A5066683906- Estrogen and related hormone effects
- Advanced Breast Cancer Therapies
- Cancer, Hypoxia, and Metabolism
- Lung Cancer Research Studies
- Cancer therapeutics and mechanisms
- Metal-Organic Frameworks: Synthesis and Applications
- Membrane-based Ion Separation Techniques
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- Cancer Treatment and Pharmacology
- Neuroblastoma Research and Treatments
- Microbial infections and disease research
- Cancer Cells and Metastasis
- Neuroendocrine Tumor Research Advances
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- RNA modifications and cancer
- PARP inhibition in cancer therapy
- Medical Imaging Techniques and Applications
- HER2/EGFR in Cancer Research
- Drug Transport and Resistance Mechanisms
- Cancer-related Molecular Pathways
- DNA and Nucleic Acid Chemistry
- Chronic Lymphocytic Leukemia Research
- Glioma Diagnosis and Treatment
Curtin University
2025
AstraZeneca (United Kingdom)
2010-2024
Johns Hopkins University
2022-2024
Harvard University
2016-2022
The University of Melbourne
2020-2021
University of Manchester
2005-2018
Cancer Research UK Manchester Institute
2005-2018
Research Network (United States)
2018
Boston Children's Hospital
2016
Manchester Academic Health Science Centre
2011-2013
Abstract Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation the receptor. The degree which all recurrent mutants can drive activities reduced sensitivity ER antagonists like fulvestrant is not established. In this report, we characterize spectrum from more than 900 patients. were detected 10%, D538G being most frequent (36%), followed by Y537S (14%). Several novel, activating also...
Abstract Purpose: The monocarboxylate transporter 1 (MCT1) inhibitor, AZD3965, is undergoing phase I evaluation in the United Kingdom. AZD3965 proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated therapeutic potential of small cell lung cancer (SCLC) seeking rationale for clinical testing this disease and putative predictive biomarkers trial use. Experimental Design: sensitivity was determined seven SCLC lines, normoxia hypoxia, a xenograft...
Abstract Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) the Phase 1 SERENA-1 study1,2 with dose-dependent safety profile. The 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) post-menopausal women HER2˗ BC disease recurrence or progression after ≤1 endocrine therapy (ET) advanced setting. Methods evaluated...
Background SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2− advanced breast cancer. Parts A B aim to determine the safety tolerability monotherapy define doses for clinical evaluation. Patients Methods Women aged 18 years or older metastatic recurrent cancer, refractory (or intolerant) therapy were assigned 25 mg up 450 once daily (QD; escalation) 75, 150, 300 QD (expansion). Safety tolerability, anti-tumor...
BUB1 is a budding yeast gene required to ensure that progression through mitosis coupled correct spindle assembly. Two related human protein kinases, Bub1 and BubR1, both localise kinetochores during mitosis, suggesting they play role in delaying anaphase until all chromosomes achieve correct, bipolar attachment the spindle. However, how activities of BubR1 are regulated by events their regulate downstream cell cycle not known. To investigate we characterised relative localisations presence...
The spindle checkpoint maintains genome stability by inhibiting Cdc20-mediated activation of the anaphase promoting complex/cyclosome (APC/C) until all chromosomes correctly align on microtubule apparatus via their kinetochores. BubR1, an essential component this checkpoint, localises to kinetochores and its kinase activity is regulated kinesin-related motor protein Cenp-E. BubR1 also inhibits APC/CCdc20 in vitro, thus providing a molecular link between kinetochore-microtubule interactions...
Abstract Purpose: Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer (SCLC), a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity tumor tissue identify drug targets and patient-relevant models interrogate novel therapies. Following our development circulating patient–derived explants (CDX) as that faithfully mirror patient disease, here we exploit CDX examine new therapeutic options SCLC. Experimental Design: We...
BackgroundOver the past decade, numerous reports describe generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling preclinical drug testing, requirement a biopsy limits available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive easier to obtain. Here,...
Herein we report the optimization of a series tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for treatment ER+ breast cancer. Structure based design together with systematic investigation each region molecular architecture led to identification N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated be highly potent SERD that...
Abstract Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for receptor–positive (ER+) breast cancer, as they achieve greater inhibition ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated preclinical pharmacology efficacy next-generation oral SERD camizestrant (AZD9833) assessed ER–co-targeting strategies by combining with CDK4/6 inhibitors (CDK4/6i) PI3K/AKT/mTOR-targeted in models...
Small cell lung cancer (SCLC) is a neuroendocrine characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified population of long-term tumor-propagating cells (TPCs) in mouse model SCLC. This population, marked high levels EpCAM CD24, also prevalent human primary SCLC tumors. Murine TPCs are numerous highly proliferative but not intrinsically chemoresistant, indicating that all clinical features linked TPCs. possess distinct transcriptional profile...
1032 Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+, HER2− advanced breast cancer (ABC). Parts A/B (escalation/expansion) assessed monotherapy and have been presented previously. C/D examine combination palbociclib; here we present mature data from 75 mg being the dose currently under investigation 3 studies SERENA-4 (NCT04711252) SERENA-6 (NCT04964934). Methods: The primary objective was to determine safety tolerability once...
Abstract Background PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico‐striato‐pallido‐thalamic loops differentially susceptible hyperdopaminergic effects with treatment. As the choice titration of symptomatic medications are guided primarily by symptoms, it is important understand their cognitive implications. Objective To investigate acute medication administration on executive function Parkinson's disease...
Abstract Targeting the estrogen receptor alpha (ERα) pathway is validated in clinic as an effective means to treat ER+ breast cancers. Here we present development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation ER antagonism cancer cell lines. However, upon dosing compound vivo observe - disconnect. lower than expected based on data. Investigation into potential causes for...
1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer disease recurrence or progression after ≤1 endocrine therapy the setting Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant clinically meaningful benefit vs F progression-free survival (PFS) overall...
Herein, we report the optimization of a meta-substituted series selective estrogen receptor degrader (SERD) antagonists for treatment ER+ breast cancer. Structure-based design together with use modeling and NMR to favor bioactive conformation led highly potent basic SERDs promising physicochemical properties. Issues hERG activity resulted in strategy zwitterion formation ultimately identification 38. This compound was shown be SERD capable effectively degrading ERα both MCF-7 CAMA-1 cell...
Abstract Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+/HER2− advanced breast cancer. Data for as monotherapy and combination palbociclib or abemaciclib have been presented previously.1–3 Here we present data from parts I J (dose ranging expansion, respectively), which examined the pan-AKT inhibitor capivasertib. Methods: The primary objective was to determine safety tolerability 75 mg once daily (QD) capivasertib 400 twice...
Despite their limited benefits and serious adverse effects, psychotropics remain frequently prescribed for neuropsychiatric symptoms (NPS) of dementia. Psychotropic polypharmacy, the use two or more concomitant psychotropic medications, is therefore not recommended people with The objectives this study were to investigate prevalence polypharmacy in Australians living dementia whose caregivers sought external NPS support from Dementia Support Australia (DSA; national provider support)...
Solid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target and promote apoptosis particularly appealing, as few normal tissues experience hypoxia. We have found the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes death human colorectal carcinoma small lung lines exposed This induction of was mediated through downregulation myeloid leukemia sequence 1 (Mcl-1),...
Objective National guidelines discourage routine chest radiographs (CXRs) to confirm suspected pneumonia in children managed as outpatients. However, limiting CXRs may lead antibiotic overuse. We examined the impact of and clinical suspicion on treatment for with pneumonia. Methods Children aged 3 months 18 years undergoing CXR a pediatric emergency department were prospectively enrolled. Before CXR, physicians indicated their initial plan antibiotics (yes or no) radiographic (<5%, 5–10%,...
Abstract Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) in Phase 2 clinical development for the treatment of ER+ HER2− breast cancer. Here we report data from Parts C D ongoing 1 study (SERENA-1) examining combination with palbociclib, together updated A B monotherapy. Methods: SERENA-1 (NCT03616587) open-label pre- post-menopausal women ER+, advanced cancer who have previously received ≥1 endocrine therapy ≤2 prior chemotherapies. Prior...