Alexander W. Wyatt
A5055207707- Prostate Cancer Treatment and Research
- Cancer Genomics and Diagnostics
- Cancer, Lipids, and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Prostate Cancer Diagnosis and Treatment
- Genetic factors in colorectal cancer
- Bladder and Urothelial Cancer Treatments
- Epigenetics and DNA Methylation
- PARP inhibition in cancer therapy
- Molecular Biology Techniques and Applications
- Renal cell carcinoma treatment
- Estrogen and related hormone effects
- Cancer Immunotherapy and Biomarkers
- RNA modifications and cancer
- Cancer, Hypoxia, and Metabolism
- Urinary and Genital Oncology Studies
- Ocular Disorders and Treatments
- Glutathione Transferases and Polymorphisms
- Cancer-related gene regulation
- Cerebrovascular and genetic disorders
- Radiomics and Machine Learning in Medical Imaging
- Renal and related cancers
- Kruppel-like factors research
- Mass Spectrometry Techniques and Applications
- Multiple Myeloma Research and Treatments
University of British Columbia
2016-2025
Canada's Michael Smith Genome Sciences Centre
2021-2025
The Prostate Centre
2015-2023
University of British Columbia Hospital
2018
Vancouver General Hospital
2014-2018
Tampere University
2017
BC Cancer Agency
2013-2017
Oregon Health & Science University
2017
University of California, Davis
2017
Douglas College
2017
Abstract Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC abiraterone or enzalutamide and performed whole-exome deep targeted 72-gene sequencing of plasma cell-free DNA prior therapy. For these agents, which have never been directly compared, time progression was similar. Defects BRCA2 ATM were strongly associated poor clinical outcomes...
Although novel agents targeting the androgen-androgen receptor (AR) axis have altered treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with to abiraterone acetate and enzalutamide mCRPC patients.Plasma was collected from 62 patients ceasing (n = 29), 19), or other 14) due disease progression....
Abstract Mechanisms controlling the emergence of lethal neuroendocrine prostate cancer (NEPC), especially those that are consequences treatment-induced suppression androgen receptor (AR), remain elusive. Using a unique model AR pathway inhibitor–resistant cancer, we identified AR-dependent control neural transcription factor BRN2 (encoded by POU3F2) as major driver NEPC and aggressive tumor growth, both in vitro vivo. Mechanistic studies showed directly suppresses transcription, which is...
Background: Real-time knowledge of the somatic genome can influence management patients with metastatic castration-resistant prostate cancer (mCRPC). While routine tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample genome. However, no systematic comparisons matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling replace need for direct sampling. Methods: We targeted sequencing...
Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank transplantable patient-derived xenografts capture biologic molecular heterogeneity currently confounding prognostication therapy development. Xenografts preserved histopathology, genome architecture, global gene expression donor tumors. Moreover, their aggressiveness matched patient observations, response to androgen withdrawal correlated with tumor...
The molecular landscape underpinning response to the androgen receptor (AR) antagonist enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) is undefined. Consequently, there an urgent need for practical biomarkers guide therapy selection and elucidate resistance. Although tissue biopsies are impractical perform routinely majority of mCRPC, analysis plasma cell-free DNA (cfDNA) has recently emerged as a minimally invasive method explore tumor...
More potent targeting of the androgen receptor (AR) in advanced prostate cancer is driving an increased incidence neuroendocrine (NEPC), aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 RB1 aberration. We modeled development NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft found that placental gene PEG10 de-repressed during adaptive response AR interference subsequently...
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination (HRR) such as
The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, binding site receptor, competing with endogenous androgenic steroids. Several mutations in this have been associated poor prognosis resistance to conventional cancer drugs. In order develop an effective CRPC therapy, it crucial understand effects...
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary point, may be published when key planned co‐primary or secondary analyses are not yet available. Trial Updates provide an opportunity to disseminate additional results from studies, in JCO elsewhere, for which point has already been reported. STOMP and ORIOLE trial reports suggested metastasis-directed therapy (MDT) oligometastatic castration-sensitive...
Abstract Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating DNA (ctDNA) samples from 104 mUC patients, compare same-patient tissue obtained during invasive surgery. Patient ctDNA abundance independently prognostic for overall survival in patients...
No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility risk stratification unclear. Here, we intersect ctDNA%, treatment outcomes, clinical characteristics across 738 plasma samples from 491 male mCRPC patients two randomized multicentre phase II trials a prospective province-wide blood biobanking program. ctDNA% correlates...
[177Lu]Lu-prostate-specific membrane antigen (PSMA) therapy has a favorable toxicity profile in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasm (t-MN) been described after [177Lu]Lu-DOTATATE but not, to our knowledge, yet reported [177Lu]Lu-PSMA. This case series describes 5 mCRPC who developed t-MN [177Lu]Lu-PSMA at institution. Methods: In this single-center retrospective analysis, we reviewed all treated Patients biopsy-proven during...
The current paradigm of cancer care relies on predictive nomograms which integrate detailed histopathology with clinical data. However, when predictions fail, the consequences for patients are often catastrophic, especially in prostate where influence decision to therapeutically intervene. We hypothesized that high dimensional data afforded by massively parallel sequencing (MPS) is not only capable providing biological insights, but may aid molecular pathology tumours. assembled a cohort six...
Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool profile genome real-time, critically underexplored cancer.Experimental Design: We applied combination whole-exome sequencing targeted across 50 cancer driver genes plasma cell-free (cfDNA) from 51 patients...
Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs rising serum PSA levels, implicating AR full-length (ARFL) or variants (AR-Vs) disease progression.To define functional roles of ARFL and AR-Vs ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon-1, intron-1, exon-8 pre-mRNA knockdown alone AR-Vs, examined their effects three...