A5046835489- PARP inhibition in cancer therapy
- Ovarian cancer diagnosis and treatment
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Sarcoma Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Cancer Treatment and Pharmacology
- HER2/EGFR in Cancer Research
- Colorectal Cancer Treatments and Studies
- Kruppel-like factors research
- Ubiquitin and proteasome pathways
- Plant Virus Research Studies
- Immune Cell Function and Interaction
- Toxin Mechanisms and Immunotoxins
- Cancer Research and Treatments
- Nutrition, Genetics, and Disease
- Protein Degradation and Inhibitors
- Breast Cancer Treatment Studies
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- BRCA gene mutations in cancer
- Epigenetics and DNA Methylation
Walter and Eliza Hall Institute of Medical Research
2017-2025
The University of Melbourne
2017-2025
University of Washington
2024
Abstract Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and cancer patients. The 12 HGSOC patient-derived xenografts (PDX) the rucaparib was assessed, variable dose-dependent responses observed chemo-naive BRCA1/2 -mutated PDX, no PDX...
Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and resistance. Methylation gene promoters have a range impacts on risk, clinical stratification therapeutic outcomes. We provide several important examples genes, be silenced or activated by promoter methylation highlight their implications. These include the mismatch repair genes MLH1 MSH2, homologous...
In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and emerging biomarkers PARP inhibitor (PARPi) sensitivity. promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with most or all examined CpG sites the show PARPi. Both complete heterogeneous...
Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals advanced uLMS having five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed ~ 10% cases, reports some benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this defect. In report, we screened uLMS, accrued nationally, for mutations HR explored new approaches to therapeutic targeting. A cohort 58...
Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied susceptibility gene whose promoter sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived xenograft PH039, which lacks HR but harbors methylation, was selected for by cyclical niraparib treatment...
DNA methyltransferase 1 inhibitor (DNMT1i) therapy is a promising option for increasing immune response as part of combination cancer therapy. High–grade serous ovarian carcinoma (HGSOC) highly aggressive with poor survival outcomes, where DNMT1i being increasingly explored. HGSOC epigenetically silenced BRCA1 has been shown to respond PARP (PARPi) treatment – core targeted HGSOC. However, loss silencing even single allele causes PARPi and platinum chemotherapy resistance. We tested whether...
splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, clinical impact underlying drivers of
Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease.To determine the potential anti-microtubule agent (AMA) (paclitaxel, vinorelbine eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing patient-derived xenograft (PDX) models HGSC.Of 13 PRR PDX, six were primary PRR,...
e17634 Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and clear cell adenocarcinoma (OCCA), have limited treatment options molecular alterations that drive proliferation drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used first-line of most cancers; however, the AMA eribulin known to additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho Cancer 82:4457,...
Abstract Epigenetic silencing of homologous recombination repair genes through promoter methylation in ovarian cancer may lead to a deficiency (HRD) phenotype with prognostic and therapeutic implications. The objectives this study were evaluate somatic as marker HRD BRCA wild-type cancer, assess impact chemotherapy on methylation, determine the frequency constitutional its association methylated cancers. BRCA1 RAD51C quantitative was assessed using highly sensitive specific digital droplet...
Up to 17% of high grade serous ovarian carcinomas (HGSOC) harbour BRCA1 promoter methylation (meBRCA1), making them susceptible treatment with targeted PARP inhibitor (PARPi) therapy. Unfortunately, meBRCA1 loss can be acquired following PARPi or platinum chemotherapy, resulting in re–expression and resistance. Our understanding stability HGSOC is currently limited, part due a paucity pre–clinical models homozygous meBRCA1. Herein, we describe the generation several OVCAR8 cell line...
ABSTRACT While loss of BRCA1 promoter methylation has been shown to cause PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSC), the impacts RAD51C (me ) remain unresolved. In this study, three PARPi-responsive HGSC patient-derived xenografts (PDX) with gene silencing and homologous recombination deficiency were found have either homogeneous or heterogeneous patterns me . PDX could lose following PARPi treatment (rucaparib/niraparib), where a single unmethylated...
ABSTRACT Acquired PARP inhibitor (PARPi) resistance in BRCA1 - or BRCA2 -mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied susceptibility gene whose promoter sometimes methylated the tumor, leading to homologous recombination deficiency and PARPi sensitivity. For this study, PARPi-sensitive patient-derived xenograft PH039, which lacks demonstrable repair but harbors methylation, was selected for by...
Abstract Background: Acquired PARP inhibitor (PARPi) resistance in high-grade serous ovarian cancer (HGSOC) as a result of restored homologous recombination has been observed following secondary mutations that restore full-length protein BRCA1, BRCA2, RAD51C, and RAD51D. Additionally, loss BRCA1 methylation also shown to confer resistance. However, little is known about the role RAD51C acquired PARPi In ARIEL2 Part 1, phase 2 study rucaparib carcinoma, four (2%) tumors demonstrated...
Abstract Background: Acquired PARP inhibitor (PARPi) resistance in High Grade Serous Ovarian Carcinoma (HGSOC) commonly occurs via restored homologous recombination DNA repair due to secondary mutations BRCA1/2. However, overexpression of certain BRCA1 splice isoforms can also contribute PARPi HGSOC. This includes the D11q isoform BRCA1, where deleterious 11q region (exon 10) be spliced out resulting a truncated but partially functional protein. Here we describe four HGSOC Patient Derived...
Abstract Purpose Applying current treatment guidelines to elderly breast cancer (BC) patients is challenged by limited trial guidance, higher toxicities, and non-cancer related mortality. This study investigated adherence multidisciplinary team meeting (MDTM) recommendations in women with HER2 positive BC (HER2+BC) its impacts on patient survival. Methods retrospective multicentre cohort collected data from 305 primary diagnosis of HER2+BC. Women aged ≥65 years were classified into...
Abstract The high mortality (&gt;80%) seen in high-grade serous ovarian cancer (HGSOC) highlights the unmet clinical need for treatments capable of producing long-term sustained responses. related cancer, carcinosarcoma (OCS), has even poorer survival rates, which is due part to being a rare but also because its unique phenotype. OCS are composed both epithelial (carcinoma) and mesenchymal (sarcoma) components molecular analysis shown that most monoclonal derived from common progenitor...