Publications by authors named "Joseph J Sacco"

22 Publications

  • Page 1 of 1

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.

Nature 2022 May 4. Epub 2022 May 4.

University of Bradford, Institute of Cancer Therapeutics, Bradford, UK.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T cells. Accordingly, in mouse models, PI3Kδi decreased the number of T cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T cells, accompanied by expansion of pathogenic T helper 17 (T17) and type 17 CD8 T (T17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
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http://dx.doi.org/10.1038/s41586-022-04685-2DOI Listing
May 2022

Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma.

J Clin Oncol 2022 Mar 7:JCO2101805. Epub 2022 Mar 7.

Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.

Purpose: This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).

Methods: In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017.

Results: Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.

Conclusion: Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.
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http://dx.doi.org/10.1200/JCO.21.01805DOI Listing
March 2022

Genetic variants associated with mandibular osteoradionecrosis following radiotherapy for head and neck malignancy.

Radiother Oncol 2021 12 30;165:87-93. Epub 2021 Oct 30.

Liverpool Head & Neck Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, University of Liverpool, United Kingdom; Head and Neck Unit, Liverpool University Hospital NHS Foundation Trust, Aintree University Hospital, United Kingdom.

Background/aim: Utilising radiotherapy in the management of head and neck cancer (HNC) often results in long term toxicities. Mandibular osteoradionecrosis (ORN) represents a late toxicity associated with significant morbidity. We aim to identify a panel of common genetic variants which can predict ORN to aid development of personalised radiotherapy protocols.

Method: Single nucleotide polymorphism (SNP) arrays were applied to DNA samples from patients who had prior HNC radiotherapy and minimum two years follow-up. A case cohort of mandibular ORN was compared to a control group of participants recruited to CRUK HOPON clinical trial. Relevant clinical parameters influencing ORN risk (e.g. smoking/alcohol) were collected. Significant associations from array data were internally validated using polymerase chain reaction (PCR) and pyrosequencing.

Results: Following inclusion of 141 patients in the analysis (52 cases, 89 controls), a model predictive for ORN was developed; after controlling for alcohol consumption, smoking, and age, 4053 SNPs were identified as significant. This was reduced to a representative model of 18 SNPs achieving 92% accuracy. Following internal technical validation, a six SNP model (rs34798038, rs6011731, rs2348569, rs530752, rs7477958, rs1415848) was retained within multivariate regression analysis (ROC AUC 0.859). Of these, four SNPs (rs34798038 (A/G) (p 0.006), rs6011731 (C/T) (p 0.018), rs530752 (A/G) (p 0.046) and rs2348569 (G/G) (p 0.005)) were significantly associated with the absence of ORN.

Conclusion: This is the first genome wide association study in HNC using ORN as the endpoint and offers new insight into ORN pathogenesis. Subject to validation, these variants may guide patient selection for personalised radiotherapy strategies.
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http://dx.doi.org/10.1016/j.radonc.2021.10.020DOI Listing
December 2021

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.

N Engl J Med 2021 09;385(13):1196-1206

From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.).

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.

Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.

Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.

Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
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http://dx.doi.org/10.1056/NEJMoa2103485DOI Listing
September 2021

Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma.

J Immunother Cancer 2021 03;9(3)

First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response.

Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.

Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8 T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8 T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8 T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8 T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions.

Conclusions: This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy.

Trial Registration Number: NCT02366195.
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http://dx.doi.org/10.1136/jitc-2020-001621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011715PMC
March 2021

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

Br J Cancer 2021 05 15;124(10):1661-1669. Epub 2021 Mar 15.

Department of Oncology, Churchill Hospital, Oxford, UK.

Background: Immune checkpoint blockers (ICBs) activate CD8 T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.

Methods: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8 T cells was sequenced and differential gene expression according to irAE development assessed.

Results: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8 T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.

Conclusions: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.
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http://dx.doi.org/10.1038/s41416-021-01310-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110747PMC
May 2021

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

Br J Cancer 2020 07 18;123(2):207-215. Epub 2020 May 18.

Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.

Background: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes.

Methods: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed.

Results: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03).

Conclusions: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.
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http://dx.doi.org/10.1038/s41416-020-0882-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374736PMC
July 2020

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development.

J Pathol 2020 04;250(4):420-439

Department of Molecular and Clinical Cancer Medicine, ITM, University of Liverpool, Liverpool, UK.

Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour-infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8 T lymphocytes and tumour-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1, and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216965PMC
April 2020

Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck.

Cell Death Dis 2019 12 4;10(12):912. Epub 2019 Dec 4.

Liverpool Head and Neck Centre, Liverpool, L69 3GE, UK.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide, with overall survival of less than 50%. Current therapeutic strategies involving a combination of surgery, radiation, and/or chemotherapy are associated with debilitating side effects, highlighting the need for more specific and efficacious therapies. Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors. In order to explore the therapeutic potential of BH3 mimetics in the treatment of SCCHN, we assessed the expression levels of BCL-2, BCL-X, and MCL-1 via Western blots and immunohistochemistry, in cell lines, primary cells derived from SCCHN patients and in tissue microarrays containing tumor tissue from a cohort of 191 SCCHN patients. All preclinical models exhibited moderate to high levels of BCL-X and MCL-1, with little or no BCL-2. Although expression levels of BCL-X and MCL-1 did not correlate with patient outcome, a combination of BH3 mimetics to target these proteins resulted in decreased clonogenic potential and enhanced apoptosis in all preclinical models, including tumor tissue resected from patients, as well as a reduction of tumor volume in a zebrafish xenograft model of SCCHN. Our results show that SCCHN is dependent on both BCL-X and MCL-1 for apoptosis evasion and combination therapy targeting both proteins may offer significant therapeutic benefits in this disease.
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http://dx.doi.org/10.1038/s41419-019-2150-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892862PMC
December 2019

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome.

Pigment Cell Melanoma Res 2019 07 19;32(4):564-575. Epub 2019 Feb 19.

Liverpool Ocular Oncology Research Group, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.
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http://dx.doi.org/10.1111/pcmr.12767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849808PMC
July 2019

Recent breakthroughs in metastatic uveal melanoma: a cause for optimism?

Future Oncol 2018 Jun 9;14(14):1335-1338. Epub 2018 May 9.

Liverpool Ocular Oncology Research Group, Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK.

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http://dx.doi.org/10.2217/fon-2018-0116DOI Listing
June 2018

The deubiquitylase USP15 regulates topoisomerase II alpha to maintain genome integrity.

Oncogene 2018 04 12;37(17):2326-2342. Epub 2018 Feb 12.

Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges. These bridges fail to decatenate, and at mitotic exit form micronuclei that are indicative of genome instability. We also describe the cell cycle-dependent behaviour for two major isoforms of USP15, which differ by a short serine-rich insertion that is retained in isoform-1 but not in isoform-2. Although USP15 is predominantly cytoplasmic in interphase, we show that both isoforms move into the nucleus at prophase, but that isoform-1 is phosphorylated on its unique S229 residue at mitotic entry. The micronuclei phenotype we observe on USP15 depletion can be rescued by either USP15 isoform and requires USP15 catalytic activity. Importantly, however, an S229D phospho-mimetic mutant of USP15 isoform-1 cannot rescue either the micronuclei phenotype, or accumulation of TOP2A. Thus, S229 phosphorylation selectively abrogates this role of USP15 in maintaining genome integrity in an isoform-specific manner. Finally, we show that USP15 isoform-1 is preferentially upregulated in a panel of non-small cell lung cancer cell lines, and propose that isoform imbalance may contribute to genome instability in cancer. Our data provide the first example of isoform-specific deubiquitylase phospho-regulation and reveal a novel role for USP15 in guarding genome integrity.
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http://dx.doi.org/10.1038/s41388-017-0092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916918PMC
April 2018

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma.

J Pathol Clin Res 2018 Jan 13;4(1):26-38. Epub 2017 Nov 13.

Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer MedicineInstitute of Translational Medicine, University of LiverpoolLiverpoolUK.

Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow-up data were available for all patients. gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1-positiveM3 UMs were associated with prolonged survival compared to nBAP1-negative M3 UMs (Log rank,  = 0.014). nBAP1 protein loss did not correlate with a mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing 'predominantly diffuse' in most nBAP1-negative UM, a distinct 'focal perinuclear' expression pattern - localized immediately adjacent to the cis Golgi - was seen in 31% (18/59). These tumours tended to carry loss-of-function mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non-genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1-negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.
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http://dx.doi.org/10.1002/cjp2.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783957PMC
January 2018

Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics.

Pigment Cell Melanoma Res 2018 03 15;31(2):253-266. Epub 2017 Oct 15.

Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.

Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models. The poor overall response of UM cells to FDA-approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1-dependent kinase subnetwork in JQ1-exposed cells that contained multiple cell cycle-regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome-wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients.
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http://dx.doi.org/10.1111/pcmr.12650DOI Listing
March 2018

Gene expression profiling in bladder cancer identifies potential therapeutic targets.

Int J Oncol 2017 Apr 2;50(4):1147-1159. Epub 2017 Mar 2.

School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Despite advances in management, bladder cancer remains a major cause of cancer related complications. Characterisation of gene expression patterns in bladder cancer allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Hypergeometric analysis was used to identify canonical pathways and curated networks having statistically significant enrichment of differentially expressed genes. Osteopontin (OPN) expression was validated by immunohistochemistry. Hierarchical clustering defined signatures, which differentiated between cancer and healthy tissue, muscle-invasive or non-muscle invasive cancer and healthy tissue, grade 1 and grade 3. Pathways associated with cell cycle and proliferation were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer compared to healthy tissue. The present study contributes to a growing body of work on gene expression signatures in bladder cancer. The data support an important role for osteopontin in bladder cancer, and identify several pathways worthy of further investigation.
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http://dx.doi.org/10.3892/ijo.2017.3893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363876PMC
April 2017

Challenges and Strategies in Precision Medicine for Non-Small-Cell Lung Cancer.

Curr Pharm Des 2016 ;22(28):4374-85

Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Daulby Street, L69 3GA.

Lung cancer is the most common cause of cancer- related death worldwide, causing over 1.2 million deaths each year. Non-small-cell lung cancer (NSCLC) consists of a group of malignancies that are pathologically and molecularly diverse but that are all characterised by a poor prognosis. Survival rates for lung cancer patients have improved very slowly and only to a modest degree owing partly to poor funding for research into this malignancy and stigma associated with smoking, as well as relative chemo-resistance. However, in recent years, NSCLC has become an exemplar for precision medicine, mainly following development of drugs targeting the receptors of epidermal growth factor and anaplastic lymphoma kinase. While epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors are only applicable to a minority of patients and benefits are almost invariably short-lived, current studies indicate that at least 50% of patients with NSCLC have a targetable mutation. With a growing armamentarium of inhibitors against these targets in development, there is a hope that a greater proportion of patients will benefit from precision medicine and that such benefits will be sustained. However, there remain significant challenges in the development of precision medicine in NSCLC. These include: identification and validation of new targets; ensuring biopsies are fit for purpose; tumour heterogeneity; requirements for serial tumour assessments; and not least cost. In this review, we will discuss the current status of precision medicine in NSCLC as well as how basic and translational research are paving the way towards overcoming the above challenges. In addition, we will pay attention to clinical strategies in respect to liquid biopsies and the potential use of extracellular vesicles such as exosomes in cancer therapeutics.
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http://dx.doi.org/10.2174/1381612822666160603014932DOI Listing
March 2018

Systemic listeriosis following vaccination with the attenuated Listeria monocytogenes therapeutic vaccine, ADXS11-001.

Hum Vaccin Immunother 2016 04 30;12(4):1085-6. Epub 2015 Nov 30.

a Department of Molecular and Clinical Cancer Medicine , Institute of Translational Medicine, University of Liverpool , Liverpool , UK.

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http://dx.doi.org/10.1080/21645515.2015.1121338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962931PMC
April 2016

Dysregulation of the Met pathway in non-small cell lung cancer: implications for drug targeting and resistance.

Transl Lung Cancer Res 2015 Jun;4(3):242-52

1 Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK ; 2 Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK .

The receptor tyrosine kinase, Met, orchestrates a complex signalling network that physiologically drives a programme of 'invasive growth'. In cancer however, this process may be co-opted to promote proliferation, survival and metastasis of cancer cells. Met is thus a key therapeutic target, not least in non-small cell lung cancer (NSCLC) where it is one of the most commonly dysregulated driver oncogenes. Identifying robust biomarkers that allow the selection of patients most likely to respond to Met targeted therapies will however be essential to realising their potential. This has been underlined recently by the early termination of three pivotal phase III trials investigating Met targeted agents in NSCLC, all of which failed to show clinical benefit. In contrast to these trials, which were relatively unselective, a couple of early phase trials have recently been instigated that select patients on the basis of Met amplification. While still at an early stage, interim results are relatively encouraging and strengthen the rationale for using Met amplifaction as a biomarker. Here we will discuss this and other aberrations in Met signalling in relation to their significance in the therapeutic targeting of Met.
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http://dx.doi.org/10.3978/j.issn.2218-6751.2015.03.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483475PMC
June 2015

Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors.

Oncotarget 2015 May;6(15):13757-71

Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Histone deacetylases are important targets for cancer therapeutics, but their regulation is poorly understood. Our data show coordinated transcription of HDAC1 and HDAC2 in lung cancer cell lines, but suggest HDAC2 protein expression is cell-context specific. Through an unbiased siRNA screen we found that BRCA1-associated protein 1 (BAP1) regulates their expression, with HDAC2 reduced and HDAC1 increased in BAP1 depleted cells. BAP1 loss-of-function is increasingly reported in cancers including thoracic malignancies, with frequent mutation in malignant pleural mesothelioma. Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines, and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation. We find that BAP1 regulates HDAC2 by increasing transcript abundance, rather than opposing its ubiquitylation. Importantly, although total cellular HDAC activity is unaffected by transient depletion of HDAC2 or of BAP1 due to HDAC1 compensation, this isoenzyme imbalance sensitizes MSTO-211H cells to HDAC inhibitors. However, other established mesothelioma cell lines with low endogenous HDAC2 have adapted to become more resistant to HDAC inhibition. Our work establishes a mechanism by which BAP1 loss alters sensitivity of cancer cells to HDAC inhibitors. Assessment of BAP1 and HDAC expression may ultimately help identify patients likely to respond to HDAC inhibitors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537048PMC
http://dx.doi.org/10.18632/oncotarget.3765DOI Listing
May 2015

The average body surface area of adult cancer patients in the UK: a multicentre retrospective study.

PLoS One 2010 Jan 28;5(1):e8933. Epub 2010 Jan 28.

Department of Medical Oncology, Clatterbridge Centre for Oncology, Merseyside, United Kingdom.

The majority of chemotherapy drugs are dosed based on body surface area (BSA). No standard BSA values for patients being treated in the United Kingdom are available on which to base dose and cost calculations. We therefore retrospectively assessed the BSA of patients receiving chemotherapy treatment at three oncology centres in the UK between 1(st) January 2005 and 31(st) December 2005.A total of 3613 patients receiving chemotherapy for head and neck, ovarian, lung, upper GI/pancreas, breast or colorectal cancers were included. The overall mean BSA was 1.79 m(2) (95% CI 1.78-1.80) with a mean BSA for men of 1.91 m(2) (1.90-1.92) and 1.71 m(2) (1.70-1.72) for women. Results were consistent across the three centres. No significant differences were noted between treatment in the adjuvant or palliative setting in patients with breast or colorectal cancer. However, statistically significant, albeit small, differences were detected between some tumour groups.In view of the consistency of results between three geographically distinct UK cancer centres, we believe the results of this study may be generalised and used in future costings and budgeting for new chemotherapy agents in the UK.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008933PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812484PMC
January 2010

Emerging roles of deubiquitinases in cancer-associated pathways.

IUBMB Life 2010 Feb;62(2):140-57

Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, L69 3BX, UK.

Deubiquitinases (DUBs) are emerging as important regulators of many pathways germane to cancer. They may regulate the stability of key oncogenes, exemplified by USP28 stabilisation of c-Myc. Alternatively they can negatively regulate ubiquitin-dependent signalling cascades such as the NF-kappaB activation pathway. We review the current literature that associates DUBs with cancer and discuss their suitability as drug targets of the future.
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http://dx.doi.org/10.1002/iub.300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165618PMC
February 2010

A neurological phenotype in mice with DNA repair gene Ercc1 deficiency.

DNA Repair (Amst) 2008 Feb 3;7(2):281-91. Epub 2007 Dec 3.

Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.

Transcription-coupled repair of endogenous DNA damage appears crucial for the maintenance of the central and peripheral nervous systems. Ercc1 is essential for nucleotide excision repair and is also involved in recombination repair and the repair of interstrand cross-links. We have investigated the neurological phenotype of Ercc1-deficient mice where the liver dysfunction has been corrected by an Ercc1 transgene controlled by a liver-specific promoter. We observed poor coordination, ataxia and loss of visual acuity, but saw no evidence of the anticipated histopathological neurodegeneration, or of abnormal neuromuscular junctions. Instead we observed uraemic encephalopathy, a brain disease resulting from kidney failure. This diagnosis was supported by histopathological signs of kidney disease, as well as proteinuria. When we examined archival sections from neural-specific Ercc1 knockout mice, which showed the same reduced growth and died at the same age as the liver-corrected Ercc1 knockouts, we found no evidence of kidney pathology or encephalopathy. Thus, while some aspects of the Ercc1-deficient phenotype are indicative of functional neurodegeneration, we obtained no structural evidence for this. The structural changes observed in the brains of liver-corrected Ercc1 knockouts appear to be a secondary consequence of kidney failure arising from Ercc1 deficiency.
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http://dx.doi.org/10.1016/j.dnarep.2007.10.005DOI Listing
February 2008
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