My Publications by Andrew Redfern
Proceedings of the National Academy of Sciences, 2013
The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including p... more The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression. Furthermore, each of the RISC proteins, together with Argonaute 2, associates with SRA and specific pre-microRNAs in both the nucleus and cytoplasm, providing evidence for links between NR-mediated transcription and some of the factors involved in miRNA processing.
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Molecular Cell, 2006
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Molecular Cancer Therapeutics, 2013
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Papers by Andrew Redfern
Cancer Research, 2021
Breast cancer affects one in seven women and kills more than 600,000 women each year. Compared to... more Breast cancer affects one in seven women and kills more than 600,000 women each year. Compared to the 98.9% survival rate of patients with localized breast cancer, the five-year survival rate of patients with distant metastasis is only 28.1%. Using cDNA arrays and patient datasets, we found that a protein called bone morphogenetic protein 4 (BMP4) is downregulated in highly metastatic breast cancer cells and in high-grade breast tumors. BMP4 is a ligand in the TFGβ/BMP cytokine family and has the capacity to suppress TGFβ signaling through induction of SMAD6 and SMAD7. In several different preclinical metastasis models, we have shown that restored BMP4 expression in breast cancer cells with metastatic capacity does not alter primary tumor growth but results in significantly reduced metastasis to lung, liver and spine (p< 0.01), following primary tumor resection. MDA-MB-231HM cells with or without enforced BMP4 expression were recovered from primary mammary tumors and subjected to...
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Interpretation of SEIFA variables. Table S1. Characteristics of the Aboriginal (n = 129) and non-... more Interpretation of SEIFA variables. Table S1. Characteristics of the Aboriginal (n = 129) and non-Aboriginal (n = 131) women with FFDM mammograms. Table S2. Univariate regression results for absolute dense area and percentage dense area among Aboriginal (n = 129) and non-Aboriginal (n = 131) women with FFDM mammograms. Table S3. Regression results for absolute dense area among Aboriginal (n = 387) and non-Aboriginal (n = 430) women with FFDM mammograms where SEIFA and ARIA scores are based on full residential address. Table S4. Regression results for percentage dense area among Aboriginal (n = 387) and non-Aboriginal (n = 430) women with FFDM mammograms where SEIFA and ARIA scores are based on full residential address. (DOCX 39 kb)
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Breast Cancer Research, 2019
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Cancer Research, 2016
Background: Intravenous (IV) trastuzumab has proven clinical benefits in patients (pts) with huma... more Background: Intravenous (IV) trastuzumab has proven clinical benefits in patients (pts) with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). The use of pertuzumab, which targets HER2 through an independent epitope to that of trastuzumab, in combination with IV trastuzumab and docetaxel has shown improved efficacy with acceptable toxicity in metastatic (m) BC. Subcutaneous (SC) and IV trastuzumab formulations have shown comparable efficacy. This study aimed to assess the safety, tolerability, and efficacy of combining IV pertuzumab with SC trastuzumab and a taxane, as 1st-line therapy in pts with HER2+ mBC, a combination for which results have not previously been reported. Here we present demographics and interim safety data. Methods: This is an open-label, multicentre, phase IIIb study. The primary objective was the safety and tolerability of IV pertuzumab with SC trastuzumab and investigator's choice of taxane. Pts aged ≥18 years with confirmed HER2...
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Cancer Research, 2011
Background The use of trastuzumab (H)-based therapy for HER2−positive BC has significantly altere... more Background The use of trastuzumab (H)-based therapy for HER2−positive BC has significantly altered outcomes. Yet up to 64% of metastatic patients (pts) fail to respond (Robert JCO 2006) and most pts will progress within 24–42 months (m) following an initial response for metastatic disease. Preclinical data suggest several in vitro resistance mechanisms but confirmatory in vivo data are lacking, preventing optimal personalized care. This ongoing proof-of-concept study examines serial bx in pts with HER2−positive metastatic BC in order to assess BM profiles across multiple lines of treatment. Methods: Key eligibility criteria include: centrally confirmed HER2 status, minimum of 1 disease site considered suitable for serial bx, normal coagulation profile and cardiac function, prior adjuvant/neoadjuvant taxane and H completed ≥12 m and ≥6 m respectively, ECOG ≤2. Pts receive q3wk H with clinician choice of taxane (docetaxel 75–100 mg/m2 q21, paclitaxel 80 mg/m2 weekly or 175 mg/m2 q21 [...
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Epithelial to mesenchymal transition (EMT) is the process whereby sessile, polarised epithelial c... more Epithelial to mesenchymal transition (EMT) is the process whereby sessile, polarised epithelial cells alter the expression of key adhesion and regulatory molecules, and gain the ability to survive and migrate as single cells. While this process occurs normally in development we now recognize that metastasis has many elements in common with developmental EMT, which is subverted by carcinoma cells to allow metastatic spread. Cancer cells rarely undergo a full conversion to them esenchymal phenotype, and instead appear to occupy a range of positions along a phenotypic spectrum between epithelial and mes-enchymal states. The Mitogen Activated Protein Kinase (MAPK) signaling cascade, which signals through MEK and ERK proteins, has previously been implicated in the regulation of EMT. In this work, we have used previously established breast cancer derived cell line models of epithelial-mesenchymal plasticity and applied RNA sequencing to measure transcriptional changes that occur as cells ...
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Epithelial to mesenchymal transition (EMT) is the process whereby sessile, polarised epithelial c... more Epithelial to mesenchymal transition (EMT) is the process whereby sessile, polarised epithelial cells alter the expression of key adhesion and regulatory molecules, and gain the ability to survive and migrate as single cells. While this process occurs normally in development we now recognize that metastasis has many elements in common with developmental EMT, which is subverted by carcinoma cells to allow metastatic spread. Cancer cells rarely undergo a full conversion to them esenchymal phenotype, and instead appear to occupy a range of positions along a phenotypic spectrum between epithelial and mes-enchymal states. The Mitogen Activated Protein Kinase (MAPK) signaling cascade, which signals through MEK and ERK proteins, has previously been implicated in the regulation of EMT. In this work, we have used previously established breast cancer derived cell line models of epithelial-mesenchymal plasticity and applied RNA sequencing to measure transcriptional changes that occur as cells ...
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Poster Session Abstracts, 2020
Breast cancer (BrCa) incidence is lower in Aboriginal Australian women but carries more than doub... more Breast cancer (BrCa) incidence is lower in Aboriginal Australian women but carries more than double the risk of death. However, rates of Aboriginal BrCa diagnosis are increasing, hypothesized to be due to lifestyle changes. Thus, with rising incidence and higher mortality, deaths due to BrCa are rising in absolute terms in Aboriginal women. Studies of this higher death rate thus far have been epidemiological, exploring factors such as higher stage at diagnosis, younger age, increased co-morbidities, remoteness, socioeconomic disadvantage, and access to culturally sensitive health services. Collectively, these factors do not fully explain this higher rate of death. However, no study has explored any aspect of tumour or host biology in Aboriginal BrCa. We have studied a cohort of 262 Aboriginal women identified from the WA Cancer Registry comprising all cases diagnosed with BrCa in Western Australia for the period 2001-2016. Remoteness, in the form of an Accessibility/Remoteness Index of Australia (ARIA) score, was calculated from address at the time of diagnosis for each patient. All participants were then matched 2:3 by remoteness of residence and age with non-Aboriginal patients. Mortality data including cause was collected through state Death Registry linkage. Basic tumour parameters as well as receptor expressions were extracted from routine pathology assessment data with extra sections scored for missing values when tissue was available. A BrCa sub-type was assigned to each participant based on a modified IHC4 method using tumour grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status. A significant detriment was found for Indigenous BrCa mortality, univariate hazard ratio (HR)=4.19 (95% confidence interval (CI) 2.42 - 7.25, p Citation Format: Andrew David Redfern, Lisa J Spalding, Edward YC Lee, Connor F Redfern, Leanne Pilkington, Max Bulsara, Richard Trevithick, Katie Meehan. Aggressive tumour biology contributes to poor breast cancer outcomes for indigenous Australians [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-09.
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Blood, 2021
Background: Sickle cell disease (SCD) is caused by polymerization of sickle hemoglobin (HbS), res... more Background: Sickle cell disease (SCD) is caused by polymerization of sickle hemoglobin (HbS), resulting in red blood cell (RBC) sickling, RBC destruction, vaso-occlusion and end-organ damage. GBT021601 is an oral, small molecule, next-generation HbS polymerization inhibitor. Similar to voxelotor, the first generation HbS polymerization inhibitor, GBT021601 increases hemoglobin-oxygen (Hb-O2) affinity and stabilizes hemoglobin (Hb) in the oxy-hemoglobin (oxyHb) state, thereby inhibiting polymerization of HbS in RBCs. The fraction of Hb bound to drug - (Hb occupancy) approximates the oxyHb molecules per RBC. Compared to voxelotor, GBT021601 has the potential to achieve higher Hb occupancies. GBT021601 achieves greater exposures per dose and is more potent as measured by improvements in hematological parameters in an in vivo SCD mouse model (Dufu, Kobina 2020). We hypothesized that GBT021601 would achieve a substantial reduction in RBC hemolysis and increase in hemoglobin while maintai...
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Palbociclib was approved in the United States in 2015 to treat estrogen receptor-positive/human e... more Palbociclib was approved in the United States in 2015 to treat estrogen receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This study evaluated outcomes and safety in patients treated with palbociclib in Australia and India with hormone receptor-positive (HR+)/HER2- ABC before palbociclib became commercially available. Postmenopausal women (≥18 years) with HR+/HER2- ABC who were appropriate candidates for letrozole therapy received palbociclib 125 mg once daily for 21 days followed by 7 days off, and letrozole 2.5 mg once daily (continuous). Safety, tumor response, and patient-reported outcomes (Australian cohort) were evaluated. In total, 252 patients received palbociclib plus letrozole (Australia, n = 152; India, n = 100). More patients in the Australian versus Indian cohort had received prior chemotherapy (advanced/metastatic setting: 45.9% vs. 32.0%), endocrine therapy (advanced/metastatic setting: 63.2% vs. 54.3%), and advanced/metastatic therapies (61.8% vs. 31.0%). The most frequently reported all-grade palbociclib-related treatment-emergent adverse events were neutropenia (66.7%), fatigue (35.3%), and stomatitis (26.6%); grade 3/4 neutropenia was reported as palbociclib-related in 62.7% of patients. Febrile neutropenia was reported in six patients (2.4%). Eight patients (3.2%) discontinued because of an adverse event. The objective response rate was 19.4% (95% CI, 14.7%-24.9%) overall and 2.3% in Australian patients with ≥2 lines of prior therapy for metastatic disease. Patient-reported quality of life scores were maintained throughout the study. In an expanded access setting in Australia and India, palbociclib plus letrozole was well tolerated in patients with HR+/HER2- ABC, with a safety profile consistent with previous reports.
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<jats:title>Abstract</jats:title> <jats:p>Background: Inclacumab, a fully human... more <jats:title>Abstract</jats:title> <jats:p>Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD.</jats:p> <jats:p>Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported.</jats:p> <jats:p>Results: Fifteen subjects received a single dose of inclacumab 20 mg/kg (n=6) or 40 mg/kg (n=9). Fourteen subjects completed the study. Median age was 42 years (range 22 - 52 years); median body weight was 73.6 kg (range 63.7 - 89.3 kg). Through the pre-specified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) &amp;gt; grade 1 (mild) nor dose-limiting toxicities were reported. During the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were headache, myalgia, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean C max following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated predose PLA formation was 33 - 39% across cohorts and decreased to 9-14% at 2 hours following end of infusion. PLA inhibition was sustained through at least 12 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects.</jats:p> <jats:p>Conclusions: Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects. Durable inhibition of TRAP-activated PLA formation was observed through at least 12 weeks, consistent with prior observations. Overall, the results support a Phase 3 dose of 30 mg/kg every 12 weeks in patients with SCD-related VOCs.</jats:p> <jats:p>Funding: This study was supported by Global Blood Therapeutics.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Mayer: Global Blood Therapeutics: Consultancy. Redfern: Linear Clinical Research: Current Employment; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board; Eisai: Other: Advisory Board; Astra Zeneca: Other: Advisory Board. Geng: Global Blood Therapeutics: Current Employment. Shi: Global Blood Therapeutics: Current Employment. van Zutphen-van Geffen: Global Blood Therapeutics: Consultancy. Kuan: Global Blood Therapeutics: Consultancy. Koeck: Global Blood Therapeutics: Consultancy. Kastrissios: Global Blood Therapeutics: Consultancy. Patel: Global Blood Therapeutics: Consultancy. Davis: Global Blood Therapeutics: Current Employment. Yue: Global Blood Therapeutics: Current Employment.</jats:p> </jats:sec>
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Cancer Research, 2022
Background Estrogen receptor (ER) positive breast cancers (BCs) are less likely to relapse than o... more Background Estrogen receptor (ER) positive breast cancers (BCs) are less likely to relapse than other types, due to a lower propensity to disseminate and to sensitivity to anti-estrogen drugs in the adjuvant setting. However, combined analysis of DNA mutation and mRNA expression profiles in BC identifies a number of Integrative Clusters (IntClus), one of which, IntClus2, is characterized by ER positivity but high relpase and mortality. A hallmark of IntClus2 tumours is an amplification of chromosome 11, at the center of which lies the gene for the protein AAMDC. Pre-clinical research shows this protein to drive proliferation, migration, colony formation, switching between glucose and lipid metabolism, folate metabolism and anti-estrogen resistance. We postulated that resultant clinical behaviours could include; high relapse and mortality, anti-estrogen resistance, an interaction with the protective effect on relapse from statins and sensitivity to fluorouracil (FU)-based therapies. ...
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Supplemental Material for Measuring height and weight as part of routine mammographic screening f... more Supplemental Material for Measuring height and weight as part of routine mammographic screening for breast cancer by Ellie Darcey, Ravi Ambati, Helen Lund, Andrew Redfern, Christobel Saunders, Sandra Thompson, Elizabeth Wylie and Jennifer Stone in Journal of Medical Screening
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Pathology, 2022
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Annals of Oncology, 2019
Abstract Background In Australia, Indigenous people are natives and custodians of land. The morta... more Abstract Background In Australia, Indigenous people are natives and custodians of land. The mortality risk is more than double in Indigenous breast cancer women as compared to non- Indigenous women but carries lower incidence risk. Between 2001 and 2010 Indigenous Western Australian women who developed breast cancer were four times more likely to die of the disease than non-Indigenous women of the same age. The data is scarce but many factors are being studied. The effect of remoteness on mortality of indigenous women still needed to be established. The aim is to analyse remoteness as a factor causing effect on survival in Indigenous breast cancer women. Methods The data is collected retrospectively from Western Australian cancer Registry mostly, among other sources. A cohort of 100 patients was selected from database including half of indigenous and half non-indigenous women (1:1). At time of writing, 37 Indigenous and 33 Non–Indigenous breast cancer women data was available. The data collected, to analyze the median survival time (months) of patients with respect to Distance (Metropolitan vs Rural) and Indigenous & Non-Indigenous status. Results In survival analysis, it has been observed that both indigenous and non-indigenous who live in metropolitan showed better 10 year survival; 184 months while who were in rural area showed reduced median survival time 130 months and differences among them was found to be significant (p = 0.03), suggesting better survival was associated with patients who live in metropolitan area. However, on analyzing the survival of Indigenous patients with respect to distance, it wasn’t statistically significant (p = 0.19) but still showed higher median survival for patients living in metropolitan area (153 months) as compared to remote rural areas (110 months). Further analyzing indigenous breast cancer patients outcomes with respect to metro area (153 months), 1000km or less and greater then 1000km (87 months); higher survival benefit trend for patient’s living close to metro area. Conclusions The data suggest that the Indigenous breast cancer women have inferior survival outcomes with respect to distance from metropolitan area, highlighting a strong co-relation of remoteness and survival disadvantage. Legal entity responsible for the study A. Khan, A. Redfern. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.
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Molecular Cancer Therapeutics, 2013
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Cell Communication and Signaling, 2015
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My Publications by Andrew Redfern
Papers by Andrew Redfern