A5082237249- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Microtubule and mitosis dynamics
- Cancer Immunotherapy and Biomarkers
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Melanoma and MAPK Pathways
- Immunotherapy and Immune Responses
- Cutaneous Melanoma Detection and Management
- Cancer-related gene regulation
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Lung Cancer Treatments and Mutations
- Inflammasome and immune disorders
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- Cancer-related molecular mechanisms research
- Cancer Genomics and Diagnostics
- Trace Elements in Health
- Telomeres, Telomerase, and Senescence
- Protein Degradation and Inhibitors
- Glioma Diagnosis and Treatment
- Cancer Cells and Metastasis
- Genetic factors in colorectal cancer
- Cancer Diagnosis and Treatment
Peter MacCallum Cancer Centre
2021-2024
The University of Melbourne
2021-2024
University of Otago
2011-2021
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX),...
Constitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor responses in cancer, although factors involved PD-L1 regulation are poorly understood. Here we show that loss global DNA methylation, particularly intergenic regions and repeat elements, is associated with constitutive (PD-L1CON), versus inducible (PD-L1IND), melanoma cell lines. We further this accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) strongly correlated methylome...
Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, studies metastasis-related epigenetic drivers, part because a framework for identifying driver changes metastasis has not established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns three cutaneous primary and metastatic melanoma cell line pairs identify...
Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. The majority CRC deaths are caused by tumor metastasis, even following treatment. There strong evidence for epigenetic changes, such as DNA methylation, accompanying metastasis poorer patient survival. Earlier detection better understanding molecular drivers critical clinical importance. Here, we identify signature advanced performing whole genome-scale methylation full transcriptome analyses paired primary...
Chromosome position 9p21 encodes three-tumor suppressors p16INK4a, p14ARF, and p15INK4b, the long non-coding RNA ANRIL (antisense noncoding in INK4 locus). The rs11515 single nucleotide polymorphism p16INK4a/p14ARF 3′ untranslated region is associated with glioblastoma, melanoma, other cancers. This study investigated frequency effect of genotypes breast cancer. Genomic DNA samples from 400 women (200 200 without a diagnosis cancer) were genotyped for major © minor (G) alleles. was also 108...
Prognostic markers for glioblastoma multiforme (GBM) are important patient management. Recent advances have identified prognostic GBMs that use telomerase or the alternative lengthening of telomeres (ALT) mechanism telomere maintenance. Approximately 40% no defined maintenance (NDTMM), with a mixed survival affected individuals. This study examined genetic variants in cyclin-dependent kinase inhibitor 2A (CDKN2A) gene encodes p16(INK4a) and p14(ARF) tumor suppressors, isocitrate...
Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved survival melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to associated transcriptomic changes has also been shown be accompanied by increased expression programmed death ligand 1 (PD-L1), a potent inhibitor immune response. Intrinsic upregulation PD-L1...
<div>Abstract<p>Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring <i>CCNE1</i> amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using...
Aim: Validation of sequencing-based DNA methylation data is an important step for meaningful translation findings. However, there has been limited assessment different platforms to validate from next generation sequencing. Methods: We performed a comparative analysis between the genome-wide platform reduced representation bisulfite sequencing with targeted, Sequenom EpiTyper (four genes were analyzed in 15 cell lines covering 52 CpG sites). Results: show that accuracy validation...
<p>Description of methods to synthesize INX-315</p>
Melanoma, the most aggressive skin cancer type, is responsible for 75% of related deaths worldwide. Given that New Zealand (NZ) has world's highest melanoma incidence, we sought to determine frequency mutations in NZ melanomas recurrently mutated genes. were from localities distributed between North (35°S-42°S) and South Islands (41°S-47°S). A total 529 analyzed BRAF exon 15 by Sanger sequencing, also Sequenom MelaCarta MassARRAY. While, a relatively low incidence BRAFV600E (23.4%) was...
Abstract Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved survival melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to associated transcriptomic changes, has also been shown be accompanied by increased expression programmed death ligand 1 (PD-L1), a potent inhibitor immune response. Intrinsic upregulation...
OPINION article Front. Oncol., 09 August 2013Sec. Cancer Genetics Volume 3 - 2013 | https://doi.org/10.3389/fonc.2013.00205
Sequencing-based genome-wide DNA methylation, gene expression studies and associated data on paired colorectal cancer (CRC) primary liver metastasis are very limited. We have profiled the methylome transcriptome of matched CRC samples from same patients. Genome-scale methylation levels were examined using Reduced Representation Bisulfite Sequencing (RRBS) RNA-Seq, respectively. To investigate patterns, we generated a total 1.01 × 109 RRBS reads 4.38 108 RNA-Seq tissues. Here, describe in...
<p>INX-315 delays the onset of acquired CDK4/6i resistance. <b>A,</b> Representative images from a clonogenic assay in which MCF7 and T47D cells were treated with control vehicle, abemaciclib (500 nmol/L), INX-315 (300 nmol/L for MCF7, 100 T47D), or combination. Six technical replicates per condition. <b>B,</b> (right) quantification (left) after treating as <b>A</b> 7 days followed by staining beta-galactosidase (β-gal) activity (scale bar = μm)....
<p>TIS after INX-315 treatment of <i>CCNE1-</i>amplified cancers. <b>A,</b> Left, representative images staining OVCAR3 and MKN1 cells for beta-galactosidase activity with (scale bar = 100 μm). Experiments performed three technical replicates. Right, quantification integrated signal per cell. Dashed line indicates cutoff used to define positivity, numbers represent percentage beta-galactosidase–positive cells. <b>B,</b> DAPI phalloidin relative...
<p>Discovery and characterization of INX-315. <b>A,</b> Amino acid sequence homology at the ATP-binding pockets several CDKs. <b>B,</b> Derivation INX-315 through serial modifications trilaciclib, a CDK4/6i. Table indicates biochemical IC<sub>50</sub>s (± SEM) to cyclin/CDK pairings shown using Nanosyn assay. Trilaciclib IC<sub>50</sub> for CDK1/cyclin B1 was ND (for trilaciclib: <i>n</i> = 6 CDK2/cyclin E1 A2, 9 CDK4/cyclin...
<p>INX-315 delays the onset of acquired CDK4/6i resistance. <b>A,</b> Representative images from a clonogenic assay in which MCF7 and T47D cells were treated with control vehicle, abemaciclib (500 nmol/L), INX-315 (300 nmol/L for MCF7, 100 T47D), or combination. Six technical replicates per condition. <b>B,</b> (right) quantification (left) after treating as <b>A</b> 7 days followed by staining beta-galactosidase (β-gal) activity (scale bar = μm)....