Susan A Burchill

• PhD BSc
• Group Leader at University of Leeds

PURPOSE Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS Patients age 1-21 years with RR-HRNB with adequate org...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

Models that more accurately reflect Ewing sarcoma (ES) will enable the prioritization of novel targeted agents from bench to clinic. To date, development of an ES mouse model have been unsuccessful1 and engraftment of human ES in mice is variable2. Coupled with a moral obligation to minimize the use of mammals, we have established and characterized...

EWSR1-ETS fusion genes result in upregulation and high expression of the oncogene MYC-C in Ewing sarcoma (ES). MYC-C is therefore an attractive therapeutic target in these aggressive cancers with limited treatment options. Unsuccessful efforts to target MYC-C proteins directly have resulted in the development of inhibitors to associated stabilizing...

Outcomes for most patients with Ewing sarcoma (ES) have remained unchanged for the last 30 years, emphasising the need for more effective and tolerable treatments. We have hypothesised that using small-molecule inhibitors to kill the self-renewing chemotherapy-resistant cells (Ewing sarcoma cancer stem-like cells; ES-CSCs) responsible for progressi...

Background: Ewing sarcoma (ES) is the second most common primary bone malignancy, with an urgent need for new treatments. ES is associated with high rates of progression and relapse, driven by drug-resistant cells capable of migration, self-renewal and single-cell tumorigenesis, termed cancer stem-like cells (CSCs). Membrane-type 1 matrix metallop...

Since Ewing sarcoma (ES) is a stem cell-like cancer1, improved outcome for some patients will be realised when treatments to eradicate ES stem-like cells (ES-CSCs) are evaluated in clinical trials. Therefore, we have identified small molecules that kill ES-CSCs, and examined their efficacy alone and in combination with chemotherapy. ES patient-deri...

The poor survival rates and limited treatment options for patients with relapsed/metastatic Ewing sarcoma (ES) highlights the need for more personalized targeted therapeutic approaches. In this project, we have investigated the prognostic potential of Aurora kinase expression in ES patients and evaluated the activity of Aurora kinase inhibitors in...

Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a pa...

Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a pa...

Purpose The development of biomarkers and molecularly targeted therapies for patients with Ewing sarcoma (ES) in order to minimise morbidity and improve outcome is urgently needed. Here, we set out to isolate and characterise patient-derived ES primary cell cultures and daughter cancer stem-like cells (CSCs) to identify biomarkers of high-risk dise...

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis met...

Purpose: Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as predictive and pharmacodynamic biomarkers. Experimental design: We collected matched blood and bone marrow samples from 40 patients with neuroblastoma to detect GD2+/CD45- n...

Patients with osteosarcoma (OST) frequently relapse with drug resistant disease, consistent with the hypothesis that tumours contain a cancer stem-like cell (CSCs) population that survives chemotherapy to re-populate the tumour at local or metastatic sites. We describe a dual functional approach to isolate OST-CSCs and identify the ABC transporter...

Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)–dependent arginine uptake...

Background Cancer stem-like cells (CSCs) are responsible for disease progression and relapse (Schatton et al, Bioessays 2009, 31:1038-49). Therefore, the eradication of Ewing's sarcoma (ES)-CSCs is expected to improve outcome for patients. Since the transfer of exosome cargo between cells drives ES progression (Ventura et al, Oncogene, 2016, 35:394...

Aims: The aim of this study was to explore the correlation of hTERT splice variant expression with MCPH1/BRIT1 and BRCA1 expression in epithelial ovarian cancer (EOC) samples. Background: Telomerase activation can contribute to the progression of tumors and the development of cancer. However, the regulation of telomerase activity remains unclear...

1 Background The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event‐free survival (EFS). 2 Methods Bone marrow aspirates and peripheral blood sampl...

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not prev...

Background: The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. Methods: A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 201...

Overexpression of plasma membrane multidrug resistance-associated protein 1 (MRP-1) in Ewing's sarcoma (ES) predicts poor outcome. MRP-1 is also expressed in mitochondria, and we have examined the submitochondrial localization of MRP-1 and investigated the mechanism of MRP-1 transport and role of this organelle in the response to doxorubicin. The m...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Activation of canonical and noncanonical Wnt signaling pathways in the initiation of the Ewing's sarcoma family of tumors (ESFT) migratory phenotype has been investigated using an in vitro model of ESFT. Human embryonic stem (hES) cells transfected with a doxycycline-inducible...

To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk. RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), a...

Background: Primary Ewing's sarcoma family of tumours (ESFTs) may respond to chemotherapy, although many patients experience subsequent disease recurrence and relapse. The survival of ESFT cells following chemotherapy has been attributed to the development of resistant disease, possibly through the expression of ABC transporter proteins. Methods:...

Overexpression of plasma membrane multi-drug resistance protein 1 (MRP-1) can lead to multidrug resistance. In this study, we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues. MRP-1 expression and subcellular localisation in normal and cancer cells and tissues was examined by d...

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Glutathione (GSH) is implicated in drug resistance mechanisms of several cancers and is a key regulator of cell death pathways within cells. We studied Ewing's sarcoma family of tumours (ESFT) cell lines and three mechanistically distinct anticancer agents (fenretinide, doxorubicin, and vincristine) to investigate whether the GSH antioxidant system...

Overexpression of plasma membrane MRP-1 can lead to multidrug resistance. In this study we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues and investigate the functional significance of mitochondrial MRP-1 with a view to identifying a new therapeutic starategy. MRP-1 expressio...

In many cancers, including neuroblastoma, microRNA (miRNA) expression profiling of peripheral blood (PB) and bone marrow (BM) may increase understanding of the metastatic process and lead to the identification of clinically informative biomarkers. The quality of miRNAs in PB and BM samples archived in PAXgene™ blood RNA tubes from large-scale clini...

Reactive oxygen species (ROS) are highly reactive by-products of energy production that can have detrimental as well as beneficial effects. Unchecked, high levels of ROS result in an imbalance of cellular redox state and oxidative stress. High levels of ROS have been detected in most cancers, where they promote tumor development and progression. Ma...

Sustained p38(MAPK) phosphorylation upregulates p75 neurotrophin (p75(NTR)) and induces apoptosis in Ewing's sarcoma family of tumours (ESFT). As fenretinide induces ESFT death through sustained p38(MAPK) phosphorylation, we hypothesised that this may be effected through upregulation of death receptors (DRs) and that treatment of fenretinide plus D...

In this article (Clin Cancer Res 2009;15:6742), which was published in the November 1, 2009, issue of Clinical Cancer Research (1), there was an error in the spelling of the second author's name in the online article. It should read Susan A. Burchill. The online article has been changed to reflect this correction and to match the print. ARTICLE Re...

The biological process of metastases requires multiple individual steps to successfully establish a solid tumor at a secondary site. Tumor cell(s) need to migrate through and from the primary tumor mass, intravasate into and survive within the hemopoietic or lymphatic vascular systems, extravasate from these systems into secondary tissues and initi...

The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological proces...

Disseminating disease is a predictive and prognostic indicator of poor outcome in children with neuroblastoma. Its accurate and sensitive assessment can facilitate optimal treatment decisions. The International Neuroblastoma Risk Group (INRG) Task Force has defined standardised methods for the determination of minimal disease (MD) by immunocytology...

The Ewing's sarcoma family of tumours (ESFT) are diagnosed by EWS-ETS gene translocations. The resulting fusion proteins play a role in both the initiation and maintenance of these solid aggressive malignant tumours, suppressing cellular senescence and increasing cell proliferation and survival. EWS-ETS fusion proteins have altered transcriptional...

The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing's sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mi...

Real-time RT-PCR (QRT-PCR) is a sensitive method for the detection of minimal disease (MD) and may improve monitoring of disease status and stratification of patients for therapy. Where tumour-specific mRNAs have not been identified, the selection of which target(s) is(are) optimal for the detection of MD remains a challenge. This reflects the hete...

Ewing's sarcoma is one of the few solid tumors for which the underlying molecular genetic abnormality has been described: rearrangement of the EWS gene on chromosome 22q12 with an ETS gene family member. These translocations define the Ewing's sarcoma family of tumors (ESFT) and provide a valuable tool for their accurate and unequivocal diagnosis....

Ewing's sarcoma family of tumours (ESFT) are childhood cancers whose aggressive behaviour and propensity to relapse prompts the need for new treatment approaches. In this study, the role of cellular antioxidants in determining the sensitivity of ESFT cell lines to the cytotoxicity of the antineoplasic agent fenretinide was investigated with a view...

The role of NF-kappaB in the Ewing's sarcoma family of tumours (ESFT) and their response to fenretinide has been investigated. Basal levels of phosphorylated NF-kappaB were low in all ESFT cells. BAY 11-7082 decreased cell viability, which was accompanied by caspase-3 cleavage. This was independent of the increase in reactive oxygen species, p38(MA...

Ewing's sarcoma family tumors (ESFT) are characterized by the presence of EWSRI-ETS fusion genes. Secondary chromosome changes are frequently described, although their clinical significance is not clear. In this study, we have collected and reviewed abnormal karyotypes from 88 patients with primary ESFT and a rearrangement of 22q 12. Secondary chan...

Ewing's sarcoma family tumors (ESFT) are characterized by the presence of EWSR1-ETS fusion genes. Secondary chromosome changes are frequently described, although their clinical significance is not clear. In this study, we have collected and reviewed abnormal karyotypes from 88 patients with primary ESFT and a rearrangement of 22q12. Secondary chang...

The Ewing's sarcoma family of tumours (ESFT) are small round cell tumours characterized by the non-random EWS-ETS gene rearrangements. We have previously demonstrated that ESFT are highly sensitive to fenretinide-induced death, effected in part through a reactive oxygen species (ROS)-dependent pathway. Here, we demonstrate for the first time that t...

Identifying genes, whose expression is consistently altered by chromosomal gains or losses, is an important step in defining genes of biological relevance in a wide variety of tumour types. However, additional criteria are needed to discriminate further among the large number of candidate genes identified. This is particularly true for neuroblastom...

Chromosome 9p21 gene copy number in Ewing's sarcoma family of tumour (ESFT) cell lines and primary ESFT has been evaluated using Multiplex Ligation-dependent probe amplification, and the clinical significance of CDKN2A loss and p16/p14(ARF) expression investigated. Homozygous deletion of CDKN2A was identified in 4/9 (44%) of ESFT cell lines and 4/4...

The clinical utility of detecting minimal residual disease (MRD) in children with neuroblastoma (NB) by quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) is not clear. This in part reflects the lack of uniform methodology for analysis and reporting. Reference laboratories across Europe have therefore established standard operat...

To investigate the use of the National Cancer Institute's hollow fiber assay (HFA) to evaluate and prioritize novel treatment strategies for clinical trials in the Ewing's sarcoma family of tumors (ESFT). The growth and morphology of ESFT cell lines in hollow fibers (HFs) was characterized in vitro and in vivo. Reliability and reproducibility were...

Transfer of new anticancer agents from bench to clinical trial takes in excess of 10 years and costs up to US $500 million. Despite this massive commitment, many more new agents fail in the clinical trials than are successful. The poor performance of many investigational anticancer agents in the clinic implies that the preclinical models used to ev...

While cyto- and histological screening of bone marrow samples are still accepted as the gold standard for initial staging of neuroblastoma patients, these applications are insufficient during or after therapy because it is not always possible to detect tumour cell infiltration below the level of 1% by morphology alone. For monitoring of minimal res...

There is an urgent need for new therapeutic strategies in Ewing's sarcoma family of tumors (ESFT). In this study, we have evaluated the effect of fenretinide [N-(4-hydroxyphenyl)retinamide] in ESFT models. The effect of fenretinide on viable cell number and apoptosis of ESFT cell lines and spheroids and growth of s.c. ESFT in nu/nu mice was investi...

We have reported previously that intratumoral microvessel density (MVD) is a significant prognostic indicator of event-free survival in the Ewing's sarcoma family of tumors (ESFT). Here, the angiogenic growth factor expression profile and its relationship with MVD has been investigated in ESFT. Using ESFT model systems, the potential of these facto...

Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38(MAPK), in contrast to the transient activation of p38(MAPK) associated with bFGF-induced cell proliferation. Stem cell factor...

Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38(MAPK), in contrast to the transient activation of p38(MAPK) associated with bFGF-induced cell proliferation. Stem cell factor...

A clinical role for nonquantitative reverse transcription-PCR (RT-PCR) using prostate-specific antigen in blood samples from patients with prostate cancer remains undefined. Assay variation and detection of prostate-specific antigen mRNA illegitimate transcription may explain inconsistent results between studies. Defining levels of prostate-specifi...

The aim of this study was to conduct a systematic review, and where possible meta-analyses, of molecular and biological tumor markers described in neuroblastoma, and to establish an evidence-based perspective on their clinical value for the screening, diagnosis, prognosis, and monitoring of patients. Experimental Design: A well-defined, reproducibl...

Despite advances in the treatment of neuroblastoma (NBL), recurrence and metastases continue to pose major problems in clinical management. The relation between micrometastases and the development of secondary disease is not fully understood. However, accurate methods to detect low numbers of tumour cells may allow the evaluation of their role in t...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

There has been an explosion of knowledge and enormous progress in the fundamental understanding of the biology of cancer in recent years. This has included the realisation that cancer occurs when normal cellular functions are disturbed leading to a malignant phenotype. Much research has focussed on understanding the types of disturbances that can o...

Peripheral blood (PB) stem cell harvests are reported to contain less tumor burden than bone marrow from the same patient,[1][1] making them a more attractive source of hematopoietic progenitors for transplantation and improving tolerance to intensive therapy. Although more intensive therapies

Fibroblast growth factor receptor 3 (FGFR3) is one of four high-affinity tyrosine kinase receptors for the FGF family of ligands, frequently associated with growth arrest and induction of differentiation. The extracellular immunoglobulin (IgG)-like domains II and III are responsible for ligand binding; alternative usage of exons IIIb and IIIc of th...

Prognostic markers help to stratify patients for treatment by identifying patients with different risks of outcome (e.g. recurrence of disease), and are important tools in the management of cancer and many other diseases. Systematic review and meta-analytical approaches to identifying the most valuable prognostic markers are needed because (sometim...