
Methods: Patients (age ≥ 18) were recruited according to the criteria in NCT03525782. MUC1-specific CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. PD-1 gene KO in the CAR positive T cells was achieved using the CRISPR-Cas9 system and validated by sequencing and flow cytometry. MUC1-CAR+/PD-1- T cells at a starting dose of 2.5x106/KG were infused over 60 mins. Following treatment, patients' general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored. Circulating CART cells were checked regularly. Changes in tumor size were examined by MRI sca ns.
Results: Up to the study cutoff date, 19/9/2019, 20 patients diagnosed with NSCLC (IIIb to IV), were recruited. All participants received at least one cycle of anti-MUC1 CART cell treatment. Among the 20 treated patients, 12 received 1 cycle, 3 received 3 cycles, 2 received 3 cycles, and 1 received 4 cycles. The most common adverse events (AEs) were acute fever (3 pts, 38.2-39.8 C◦), chills (2 pts), headache (1 pt), skin rash (1 pt), diarrhea (1 pt), and nausea & vomiting (1 pt). No grade 3-5 AEs and CRS were observed. Of the 20 assessed patients, 11 presented with stable disease (SD) while 9 had progressive disease (PD). All patients had significant symptom improvements after infusion. Circulating CART cells gradually declined after infusion and the number dropped down to approximately 20% in 4 months after one cycle treatment, indicating the necessity of further cycles.
Pateetin, P, McGowan, E & Boonyaratanakornkit, V 2018, 'Quantitative proteomic analysis of breast cancer cells expressing progesterone receptor A and B', 4th Congress on Steroid Research, Seoul, Korea 2018, Seoul, Korea.
Chen, S, Lin, Y, Zhong, S, An, H, Lu, Y, Yin, M, Liang, W & McGowan, E 2018, 'Anti-MUC1 CAR-T Cells combined with PD-1 Knockout Engineered T Cells for patients with non-small cell lung cancer (NSCLC): A pilot study, ESMO Immuno-oncology conference', Annals of Oncology, ESMO Immuno-oncology conference, Geneva, Oxford University Press (OUP), Geneva.
Lin, Y, McGowan, EM & Xu, M 2017, 'FGFR1 lentivirus lung cancer cell model for anti-cancer drug discovery and the study of FGFR1 signaling pathway', Journal of stem cell research & therapy, Cell Signaling, Cell Therapy and Cancer Therapeutics 2017, Chicago, pp. 62-62.
Hatoum, D & McGowan, E 2015, 'p14ARF-p53-p21 reversing the Warburg effect – a novel proteomic global approach', 1st Australian Cancer and Metabolism Meeting, April 29th-1st May, 2015, Garvan Institute of Medical Research.
Moulder, D, Mitchell, H, Hatoum, D & McGowan, E 2015, 'P14ARF-p53 plays a major role in mitochondria dynamics in breast cancer cells', New Horizons 2015, University of Technology Sydney.
Hatoum, D, Bok, CF, Touw, A, Nassif, N & McGowan, E 2015, 'Sphingosine Kinase 1 (SK1-43kDa) isoform expression may contribute to cancer aggressiveness', New Horizons 2015, University of Technology Sydney.
Hatoum, D, Yagoub, D, Nassif, N & McGowan, E 2015, 'P14ARF-p53-p21: P14ARF-p53-p21: reprogramming metabolic regulation and function in breast cancer', New Horizons 2015, University of Technology Sydney (UTS).
Johnson, T, Cheng, YY, Williams, M, Nassif, N, McGowan, E & Reid, G 2015, 'YB1: a potential therapeutic target in malignant pleural mesothelioma', New Horizons 2015, University of Technology Sydney (UTS).
Moulder, D, Mitchell, H, Hatoum, D, Bajan, S, Hutvagner, G, Johnson, M, Mills, K, Brennan, S, Nassif, N & McGowan, E 2015, 'P14ARF-p53 plays a major role in mitochondria dynamics in breast cancer cells', New Horizons 2015, University of Technolgy Sydney (UTS).
Suurbach, JH, Habib, R, Brennan, S, Larsen, SR, Simpson, A & Martiniello-Wilks, R 2015, 'CELLULAR AND GENETIC MEDICINES ADVANCING THE TREATMENT OF METASTATIC PROSTATE CANCER', JOURNAL OF GENE MEDICINE, 9th Biennial Meeting of the Australasian-Gene-and-Cell-Therapy-Society (AGCTS), WILEY-BLACKWELL, Univ Melbourne, Univ Coll, Parkville, AUSTRALIA, pp. 198-199.
McGowan, EM & Hatoum 2017, 'Activation of the p14ARF-p53 Pathway: A Role for p14ARF-p53 in the Differential Regulation of the Annexin Family and S100-Associated Proteins.', Endocrine Reviews, 94th Annual Meeting of the USA Endocrine Society, Houston, Texas. (EM, senior author), Oxford University Press (OUP), Chicago.
Habib, R, McGowan, E, Larsen, SR & Martiniello-Wilks, R 2013, 'CHARACTERISATION OF A PRIMITIVE BONE MARROW DERIVED MESENCHYMAL STEM CELL SUBPOPULATION SHOWING IMPROVED PROSTATE CANCER TROPISM', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY-BLACKWELL, Univ Technol, Sydney, AUSTRALIA, pp. 333-333.
Suurbach, JH, McGowan, EM, Simpson, AM & Martiniello-Wilks, R 2013, 'STEM CELL-BASED DELIVERY OF SUICIDE GENE YCDUPRT THERAPY TO PROSTATE CANCER', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY-BLACKWELL, Univ Technol, Sydney, AUSTRALIA, pp. 323-323.
Hatoum, D, Martiniello-Wilks, R, Nassif, N, Yagoub, D & McGowan, EM 2013, 'THE MISNOMER OF ACTIVATING P14ARF-P53 FOR BREAST CANCER THERAPY', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY, Univ Technol, Sydney, AUSTRALIA, pp. 333-334.
McGowan, EM & yagoub, D 2012, 'Sphingosine kinase 1 isoform-specific interactions revealed through stable isotope labelling by amino acids in cell culture (SILAC)', Endocrine Reviews, June 2012. 94th Annual Meeting of the USA Endocrine Society, Houston, Texas., Oxford University Press (OUP), Houston.
McGowan, EM & Jackson, E 2011, 'Sphingosine Kinase 1 Correlates With a Neuroendocrine Phenotype in Breast Cancer in Vivo and in Vitro', European Journal of Cancer vol. 47.
McGowan, EM & Yagoub, D 2010, 'A Role for Cyclin D1 in Neoplastic Transformation in MCF-7 Breast Cancer Cells Post p14ARF-p53 Induced Senescence', Cancer Research, Supplement, P1-04-03., 33rd Annual San Antonio Breast Cancer Symposium, San Antonio.
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 2000, 'Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma', Human Reproduction, pp. 48-56.View/Download from: Publisher's site
The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, which function as ligand-activated transcription factors. In-vitro studies suggest that the isoforms differ functionally and that their relative expression in a target cell may determine the nature and magnitude of response to progesterone. We have shown recently that PRA and PRB are co-expressed in target cells of the human endometrium. The purpose of this study was to investigate the homogeneity of expression of PRA and PRB in target cells of the human uterus throughout the menstrual cycle. In the functionalis, PRA and PRB were expressed in comparable levels in glandular epithelium during the proliferative phase of the cycle, whereas there was persistence of PRB but not PRA in the glands during mid-secretory phase. In the stroma, there was predominance of the PRA isoform throughout the cycle. There was remarkable homogeneity in the relative expression of PRA and PRB in adjacent cells within the same tissue compartment, suggesting that the mechanisms regulating relative PR isoform expression are similarly active in these cells. By contrast, heterogeneity between glands was observed under some circumstances in the functionalis of the endometrium, suggesting PR isoform down-regulation by progesterone to be asynchronous. Heterogeneity was also seen between the glands of the basalis and functionalis of the endometrium implying region-specific responses to hormonal stimuli. This study demonstrates adjacent cell homogeneity in the relative expression of PRA and PRB in normal human endometrial tissue and a differential response to ovarian steroid hormones between cell types and between different regions within the same tissue.
Saad, SR, Bendall, LJ, McGowan, EM, Clarke, CL, Gottlieb, DJ & Bradstock, KF 2000, 'Effects of progesterone on the migration of breast cancer cells within bone marrow stroma.', BLOOD, AMER SOC HEMATOLOGY, pp. 152B-152B.