Publications by authors named "Joanne Edwards"

132 Publications

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

Radiat Oncol 2021 Aug 26;16(1):163. Epub 2021 Aug 26.

Institute of Cancer Sciences, Glasgow Royal Infirmary, University of Glasgow, Room 2.57, Level 2, New Lister Building, Glasgow, G31 2ER, UK.

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.

Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m oxaliplatin, 350 mg folinic acid and 400 mg/m bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.

Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).
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http://dx.doi.org/10.1186/s13014-021-01888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393812PMC
August 2021

Novel Methods of Risk Stratifying Patients for Metachronous, Pre-Malignant Colorectal Polyps: A Systematic Review.

Crit Rev Oncol Hematol 2021 Aug 9;164:103421. Epub 2021 Jul 9.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, United Kingdom.

Introduction: Despite conventional measures of future polyp risk (histology, dysplasia, size, number), surveillance places a burden on patients and colonoscopy services. We aimed to review novel risk stratification techniques.

Methods: A systematic literature review was performed for studies using genomics, transcriptomics, IHC or microbiome as markers of metachronous polyp risk.

Results: 4165 papers underwent title, 303 abstract and 215 full paper review. 25 papers were included. 49 mutations/ SNPs/ haplotypes in 23 genes/ chromosomal regions (KRAS, APC, EGFR, COX1/2, IL23R, DRD2, CYP2C9/24A1/7A1, UGT1A6, ODC, ALOX12/15, PGDH, SRC, IGSF5, KCNS3, EPHB1/ KY, FAM188b, 3p24.1, 9q33.2, 13q33.2) correlated with metachronous adenoma / advanced adenoma risk. Expression levels of 6 proteins correlated with metachronous adenoma (p53, β-catenin, COX2, Adnab-9, ALDH1A1) or sessile serrated polyp (ANXA10) risk.

Conclusion: Although genomic and IHC markers correlated with metachronous polyp risk, it seems likely that a panel of novel markers will be required to refine this risk.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103421DOI Listing
August 2021

MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer.

Cell Death Differ 2021 Jul 5. Epub 2021 Jul 5.

Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
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http://dx.doi.org/10.1038/s41418-021-00820-0DOI Listing
July 2021

The inflammatory microenvironment in screen-detected premaligant adenomatous polyps: early results from the integrated technologies for improved polyp surveillance (INCISE) project.

Eur J Gastroenterol Hepatol 2021 07;33(7):983-989

Academic Unit of Surgery, University of Glasgow, Glasgow Royal Infirmary.

Introduction: Around 40% of patients who attend colonoscopy following a positive stool screening test have adenomatous polyps. Identifying which patients have a higher propensity for malignant transformation is currently poorly understood. The aim of the present study was to assess whether the type and intensity of inflammatory infiltrate differ between screen-detected adenomas with high-grade dysplasia (HGD) and low-grade dysplasia (LGD).

Methods: A representative sample of 207 polyps from 134 individuals were included from a database of all patients with adenomas detected through the first round of the Scottish Bowel Screening Programme in NHS Greater Glasgow and Clyde (April 2009-April 2011). Inflammatory cell phenotype infiltrate was assessed by immunohistochemistry for CD3+, CD8+, CD45+ and CD68+ in a semi-quantitative manner at 20× resolution. Immune-cell infiltrate was graded as absent, weak, moderate or strong. Patient and polyp characteristics and inflammatory infiltrate were then compared between HGD and LGD polyps.

Results: CD3+ infiltrate was significantly higher in HGD polyps compared to LGD polyps (74 vs. 69%; P < 0.05). CD8+ infiltrate was significantly higher in HGD polyps compared to LGD polyps (36 vs. 13%; P < 0.001) whereas CD45+ infiltrate was not significantly different (69 vs. 64%; P = 0.401). There was no significant difference in CD68+ infiltrate (P = 0.540) or total inflammatory cell infiltrate (calculated from CD3+ and CD68+) (P = 0.226).

Conclusions: This study reports an increase in CD3+ and CD8+ infiltrate in HGD colonic adenomas when compared to LGD adenomas. It may therefore have a use in the prognostic stratification and treatment of dysplastic polyps.
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http://dx.doi.org/10.1097/MEG.0000000000002202DOI Listing
July 2021

The relationship between β-catenin and patient survival in colorectal cancer systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Jul 13;163:103337. Epub 2021 May 13.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom. Electronic address:

β-catenin is a key component of Wnt signalling, which plays a crucial role in CRC progression. Therefore, a meta-analysis was performed to assess the prognostic value of β-catenin expression in CRC patients. PubMed and Web of Science were searched for relevant publications referring to the association between β-catenin expression and outcome of CRC patients. Review Manager version 5.4 was employed to analysis data from 28 eligible studies (containing 5475 patients). Of these, 6 provided data on DFS, 6 provided data on CSS and 18 reports provided data on OS. High nuclear β-catenin expression was significantly associated with poorer DFS, CSS and OS in patients with CRC whereas, low membranous β-catenin expression was associated to poor OS. In conclusion, β-catenin has prognostic value and potential as a biomarker to stratify patients with CRC. However, further work with high quantity tissue cohorts and patient data is required to confirm this conclusion.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103337DOI Listing
July 2021

The relationship between hypoxia-inducible factor 1α (HIF-1α) and patient survival in breast cancer: Systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Mar 19;159:103231. Epub 2021 Jan 19.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences-University of Glasgow, Glasgow, UK.

Introduction: Hypoxia is a characteristic of many solid tumours and results in an increase in expression of HIF-1α. Many studies have investigated the prognostic value of HIF-1α expression in breast cancer (BC), however, the prognostic value remains unclear. Therefore, a systematic review and meta-analysis was undertaken to determine the prognostic value of HIF-1α in BC patients.

Methods: The electronic databases PubMed and Web of science were systematically searched to identify relevant papers. The clinical outcomes included disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) in BC patients. Review Manager version 5.4 was employed to analysis data from 30 eligible studies (containing 6201patients).

Results: High expression of HIF-1α was associated with poorer DFS and OS. There was an effect of survival analysis, study region, antibodies used, scoring and threshold methods on HIF-1α expression.

Conclusion: HIF-1α overexpression was significantly associated with poorer DFS and OS in breast cancer patients.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103231DOI Listing
March 2021

Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer.

J Pathol Clin Res 2021 03 18;7(2):121-134. Epub 2020 Dec 18.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, Wolfson-Wohl Cancer Research Centre, Glasgow, UK.

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM-3, LAG-3 and PD-1 in patients with stage I-III colorectal cancer. Immunohistochemistry was employed to detect TIM-3, LAG-3, PD-1 and PD-L1 in 773 patients with stage I-III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG-3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00-2.09, p = 0.049) and PD-1 (HR 1.34 95% CI 1.00-1.78, p = 0.047) associated with poor survival, whereas high TIM-3 (HR 0.60 95% CI 0.42-0.84, p = 0.003), LAG-3 (HR 0.58 95% CI 0.40-0.87, p = 0.006) and PD-1 (HR 0.65 95% CI 0.49-0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD-L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG-3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42-0.78, p = 0.001). The results suggest that individual and combined high expression of TIM-3, LAG-3, and PD-1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.
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http://dx.doi.org/10.1002/cjp2.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869939PMC
March 2021

MNK Inhibition Sensitizes -Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.

Cancer Discov 2021 May 16;11(5):1228-1247. Epub 2020 Dec 16.

Lifelong Health, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia, Australia.

-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in -mutant colorectal cancer. Using -mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRAS models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple -mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in -mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611341PMC
May 2021

The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress.

Cell Death Differ 2021 May 2;28(5):1563-1578. Epub 2020 Dec 2.

Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.

To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target.
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http://dx.doi.org/10.1038/s41418-020-00686-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166837PMC
May 2021

Determining the prognostic significance of IKKα in prostate cancer.

Prostate 2020 10 21;80(14):1188-1202. Epub 2020 Jul 21.

Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK.

Background: As the survival of castration-resistant prostate cancer (CRPC) remains poor, and the nuclear factor-κB (NF-κB) pathways play key roles in prostate cancer (PC) progression, several studies have focused on inhibiting the NF-κB pathway through generating inhibitory κB kinase subunit α (IKKα) small molecule inhibitors. However, the identification of prognostic markers able to discriminate which patients could benefit from IKKα inhibitors is urgently required. The present study investigated the prognostic value of IKKα, IKKα phosphorylated at serine 180 (p-IKKα S180) and threonine 23 (p-IKKα T23), and their relationship with the androgen receptor (AR) and Ki67 proliferation index to predict patient outcome.

Methods: A cohort of 115 patients with hormone-naïve PC (HNPC) and CRPC specimens available were used to assess tumor cell expression of proteins within both the cytoplasm and the nucleus by immunohistochemistry. The expression levels were dichotomized (low vs high) to determine the associations between IKKα, AR, Ki67, and patients'Isurvival. In addition, an analysis was performed to assess potential IKKα associations with clinicopathological and inflammatory features, and potential IKKα correlations with other cancer pathways essential for CRPC growth.

Results: High levels of cytoplasmic IKKα were associated with a higher cancer-specific survival in HNPC patients with low AR expression (hazards ratio [HR], 0.33; 95% confidence interval [CI] log-rank, 0.11-0.98; P = .04). Furthermore, nuclear IKKα (HR, 2.60; 95% CI, 1.27-5.33; P = .01) and cytoplasmic p-IKKα S180 (HR, 2.10; 95% CI, 1.17-3.76; P = .01) were associated with a lower time to death from recurrence in patients with CRPC. In addition, high IKKα expression was associated with high levels of T-cells (CD3+ P = .01 and CD8+ P = .03) in HNPC; however, under castration conditions, high IKKα expression was associated with high levels of CD68+ macrophages (P = .04), higher Gleason score (P = .01) and more prostate-specific antigen concentration (P = .03). Finally, we identified crosstalk between IKKα and members of the canonical NF-κB pathway in the nucleus of HNPC. Otherwise, IKKα phosphorylated by noncanonical NF-κB and Akt pathways correlated with members of the canonical NF-κB pathway in CRPC.

Conclusion: The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.
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http://dx.doi.org/10.1002/pros.24045DOI Listing
October 2020

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer.

Br J Cancer 2021 02 23;124(4):786-796. Epub 2020 Nov 23.

School of Medicine, University of Glasgow, Glasgow, UK.

Background: The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy.

Methods: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.

Results: GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85-5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39-3.41, p = 0.001). In TransSCOT, chemotherapy type (p = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19-4.16, p = 0.012).

Conclusions: This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.
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http://dx.doi.org/10.1038/s41416-020-01168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884404PMC
February 2021

High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro.

Biomolecules 2020 09 25;10(10). Epub 2020 Sep 25.

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.

Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established. Measuring the expression of surrogate genes for NRF2 activity in silico, in combination with validation in patients' samples, we show that the NRF2 pathway is upregulated in colorectal tumours and that high levels of nuclear NRF2 correlate with a poor patient prognosis. These results highlight the need to overcome the protection provided by NRF2 and present an opportunity to selectively kill cancer cells with hyperactive NRF2. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2 and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 in colorectal cancer cells might present a vulnerability that could potentially be therapeutically exploited by using the Aurora kinase inhibitor AT9283.
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http://dx.doi.org/10.3390/biom10101365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600603PMC
September 2020

Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer.

Prostate 2020 11 26;80(15):1353-1364. Epub 2020 Aug 26.

Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Tumor microenvironment inflammatory infiltration is proposed as a protumorigenic mechanism for prostate cancer with proinflammatory cytokines stimulating androgen receptor (AR) activity. However, association with patient prognosis remains unclear. This study derives an inflammatory gene signature associated with AR expression and investigates CD3+ and CD8+ T-lymphocyte infiltration association with AR and prognosis.

Methods: Gene profiling of inflammatory related genes was performed on 71 prostate biopsies. Immunohistochemistry on 243 hormone-naïve prostate cancers was performed for CD3, CD8, AR, and phosphorylated AR tumor expression.

Results: Multiple proinflammatory genes were differentially expressed in association with high AR expression compared with low AR expression including PI3KCA and MAKP8 (adjusted P < .05). High CD3+ and high CD8+ infiltration associated with reduced cancer-specific survival (P = .018 and P = .020, respectively). High CD3+ infiltration correlated with high tumor cytoplasmic AR expression and if assessed together, they associated with reduced cancer-specific and 5-year survival from 90% to 56% (P = .000179). High CD8+ cytotoxic infiltration associated with high androgen-independent tumor nuclear AR serine 213 phosphorylation (correlation coefficient = 0.227; P = .003) and when assessed together associated with poor clinico-pathological features including perineural invasion (P = .001). Multiple genes involved in proinflammatory signaling pathways are upregulated in high AR expressing prostate samples.

Conclusion: T-lymphocyte infiltration in hormone-naïve disease associates with androgen-independent driven disease and provides possible therapeutic targets to reduce transformation from hormone-naïve to castrate-resistant disease.
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http://dx.doi.org/10.1002/pros.24064DOI Listing
November 2020

Gut γδ T cells as guardians, disruptors, and instigators of cancer.

Immunol Rev 2020 11 24;298(1):198-217. Epub 2020 Aug 24.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Colorectal cancer is the third most common cancer worldwide with nearly 2 million cases per year. Immune cells and inflammation are a critical component of colorectal cancer progression, and they are used as reliable prognostic indicators of patient outcome. With the growing appreciation for immunology in colorectal cancer, interest is growing on the role γδ T cells have to play, as they represent one of the most prominent immune cell populations in gut tissue. This group of cells consists of both resident populations-γδ intraepithelial lymphocytes (γδ IELs)-and transient populations that each has unique functions. The homeostatic role of these γδ T cell subsets is to maintain barrier integrity and prevent microorganisms from breaching the mucosal layer, which is accomplished through crosstalk with enterocytes and other immune cells. Recent years have seen a surge in discoveries regarding the regulation of γδ IELs in the intestine and the colon with particular new insights into the butyrophilin family. In this review, we discuss the development, specialities, and functions of γδ T cell subsets during cancer progression. We discuss how these cells may be used to predict patient outcome, as well as how to exploit their behavior for cancer immunotherapy.
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http://dx.doi.org/10.1111/imr.12916DOI Listing
November 2020

Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer.

J Pathol Clin Res 2020 10 13;6(4):283-296. Epub 2020 May 13.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Histological 'phenotypic subtypes' that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I-III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I-III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893-patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146-patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (p = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy.
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http://dx.doi.org/10.1002/cjp2.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578335PMC
October 2020

Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer.

Prostate Cancer Prostatic Dis 2020 12 1;23(4):596-606. Epub 2020 May 1.

Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK.

Background: Despite increases in diagnostics and effective treatments, over 300,000 men die from prostate cancer highlighting the need for specific and differentiating biomarkers. AR phosphorylation associates with castrate-resistance, with pAR promoting transcriptional activity. We hypothesise that combined pAR and pAR reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease.

Methods: Immunohistochemistry and immunofluorescence were performed on matched hormone-naive and castrate-resistant prostate cancer samples. TempO-Seq gene profiling was analysed using DESeq2 package. LNCaP-AI cells were stimulated with DHT or EGF. WST-1 assays were performed to determine effects of Enzalutamide and BKM120 on cell viability.

Results: Following the development of castrate-resistance, pAR expression reduced and pAR expression increased. Castrate-resistance pAR expression was not associated with survival but high pAR expression was associated with reduced survival from relapse. Combined high pAR and pAR was associated with reduced survival from relapse. pAR expression was induced by 10 nM DHT or 10 nM EGF and pAR expression was induced by treatment with 10 nM EGF in LNCaP-AI cells. Cell viability was reduced following treatment with 10 nM Enzalutamide and 10 nM BKM120. Eight genes were differentially expressed between hormone-naive and castrate-resistant tumours and twenty-five genes were differentially expressed between castrate-resistant tumours with high and low pAR expression.

Conclusion: Combined pAR and pAR provides a novel prognostic biomarker for castrate-resistant disease and a potential predictive and therapeutic target for prostate cancer. Further studies will be required to investigate the combined effects of targeting AR and PI3K/AKT signalling.
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http://dx.doi.org/10.1038/s41391-020-0235-1DOI Listing
December 2020

RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome.

Cancer Res 2020 06 10;80(11):2325-2339. Epub 2020 Mar 10.

CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, United Kingdom.

The recurring association of specific genetic lesions with particular types of cancer is a fascinating and largely unexplained area of cancer biology. This is particularly true of clear cell renal cell carcinoma (ccRCC) where, although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown protumorigenic role for the genes in this disease setting. Analysis of patient tumor biopsies together with loss-of-function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared with patients with low expression. This was functionally relevant, as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability and . Transcriptional profiling of RUNX1-CRISPR-deleted cells revealed a gene signature dominated by extracellular matrix remodeling, notably affecting , and signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC. SIGNIFICANCE: These data reveal a novel unexplored oncogenic role for genes in kidney cancer and indicate that targeting the effects of RUNX transcriptional activity could be relevant for clinical intervention in ccRCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3870DOI Listing
June 2020

The NF-KB pathway and endocrine therapy resistance in breast cancer

Endocr Relat Cancer 2019 05 9;26(6):R369-R380. Epub 2019 May 9.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, Glasgow, UK

Breast cancer is a heterogeneous disease, which over time acquires various adaptive changes leading to more aggressive biological characteristics and development of treatment resistance. Several mechanisms of resistance have been established; however, due to the complexity of oestrogen receptor (ER) signalling and its crosstalk with other signalling networks, various areas still need to be investigated. This article focusses on the role of nuclear factor kappa B (NF-KB) as a key link between inflammation and cancer and addresses its emerging role as a key player in endocrine therapy resistance. Understanding the precise mechanism of NF-KB-driven endocrine therapy resistance provides a possible opportunity for therapeutic intervention.
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May 2019

Correction: BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration.

Oncogene 2020 Mar;39(11):2450

Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow, G61 1QH, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41388-019-1149-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608245PMC
March 2020

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration.

Oncogene 2020 02 18;39(8):1797-1806. Epub 2019 Nov 18.

Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow, G61 1QH, UK.

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten BRF1) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten BRF1 tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.
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http://dx.doi.org/10.1038/s41388-019-1106-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033044PMC
February 2020

Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer.

Cancer Res 2020 02 12;80(3):576-590. Epub 2019 Nov 12.

Cancer Research UK Beatson Institute, Glasgow, Scotland, United Kingdom.

Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to β-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of β-catenin activation in prostate cancer progression and treatment resistance. β-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumors with β-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of β-catenin activation, by mediating nuclear localization of NFκBp65 and β-catenin. Overall, WNT/β-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/β-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes. SIGNIFICANCE: Targeting of both AR and WNT/β-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1684DOI Listing
February 2020

The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer.

Ann Surg Oncol 2019 Dec 11;26(13):4397-4404. Epub 2019 Oct 11.

Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC).

Objective: The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC.

Methods: Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup-Makinen (KM) grade to assess the tumor inflammatory cell infiltrate.

Results: High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30-11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors.

Conclusions: Tumor budding effectively stratifies patients' survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.
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http://dx.doi.org/10.1245/s10434-019-07931-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863941PMC
December 2019

The relationship between members of the canonical NF-kB pathway, tumour microenvironment and cancer specific survival in colorectal cancer patients.

Histol Histopathol 2020 Jun 8;35(6):569-578. Epub 2019 Oct 8.

Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Background: The aim of this study was to investigate the role of the upstream kinase TAK1 and the canonical NF-κB pathway colorectal in cancer (CRC). Immunohistochemistry was used to assess the expression of TAK1/pTAK1 and canonical NF-κB pathway members in a tissue microarray of 242 patients. The relationship between expression, the tumour microenvironment and cancer-specific survival were examined.

Results: All the investigated members of the pathway were expressed in CRC tissue. In addition, cytoplasmic pTAK1 was associated with the tumour microenvironment (P=0.045) and cancer-specific survival (CSS) (P=0.032). When cytoplasmic pTAK1 was stratified by BRAF status, cytoplasmic pTAK1 expression association with CSS was strengthened (P=0.014). Cytoplasmic IKKβ was significantly associated with the inflammatory cell infiltrate (P=0.015) as graded by Klintrup Makinen grade, systemic inflammation as assessed by neutrophil-lymphocyte ratio (P=0.03) and CSS (P=0.046). On multivariate analysis cytoplasmic IKKβ was independently associated with CSS (HR 1.75,95%CI 1.05-2.91, P=0.033).

Conclusion: Cytoplasmic pTAK1 was significantly associated with CSS and this was enhanced in patients with tumours that expressed wild type BRAF. High expression of cytoplasmic IKKβ was significantly associated with decreased CSS and with markers of the tumour microenvironment. These results support the hypothesis that NF-κB pathway members are poor prognostic markers in patients with CRC, but this requires to be validated in a large independent cohort.
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http://dx.doi.org/10.14670/HH-18-168DOI Listing
June 2020

Preoperative, biopsy-based assessment of the tumour microenvironment in patients with primary operable colorectal cancer.

J Pathol Clin Res 2020 01 14;6(1):30-39. Epub 2019 Oct 14.

Academic Unit of Surgery, School of Medicine Dentistry and Nursing, College of Medicine Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

The tumour microenvironment (TME) is recognised as an important prognostic characteristic and therapeutic target in patients with colorectal cancer (CRC). However, assessment generally utilises surgically resected specimens, precluding neoadjuvant targeting. The present study investigated the feasibility of intra-epithelial CD3 T-lymphocyte density and tumour stroma percentage (TSP) assessment using preoperative colonoscopic biopsies from 115 patients who had undergone resection of stages I-III CRC, examining the relationship between biopsy and surgically resected specimen-based assessment, and the relationship with cancer-specific survival (CSS). High biopsy CD3 density was associated with high CD3 density in the invasive margin, cancer stroma and intra-epithelial compartments of surgically resected specimens (area under the curve > 0.62, p < 0.05 for all) and with high Immunoscore. High biopsy TSP predicted high TSP in resected specimens (p = 0.001). Intra-class correlation coefficient for both measures was >0.7 (p < 0.001), indicating excellent concordance between individuals. Biopsy CD3 density (hazard ratio [HR] 0.23, p = 0.002) and TSP (HR 2.23, p = 0.029) were independently associated with CSS; this was comparable to the prognostic value of full section assessment (HR 0.21, p = 0.004, and HR 2.25, p = 0.033 respectively). These results suggest that assessment of the TME is comparable in biopsy and surgically resected specimens from patients with CRC, and biopsy-based assessment could allow for stratification prior to surgery or commencement of therapy targeting the TME.
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http://dx.doi.org/10.1002/cjp2.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966701PMC
January 2020

The relationship between phosphorylation status of focal adhesion kinases, molecular subtypes, tumour microenvironment and survival in patients with primary operable ductal breast cancer.

Cell Signal 2019 08 11;60:91-99. Epub 2019 Apr 11.

Unit of Gastrointestinal cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences-University of Glasgow, Glasgow, UK.

Background: Despite advances in therapies to treat breast cancer, over 100,000 patients die in the UK of this disease per year, highlighting the need to develop effect predictive and prognostic markers for patients with primary operable ductal breast cancer. Therefore, the aim of the present study was to examine the relationship between membranous, cytoplasmic and nuclear expression of focal adhesion kinase (phosphorylated at Y 397, Y 861 and Y 925), molecular subtypes, tumour microenvironment and survival in patients with primary operable ductal breast cancer.

Methods: Four hundred and seventy-four patients presenting between 1995 and 1998 with primary operable ductal breast cancer were included in this study. Using tissue microarrays expression of membranous, cytoplasmic and nuclear tumour cell phosphorylation of FAK at Y, Y and Y was assessed, and associations with clinicopathological characteristics, tumour microenvironment and cancer-specific survival (CSS) were examined.

Results: No significant association was observed for ph-FAK Y with survival at all sites. However, high expression of membranous ph-FAK Y was associated with increased tumour grade (P < .001), molecular subtypes (P < .001), increased tumour necrosis (P < .001), high Klintrup-Mäkinen grade (P < .001), increased CD138+ plasma cells (P = .031), endocrine therapy (P = .001) and poor cancer specific survival (P = .040). Similarly, high expression of nuclear ph-FAK Y was associated with decreased age (P = .042), increased CD138+ plasma cells (P = .001) and poor cancer specific survival (P = .003). Furthermore, high expression of cytoplasmic ph-FAK Y was associated with decreased tumour grade (P < .001), less involved lymph node (P = .020), molecular subtypes (P < .001), decreased tumour necrosis (P < .001), low Klintrup-Mäkinen grade (P < .001), decreased CD4+ T-cells (P = .006), decreased CD138+ plasma cells (P = .034), endocrine therapy (P < .001), chemotherapy (P = .048), and improved cancer specific survival (P = .044). On multivariate analysis, high expression of nuclear ph-FAK Y was independently associated with reduced cancer specific survival (P = .017).

Conclusion: The results of the present study show that membranous and nuclear ph-FAK Y and cytoplasmic ph-FAK Y were associated with prognosis in patients with primary operable ductal breast cancer. In addition, high expression of nuclear ph-FAK Y was an independent prognostic factor in patients with primary operable ductal breast cancer and could be incorporated into clinical practice.
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http://dx.doi.org/10.1016/j.cellsig.2019.04.006DOI Listing
August 2019

Src family kinases, HCK and FGR, associate with local inflammation and tumour progression in colorectal cancer.

Cell Signal 2019 04 23;56:15-22. Epub 2019 Jan 23.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom.

Background: In colorectal cancer (CRC), inflammatory responses have been reported to associate with patient survival. However, the specific signalling pathways responsible for regulating inflammatory responses are not clear. Src family kinases (SFKs) impact tumourigenic processes, including inflammation.

Methods: The relationship between SFK expression, inflammatory responses and cancer specific survival (CSS) in stage I-III CRC patients was assessed using immunohistochemistry on a 272 patient discovery cohort and an extended 822 patient validation cohort.

Results: In the discovery cohort, cytoplasmic FGR associated with improved CSS (P = 0.019), with membrane HCK (p = 0.093) trending towards poorer CSS. In the validation cohort membrane FGR (p = 0.016), membrane HCK (p = 0.019), and cytoplasmic HCK (p = 0.030) all associated with poorer CSS. Both markers also associated with decreased proliferation and cytotoxic T-lymphocytes (all p < 0.05). Furthermore, cytoplasmic HCK was an independent prognostic marker compared to common clinical factors. To assess synergy a combine FGR + HCK score was assessed. The membrane FGR + HCK score strengthened associations with poor prognosis (p = 0.006), decreased proliferation (p < 0.001) and cytotoxic T-lymphocytes (p < 0.001).

Conclusions: SFKs associate with prognosis and the local inflammatory response in patients with stage I-III CRC. Active membrane FGR and HCK work in parallel to promote tumour progression and down-regulation of the local inflammatory lymphocytic response.
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http://dx.doi.org/10.1016/j.cellsig.2019.01.007DOI Listing
April 2019

Immunotherapy: enhancing the efficacy of this promising therapeutic in multiple cancers.

Clin Sci (Lond) 2019 01 18;133(2):181-193. Epub 2019 Jan 18.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom

Cancer treatments often reach a refractory period leading to treatment failure and patients developing disease recurrence. This can be due to tumour cells escaping the immune response and creating an immunosuppressive microenvironment enhancing cancer progression. Immunotherapy has become a promising tool for cancer treatment as it restores the anti-tumour response of the patient's immune system. Immune checkpoint inhibitors are the most widely studied immunotherapies worldwide and are now approved for multiple cancers. However, chimeric antigen receptor (CAR)-T cell therapy has also shown promise by targeting T lymphocytes that are genetically modified to express CARs and this is now approved to treat some haematological cancers. Although immunotherapy has shown successful treatment outcomes in multiple cancers, some patients do not respond to this treatment. Therefore, approaches to enhance the efficacy of immunotherapies are likely to be the key to improve their effectiveness. Therefore, combination therapies of checkpoint inhibitors +/- chemotherapy are at the forefront of current research. Furthermore, biomarkers that predict treatment response are now beginning to emerge. Additionally, utilising nanoparticles as a newly targeted drug delivery system to enhance CAR-T cell therapy may enhance the efficacy of the cells when re-infused within the patient. Even if efficacy is enhanced, severe immune-related adverse events (irAEs) occur that are life-threatening and could lead to therapy being stopped. Therefore, predictive biomarkers for toxicity are also needed to improve both the patient's quality of life and treatment outcomes. This review will look at the current immunotherapies in clinical trials and discuss how to enhance their efficacy.
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http://dx.doi.org/10.1042/CS20181003DOI Listing
January 2019

A review on the interactions between the tumor microenvironment and androgen receptor signaling in prostate cancer.

Transl Res 2019 04 24;206:91-106. Epub 2018 Nov 24.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

Prostate cancer growth is controlled by androgen receptor signaling via both androgen-dependent and androgen-independent pathways. Furthermore, the prostate is an immune competent organ with inflammatory changes both within the systemic and local environment contributing to the reprogramming of the prostatic epithelium with consistently elevated lymphocyte infiltration and proinflammatory cytokines being found in prostate cancer. The crosstalk between the tumor microenvironment and androgen receptor signaling is complex with both protumorigenic and antitumorigenic roles observed. However, despite an increase in immune checkpoint inhibitors and inflammatory signaling blockades available for a range of cancer types, we are yet to see substantial progress in the treatment of prostate cancer. Therefore, this review aims to summarize the tumor microenvironment and its impact on androgen receptor signaling in prostate cancer.
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http://dx.doi.org/10.1016/j.trsl.2018.11.004DOI Listing
April 2019

The association between markers of tumour cell metabolism, the tumour microenvironment and outcomes in patients with colorectal cancer.

Int J Cancer 2019 05 11;144(9):2320-2329. Epub 2019 Jan 11.

Unit of Experimental Therapeutics, Institute of Cancer Science, University of Glasgow, Glasgow, United Kingdom.

Tumour cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumour microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I-III CRC were utilised to assess tumour cell expression of MCT-1, MCT-2, LDH-1 and LDH-5 by immunohistochemistry. Expression levels were dichotomised and associations with tumour factors, the tumour microenvironment and survival analysed. Nuclear LDH-5 associates with poor prognosis (HR 1.68 95% CI 0.99-2.84, p = 0.050) and trends toward increased tumour stroma percentage (TSP, p = 0.125). Cytoplasmic MCT-2 also trends toward increased TSP (p = 0.081). When combined into a single score; nuclear LDH-5 + TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27-5.35, p = 0.009), increased tumour budding (p = 0.002) and decreased stromal T-lymphocytes (p = 0.014). Similarly, cytoplasmic MCT-2 + TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31-4.11, p = 0.003), decreased necrosis (p = 0.039), and increased tumour budding (p = 0.004). The present study reports that the combination of TSP and nuclear LDH-5 was significantly associated with survival, increased tumour budding, and decreased stromal T-lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumour progression via modulation of tumour metabolism. Moreover, MCT-2 and LDH-5 may provide promising therapeutic targets for patients with stromal-rich CRC.
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http://dx.doi.org/10.1002/ijc.32045DOI Listing
May 2019

Mannose impairs tumour growth and enhances chemotherapy.

Nature 2018 11 21;563(7733):719-723. Epub 2018 Nov 21.

Cancer Research UK Beatson Institute, Glasgow, UK.

It is now well established that tumours undergo changes in cellular metabolism. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.
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http://dx.doi.org/10.1038/s41586-018-0729-3DOI Listing
November 2018
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