ORCID Profile
0000-0002-9703-6899
Current Organisation
Australian National University
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Gene Expression (incl. Microarray and other genome-wide approaches) | Genomics | Bioinformatics | Genetics
Expanding Knowledge in the Biological Sciences | Computer Software and Services not elsewhere classified | Expanding Knowledge in the Medical and Health Sciences |
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537003.V1
Abstract: All Supplementary Methods and associated references
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-0770
DOI: 10.1158/2159-8290.22537006.V1
Abstract: Exposure-response relationship between CX-5461 levels and rDNA transcription rate in normal PBMCs
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537006
Abstract: Exposure-response relationship between CX-5461 levels and rDNA transcription rate in normal PBMCs
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537015
Abstract: Significant dermatological toxicities associated with CX-5461 treatment
Publisher: Cold Spring Harbor Laboratory
Date: 31-01-2021
DOI: 10.1101/2021.01.29.428877
Abstract: PAX5 is the master transcription factor controlling B cell identity. In humans, mutations in PAX5 account for 30% of B cell acute lymphoblastic leukemia (B-ALL) cases. Investigating the causal effects of PAX5 mutations has however been difficult due to the premature lethality of Pax5 −/− mice. Here we describe a novel mouse strain with a premature STOP mutation in Pax5 (Y351*) that produces a truncated protein and reduction in protein function, yet still allows for some B cell development to occur. A population of uncommitted and multipotent CD19 + B220 − B cells develops in the bone marrow of homozygous mice leading to the development of B-ALL. We show that the tumors frequently acquire secondary mutations in Jak3 , and Ptpn11 highlighting key pathways interacting with PAX5 during malignant transformation. Analysis of the PAX5 Y351* mice provide insight not only into the functional consequence of reduced PAX5 activity on B cell development and identity, but also provides an avenue in which to study PAX5-driven B-ALL in mice. Reduction in PAX5 function in mice induces the development of uncommitted B cells that have multipotent and malignant potential.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537003
Abstract: All Supplementary Methods and associated references
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537012
Abstract: Pharmacokinetics analysis of CX-5461 in patients with advanced hematological disease
Publisher: MDPI AG
Date: 18-05-2021
Abstract: Nucleoli form around actively transcribed ribosomal RNA (rRNA) genes (rDNA), and the morphology and location of nucleolus-associated genomic domains (NADs) are linked to the RNA Polymerase I (Pol I) transcription status. The number of rDNA repeats (and the proportion of actively transcribed rRNA genes) is variable between cell types, in iduals and disease state. Substantial changes in nucleolar morphology and size accompanied by concomitant changes in the Pol I transcription rate have long been documented during normal cell cycle progression, development and malignant transformation. This demonstrates how dynamic the nucleolar structure can be. Here, we will discuss how the structure of the rDNA loci, the nucleolus and the rate of Pol I transcription are important for dynamic regulation of global gene expression and genome stability, e.g., through the modulation of long-range genomic interactions with the suppressive NAD environment. These observations support an emerging paradigm whereby the rDNA repeats and the nucleolus play a key regulatory role in cellular homeostasis during normal development as well as disease, independent of their role in determining ribosome capacity and cellular growth rates.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537000
Abstract: All Supplementary Tables
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2014
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.PATHOL.2017.02.004
Abstract: Waldenström macroglobulinaemia (WM) is an indolent mature B cell lymphoma characterised by an infiltrate of heterogeneous B cells and hypersecretion of IgM. There are two distinct cellular populations that can be distinguished on morphology and immunophenotyping within the bone marrow. The predominant lymphoplasmacytic compartment arises at an earlier stage in ontogeny, and is responsible for the cytopenias noted during the symptomatic phase of the disease. This population is ably targeted by B cell immunodepletion. The smaller plasma cell compartment has been shown to be monotypic and to carry the MYD88L265P mutation noted in >90% of WM. Further, pathogenic IgM levels tend to correlate better with plasma cell burden as compared to lymphoplasmacytic cell burden within the bone marrow. B cell immunodepletion does not eradicate the plasma cell compartment resulting in persistent IgM levels and poor complete remission rates. In this review we discuss the different cellular compartments in WM and highlight evidence regarding the significance and impending function of the plasma cell compartment in WM. We suggest detection of plasma cells be incorporated into routine diagnostic algorithms, and highlight the need to trial incorporation of plasma cell depleting therapy into treatment algorithms to deepen responses and improve clinical outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537012.V1
Abstract: Pharmacokinetics analysis of CX-5461 in patients with advanced hematological disease
Publisher: Frontiers Media SA
Date: 03-07-2020
Publisher: American Association for Cancer Research (AACR)
Date: 08-2019
DOI: 10.1158/2159-8290.CD-18-1455
Abstract: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies. This article is highlighted in the In This Issue feature, p. 983
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537015.V1
Abstract: Significant dermatological toxicities associated with CX-5461 treatment
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2021
DOI: 10.1101/2021.01.21.427535
Abstract: The nucleolar surveillance pathway (NSP) monitors nucleolar fidelity and responds to nucleolar stresses (i.e., inactivation of ribosome biogenesis) by mediating the inhibitory binding of ribosomal proteins (RPs) to mouse double minute 2 homolog (MDM2), a nuclear-localised E3 ubiquitin ligase, which results in p53 accumulation. Inappropriate activation of the NSP has been implicated in the pathogenesis of collection of human diseases termed “ribosomopathies”, while drugs that selectively activate the NSP are now in trials for cancer. Despite the clinical significance, the precise molecular mechanism(s) regulating the NSP remain poorly understood. Using genome-wide loss of function screens, we demonstrate the ribosome biogenesis (RiBi) axis as the most potent class of genes whose disruption stabilises p53. Furthermore, we identified a novel suite of genes critical for the NSP, including a novel mammalian protein implicated in 5S ribonucleoprotein particle (5S-RNP) biogenesis, HEATR3. By selectively disabling the NSP, we unexpectedly demonstrate that a functional NSP is required for the ability of all nuclear acting stresses tested, including DNA damage, to robustly induce p53 accumulation. Together, our data demonstrates that the NSP has evolved as the dominant central integrator of stresses that regulate nuclear p53 abundance, thus ensuring RiBi is hardwired to cellular proliferative capacity.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6548299.V1
Abstract: Abstract RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m sup /sup , with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. Significance: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in i TP53 /i wild-type and mutant malignancies. i This article is highlighted in the In This Issue feature, p. 983 /i /
Publisher: Mary Ann Liebert Inc
Date: 08-2018
DOI: 10.1089/ADT.2018.861
Abstract: The nucleolus is a dynamic subnuclear compartment that has a number of different functions, but its primary role is to coordinate the production and assembly of ribosomes. For well over 100 years, pathologists have used changes in nucleolar number and size to stage diseases such as cancer. New information about the nucleolus' broader role within the cell is leading to the development of drugs which directly target its structure as therapies for disease. Traditionally, it has been difficult to develop high-throughput image analysis pipelines to measure nucleolar changes due to the broad range of morphologies observed. In this study, we describe a simple high-content image analysis algorithm using Harmony software (PerkinElmer), with a PhenoLOGIC™ machine-learning component, that can measure and classify three different nucleolar morphologies based on nucleolin and fibrillarin staining ("normal," "peri-nucleolar rings" and "dispersed"). We have utilized this algorithm to determine the changes in these classes of nucleolar morphologies over time with drugs known to alter nucleolar structure. This approach could be further adapted to include other parameters required for the identification of new therapies that directly target the nucleolus.
Publisher: CSIRO Publishing
Date: 16-04-2021
DOI: 10.1071/CH21049
Abstract: The regio-isomeric alkynyl-substituted derivatives, 2 and 3, of the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 (1) were prepared and the active one (compound 3) subjected to click reactions ([3 + 2]-cycloaddition reactions) with certain alkyl azides bearing biotin or fluorescent tags. Compounds 2 and 3, as well as four [3 + 2]-cycloadducts of the latter, were subjected to biological evaluation in a human acute myeloid leukemia cell line model. Among the six compounds tested only alkyne 3 remained active but this was less potent than parent 1.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2022
DOI: 10.1007/S10637-022-01222-W
Abstract: Background. Uterine leiomyosarcoma is a rare aggressive smooth muscle cancer with poor survival rates. RNA Polymerase I (Pol I) activity is elevated in many cancers supporting tumour growth and prior studies in uterine leiomyosarcoma revealed enlarged nucleoli and upregulated Pol I activity-related genes. This study aimed to investigate the anti-tumour potential of CX-5461, a Pol I transcription inhibitor currently being evaluated in clinical trials for several cancers, against the human uterine leiomyosarcoma cell line, SK-UT-1. Methods. SK-UT-1 was characterised using genome profiling and western blotting. The anti-tumour effects of CX-5461 were investigated using cell proliferation assays, expression analysis using qRT-PCR, and BrdU/PI based cell cycle analysis. Results. Genetic analysis of SK-UT-1 revealed mutations in TP53 , RB1 , PTEN , APC and TSC1 & 2 , all potentially associated with increased Pol I activity. Protein expression analysis showed dysregulated p53, RB1 and c-Myc. CX-5461 treatment resulted in an anti-proliferation response, G2 phase cell-cycle arrest and on-target activity demonstrated by reduced ribosomal DNA transcription. Conclusions. SK-UT-1 was confirmed as a representative model of uterine leiomyosarcoma and CX-5461 has significant potential as a novel adjuvant for this rare cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 29-11-2022
DOI: 10.1101/2022.11.29.518281
Abstract: We present the first biochemical-free technology for Real-time In Silico Enrichment of RNA species (RISER). RISER classifies RNA species from direct RNA nanopore signals, without the need for basecalling or a reference, and communicates with the sequencing hardware in real-time to enact in silico targeted RNA sequencing. We illustrate RISER for the enrichment and depletion of coding and non-coding RNA, demonstrating a 3.4-3.6x enrichment and 6.2-6.7x depletion of non-coding RNA in live sequencing experiments.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22537000.V1
Abstract: All Supplementary Tables
Start Date: 2022
End Date: 12-2024
Amount: $637,955.00
Funder: Australian Research Council
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