Publications by authors named "Loretta M S Lau"

15 Publications

  • Page 1 of 1

Efficacy of MEK inhibition in a recurrent malignant peripheral nerve sheath tumor.

NPJ Precis Oncol 2021 Feb 12;5(1). Epub 2021 Feb 12.

Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.

The prognosis of recurrent malignant peripheral nerve sheath tumors (MPNST) is dismal, with surgical resection being the only definitive salvage therapy. Treatment with chemoradiation approaches has not significantly improved patient outcomes. Similarly, trials of therapies targeting MPNST genomic drivers have thus far been unsuccessful. Improved understanding of the molecular pathogenesis of MPNST indicates frequent activation of the mitogen-activated protein kinase (MAPK) cell signaling pathway. MEK inhibitors have shown activity in preclinical studies; however, their clinical efficacy has not been reported to date. We describe here a case of sustained complete response to MEK inhibition in an adolescent patient with a recurrent metastatic MPNST with multiple alterations in the MAPK pathway, guided by a precision oncology approach.
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http://dx.doi.org/10.1038/s41698-021-00145-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881142PMC
February 2021

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer.

Nat Med 2020 11 5;26(11):1742-1753. Epub 2020 Oct 5.

Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.
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http://dx.doi.org/10.1038/s41591-020-1072-4DOI Listing
November 2020

Translating palbociclib to the clinic for DIPG - What is truly achievable?

EBioMedicine 2019 07 22;45:22. Epub 2019 Jun 22.

Children's Cancer Institute, UNSW, Sydney, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642255PMC
July 2019

Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma.

Br J Cancer 2018 09 17;119(6):693-696. Epub 2018 Sep 17.

Children's Cancer Institute, UNSW, Sydney, NSW, Australia.

Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.
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http://dx.doi.org/10.1038/s41416-018-0251-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173734PMC
September 2018

Telomere sequence content can be used to determine ALT activity in tumours.

Nucleic Acids Res 2018 06;46(10):4903-4918

Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.

The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation.
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http://dx.doi.org/10.1093/nar/gky297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007693PMC
June 2018

Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres.

Cell Rep 2017 06;19(12):2544-2556

Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia. Electronic address:

Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ∼50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy.
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http://dx.doi.org/10.1016/j.celrep.2017.05.087DOI Listing
June 2017

Whole-genome landscapes of major melanoma subtypes.

Nature 2017 05 3;545(7653):175-180. Epub 2017 May 3.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.
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http://dx.doi.org/10.1038/nature22071DOI Listing
May 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations.

J Neurooncol 2014 Aug 3;119(1):17-26. Epub 2014 May 3.

Cancer Center, Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA.

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase-negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway.
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http://dx.doi.org/10.1007/s11060-014-1456-8DOI Listing
August 2014

Advances in paediatric cancer treatment.

Transl Pediatr 2014 Apr;3(2):156-82

1 Children's Cancer Research Unit, Kid's Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia ; 2 Oncology Department, The Children's Hospital at Westmead, Westmead, NSW, Australia ; 3 Sydney Medical School, University of Sydney, Sydney, NSW, Australia.

Four out of five children diagnosed with cancer can be cured with contemporary cancer therapy. This represents a dramatic improvement since 50 years ago when the cure rate of childhood cancer was <25% in the pre-chemotherapy era. Over the past ten years, while improvement in overall survival (OS) has been marginal, progress in pediatric oncology lies with adopting risk-adapted therapeutic approach. This has been made possible through identifying clinical and biologic prognostic factors with rigorous research and stratifying patients using these risk factors, and subsequently modifying therapy according to risk group assignment. This review provides a perspective for eight distinct pediatric malignancies, in which significant advances in treatment were made in the last decade and are leading to changes in standard of care. This includes four hematologic malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL)] and four solid tumors [medulloblastoma (MB), low grade glioma (LGG), neuroblastoma (NB) and Ewing sarcoma (ES)]. Together, they comprise 60% of childhood cancer. Improved patient outcome is not limited to better survival, but encompasses reducing both short and long-term treatment-related complications which is as important as cure, given the majority of childhood cancer patients will become long-term survivors. Risk-adapted approach allows treatment intensification in the high-risk cohort while therapy can be de-escalated in the low-risk to minimize toxicity and late sequelae without compromising survival. Advances in medical research technology have also led to a rapid increase in the understanding of the genetics of childhood cancer in the last decade, facilitating identification of molecular targets that can potentially be exploited for therapeutic benefits. As we move into the era of targeted therapeutics, searching for novel agents that target specific genetic lesions becomes a major research focus. We provide an overview of seven novel agents (bevacizumab, bortezomib, vorinostat, sorafenib, tipifarnib, erlotinib and mTOR inhibitors), which have been most frequently pursued in childhood cancers in the last decade, as well as reporting the progress of clinical trials involving these agents.
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http://dx.doi.org/10.3978/j.issn.2224-4336.2014.02.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729100PMC
April 2014

Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes.

Nucleic Acids Res 2014 Feb 12;42(3):1733-46. Epub 2013 Nov 12.

Telomere Length Regulation Group, Children's Medical Research Institute, Westmead NSW 2145, Australia, Cancer Research Unit, Children's Medical Research Institute, Westmead NSW 2145, Australia, Terry Fox Laboratory, BC Cancer Agency, Vancouver V5Z 1L3, Canada, Sydney Medical School, University of Sydney, Sydney NSW 2006, Australia and Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead NSW 2145, Australia.

Telomeres are terminal repetitive DNA sequences on chromosomes, and are considered to comprise almost exclusively hexameric TTAGGG repeats. We have evaluated telomere sequence content in human cells using whole-genome sequencing followed by telomere read extraction in a panel of mortal cell strains and immortal cell lines. We identified a wide range of telomere variant repeats in human cells, and found evidence that variant repeats are generated by mechanistically distinct processes during telomerase- and ALT-mediated telomere lengthening. Telomerase-mediated telomere extension resulted in biased repeat synthesis of variant repeats that differed from the canonical sequence at positions 1 and 3, but not at positions 2, 4, 5 or 6. This indicates that telomerase is most likely an error-prone reverse transcriptase that misincorporates nucleotides at specific positions on the telomerase RNA template. In contrast, cell lines that use the ALT pathway contained a large range of variant repeats that varied greatly between lines. This is consistent with variant repeats spreading from proximal telomeric regions throughout telomeres in a stochastic manner by recombination-mediated templating of DNA synthesis. The presence of unexpectedly large numbers of variant repeats in cells utilizing either telomere maintenance mechanism suggests a conserved role for variant sequences at human telomeres.
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http://dx.doi.org/10.1093/nar/gkt1117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919612PMC
February 2014

Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of Alternative Lengthening of Telomeres.

PLoS One 2012 20;7(11):e50062. Epub 2012 Nov 20.

Cancer Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia.

Alternative Lengthening of Telomeres (ALT) is a non-telomerase mechanism of telomere lengthening that occurs in about 10% of cancers overall and is particularly common in astrocytic brain tumors and specific types of sarcomas. Somatic cell hybridization analyses have previously shown that normal telomerase-negative fibroblasts and telomerase-positive immortalized cell lines contain repressors of ALT activity, indicating that activation of ALT results from loss of one or more unidentified repressors. More recently, ATRX or DAXX was shown to be mutated both in tumors with telomere lengths suggestive of ALT activity and in ALT cell lines. Here, an ALT cell line was separately fused to each of four telomerase-positive cell lines, and four or five independent hybrid lines from each fusion were examined for expression of ATRX and DAXX and for telomere lengthening mechanism. The hybrid lines expressed either telomerase or ALT, with the other mechanism being repressed. DAXX was expressed normally in all parental cell lines and in all of the hybrids. ATRX was expressed normally in each of the four telomerase-positive parental cell lines and in every telomerase-positive hybrid line, and was abnormal in the ALT parental cells and in all but one of the ALT hybrids. This correlation between ALT activity and loss of ATRX expression is consistent with ATRX being a repressor of ALT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050062PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502299PMC
May 2013

Detection of alternative lengthening of telomeres by telomere quantitative PCR.

Nucleic Acids Res 2013 Jan 25;41(2):e34. Epub 2012 Aug 25.

Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.

Alternative lengthening of telomeres (ALT) is one of the two known telomere length maintenance mechanisms that are essential for the unlimited proliferation potential of cancer cells. Existing methods for detecting ALT in tumors require substantial amounts of tumor material and are labor intensive, making it difficult to study prevalence and prognostic significance of ALT in large tumor cohorts. Here, we present a novel strategy utilizing telomere quantitative PCR to diagnose ALT. The protocol is more rapid than conventional methods and scrutinizes two distinct characteristics of ALT cells concurrently: long telomeres and the presence of C-circles (partially double-stranded circles of telomeric C-strand DNA). Requiring only 30 ng of genomic DNA, this protocol will facilitate large-scale studies of ALT in tumors and can be readily adopted by clinical laboratories.
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http://dx.doi.org/10.1093/nar/gks781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553966PMC
January 2013

Skeletal Langerhans cell histiocytosis in children: permanent consequences and health-related quality of life in long-term survivors.

Pediatr Blood Cancer 2008 Mar;50(3):607-12

Division of Haematology/Oncology, Hospital for Sick Children, University of Toronto, Ontario, Canada.

Background: The skeleton is the most frequently involved organ in Langerhans cell histiocytosis (LCH) in children, and bone LCH generally has an excellent long-term survival. Although permanent consequences (PC) are described in half of the survivors thus raising concerns for quality of life (QOL), the impact on quality of life has not been formally studied.

Methods: A retrospective review was performed on 124 LCH patients with skeletal involvement, followed by prospective evaluation of PC and health-related QOL using age-appropriate validated study tools (PedsQL or SF-36).

Results: Of the 116 survivors, PC were found in 34 (29%) patients, of whom 8 had more than 1 PC. PC were significantly more frequent in multi-system (M-S) than in single system (S-S) LCH (73% vs. 17%; P < 0.0001). While diabetes insipidus (65%) was the most common PC in M-S LCH, cosmetic and orthopedic problems made up the majority of PC in S-S LCH. The median follow-up time was 8.5 years. 27 patients completed the PedsQL survey and 22 the SF-36 survey. The QOL scores for LCH patients were not significantly different from healthy children in the PedsQL survey and from young adults in the SF-36 survey. In addition, the QOL scores were very similar between patients with and without PC and between patients with M-S and S-S LCH.

Conclusions: Children with M-S LCH had a significantly higher risk of developing PC. Skeletal LCH did not adversely affect the quality of life of survivors, including those with PC who appeared to adapt to their disabilities and medical problems.
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http://dx.doi.org/10.1002/pbc.21322DOI Listing
March 2008