Chris Pepper

Chris Pepper
Brighton and Sussex Medical School | BSMS · Department of Clinical and Laboratory Investigation

BSc (Hons), PhD

About

258
Publications
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Publications

Publications (258)
Article
Full-text available
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepi...
Article
Full-text available
The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibitio...
Article
Full-text available
In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then a...
Article
Purpose: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemo-immunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10-15% variant allele frequency (VAF) remains unclear. Experimental design: Using a training/validation approach, we retrospe...
Article
Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report...
Article
CLL remains incurable despite BCR-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate, which is activated by unmethylated CpG-DNA. Here, we show that plasma from CLL patients contains significantly m...
Article
Background - Although there has been a revolution in the treatment of chronic lymphocytic leukemia (CLL), the challenge remains to identify the right drugs for the right patients. It is widely accepted that CIT, including the 'gold standard' fludarabine, cyclophosphamide and rituximab (FCR), is contraindicated for patients with TP53 disruption and,...
Article
Full-text available
Introduction: Zinc oxide nanoparticles (ZnO NPs) have recently attracted attention as potential anti-cancer agents. To the best of our knowledge, the toxicity of ZnO NPs against human chronic myeloid leukemia cells (K562 cell line) has not been studied using transcriptomics approach. Objective: The goals of this study were to evaluate the capabi...
Article
Full-text available
Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low...
Article
Cancer remains one of the leading causes of death in the developed world and despite impressive advances in therapeutic modalities, only a small subset of patients are currently cured. The underlying genetic heterogeneity of cancers clearly plays a crucial role in determining both the clinical course of individual pathologies and their responses to...
Article
CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The extensively validated 30% of positive CLL cells cut-off value is able to separate CLL patients into two subgroups with different prognosis, but it does not consider the pattern of CD49d expression. In the present study, we analysed a cohort of 1,630 CLL samples an...
Article
The increased incidence of chronic lymphocytic leukemia (CLL) in first-degree relatives of affected patients indicates an element of genetic susceptibility to this malignancy, borne out in large scale genome-wide association studies (GWAS), which have identified over 40 constitutional risk alleles. Given the important genetic contribution to CLL su...
Article
Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T‐cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more...
Article
Full-text available
Colorectal cancer (CRC) remains one of the most lethal human malignancies and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CD...
Article
Full-text available
We have previously shown that dividing patients with CLL into those with telomeres inside the fusogenic range (TL-IFR) and outside the fusogenic range (TL-OFR) is powerful prognostic tool. Here, we used a high-throughput version of the assay (HT-STELA) to establish whether telomere length could predict for outcome to fludarabine, cyclophosphamide,...
Conference Paper
p>Pyrrolobenzodiazepines (PBDs) have long been of interest in chemotherapeutic research as potential clinical agents. Recently, the conjugation of non-covalently interactive moieties to the C8-position of the PBD structure via a linker of variable length has emerged as a strategy to enhance the DNA sequence specificity of PBDs. This has led to the...
Article
Full-text available
The systematic shortening of the non-covalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the non-covalent element o...
Chapter
The transcription factor nuclear factor kappa B (NF-κB) regulates the expression of over 200 genes. Many of these modulate cellular processes involved in the initiation, maintenance and growth of human malignancies. In this regard, both lymphoid and myeloid leukaemia often exhibit aberrant activation of NF-κB, implicating it in the pathology of the...
Article
Full-text available
Acetylsalicylic acid, or aspirin, is one of the most common non-steroidal anti-inflammatory drugs, which has been shown to have anti-cancer effects. However, high doses are needed making it unsuitable as an oncology agent. We have previously reported increased potency in a series of hydroxybenzoate zinc (HBZn) aspirin analogues. Here we show that 3...
Article
Telomeric crisis is the final replicative barrier to cell immortalisation; it is characterised by genome instability and cell death and is triggered when telomeres become critically short and are subjected to fusion. Pre-cancerous lesions, or early stage cancers, often show signs of a telomere crisis, suggesting that escape from telomere crisis is...
Article
Full-text available
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 con...
Article
Full-text available
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 con...
Article
Multiple myeloma is an incurable malignancy of terminally differentiated B-cells - also known as plasma cells. These malignant cells are extremely reliant on the bone marrow microenvironment for their growth and survival, as well as their acquired ability to resist therapeutic intervention. Consequently, maintaining primary myeloma cells in vitro r...
Article
Introduction: Observation is the standard of care for asymptomatic early stage chronic lymphocytic leukemia (CLL) however these cases follow a heterogenous course. Recent studies show novel biomarkers can delineate indolent from aggressive early stage disease and current clinical trials are exploring the role of early intervention in high risk case...
Article
Telomeres are structures that cap the ends of chromosomes and play a critical role in maintaining genomic integrity. Telomere length is a key determinant of telomere function, with short telomeres being subjected to aberrant DNA repair activity that leads to telomere fusion and large scale genomic rearrangements. Single telomere length analysis (ST...
Article
The characteristic clinical heterogeneity observed in chronic lymphocytic leukemia (CLL) reflects its biological diversity and as a consequence, better understanding of the biology of this disease has led to the identification of a number of useful prognostic tools. Advances in massively parallel sequencing technologies have unearthed genetic and e...
Article
Full-text available
The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer...
Article
Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patient...
Article
Full-text available
The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high-resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients...
Article
Full-text available
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We...
Data
Association between SNP genotype and a) sex; b) age at diagnosis; and c) IGHV mutational status in CLL cases
Data
Table of eQTL results for the new risk loci in CLL primary cells, as well as data from publicly available databases. Shown are all genes within 1MB of the risk SNP.
Data
Supplementary Figures, Supplementary Tables, Supplementary References.
Data
Significant pathways as determined by LENS.
Article
Full-text available
B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of...
Article
Full-text available
A 14mer peptide (T14) derived from the C-terminus of acetylcholinesterase (AChE) selectively activates metastatic breast cancer cells via the alpha-7 nicotinic receptor (α7 nAChR). This naturally occurring peptide is also present in brain, is elevated in Alzheimer's disease, and is antagonised by a cyclized variant (NBP-14). Here we investigated th...
Article
Telomere length is a prognostic factor in Chronic Lymphocytic Leukemia (CLL) with short telomere length a powerful predictor of early time to first treatment and reduced overall survival. However, little is known about telomere dynamics through the course of an individual patient's disease. Our recent longitudinal analysis of CLL B-cell telomere le...
Article
Background: Understanding the pathology of Multiple Myeloma and the testing of therapeutic options has relied heavily on isogeneic cell lines due to the inability to sustain myeloma plasma cells in long-term in vitro culture. The cell lines MM.1S and MM.1R are well recognised in the field of myeloma research, providing a model of glucocorticoid dru...
Article
Introduction: The development of resistance to antihormones in the treatment of oestrogen receptor-positive (ER+) breast cancer is a major clinical problem. There is emerging evidence that antihormones can induce expression of genes/proteins that allow a cohort of cells to evade the growth-inhibitory impact of these therapies during initial drug re...
Article
Several lines of evidence suggest that homing of tumor cells to lymphoid tissue contributes to disease progression in chronic lymphocytic leukemia (CLL). Here, we demonstrate that lymph node (LN)-derived CLL cells possess a distinct phenotype, and exhibit enhanced capacity for T-cell activation and superior immune synapse formation when compared wi...
Article
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Hydroxybenzoate (HB) compounds have shown their significance in inducing apoptosis in primary chronic lymphocytic leukemia (CLL) and cancer cell lines, including HT-1080. The current study focuses on assessing the effects of 2-, 3- and 4-hydroxybenzoate calcium (HBCa) compounds on MCF-10A, MDA-MB231 and MCF-7 epithelial breast cell lines. The HBCa-...
Article
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B-cell chronic lymphocytic leukemia (CLL) is characterized by differential BCR signaling and autoimmune complications. Complement modulates B-cell function via C3d and CD21 cross-linked to the B-cell receptor (BCR). We hypothesized that CD21 contributes to BCR signaling and participates in the autoimmunity associated with CLL. We analyzed CD21 expr...
Article
Full-text available
Hydroxybenzoate (HB) compounds have shown to modulate the morphology in human fibrosarcoma HT-1080 cells. The changes in HT-1080 cells showed marker signs of apoptosis, which included the condensation of nucleus, cell round, blebbing and the formation of apoptotic bodies. The different stages of apoptosis were assessed microscopically using differe...
Article
Full-text available
Telomere erosion and fusion have an important role in the pathology of many common human malignancies including chronic lymphocytic leukemia (CLL).1, 2 Previous studies in CLL have shown that short telomeres defined on the basis of the median value or receiver operating characteristic analysis are associated with unmutated IGHV genes, poor-risk gen...
Article
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have been extensively investigated as DNA-interactive agents since their discovery in 1963. The significant cytotoxicity of the naturally derived PBDs has led to the search for synthetic analogues that retain the cytotoxicity of the parent structure while providing an enhanced therapeutic index. There i...