A5079338108- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Advanced Proteomics Techniques and Applications
- Protein Degradation and Inhibitors
- Estrogen and related hormone effects
- Cancer, Hypoxia, and Metabolism
- Molecular Biology Techniques and Applications
- Hormonal and reproductive studies
- Cancer Genomics and Diagnostics
- Radiopharmaceutical Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Prostate Cancer Diagnosis and Treatment
- Advanced Breast Cancer Therapies
- Angiogenesis and VEGF in Cancer
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Mass Spectrometry Techniques and Applications
- Epigenetics and DNA Methylation
- Cancer Cells and Metastasis
- Cancer-related gene regulation
- Lung Cancer Research Studies
- Receptor Mechanisms and Signaling
- Cancer Immunotherapy and Biomarkers
Fred Hutch Cancer Center
2016-2025
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2006-2024
University of Washington
2006-2023
Cancer Research Center
2006-2023
Medical College of Wisconsin
2023
Memorial Sloan Kettering Cancer Center
2023
Medical College of Wisconsin Cancer Center
2023
Seattle University
2023
Clinical Research Management
2021-2023
Centro Regional de Derechos Humanos y Justicia de Género, Corporación Humanas
2023
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about impact this heterogeneity on clinical outcome. Here, we report and transcriptomic analysis 429 patients with castration-resistant (mCRPC) linked longitudinal outcomes, integrating findings from whole-exome, transcriptome, histologic analysis. For 128 treated a first-line next-generation androgen receptor signaling inhibitor (ARSI;...
Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation constitutively active splice variants, but mechanisms by which variants could mediate such effects not fully understood. Here we have identified what believe be a novel human variant in exons 5, 6, 7 deleted (ARv567es) demonstrated this can contribute progression xenograft...
Abstract Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression prostatic androgen activity at target tissue and molecular level. We determined consistency medical castration in suppressing levels androgen-regulated gene expression. expression (by microarray profiling, quantitative reverse transcription-PCR, immunohistochemistry) were measured samples from a clinical...
Abstract TMPRSS2 is an androgen-regulated cell-surface serine protease expressed predominantly in prostate epithelium. highly localized high-grade cancers and the majority of human cancer metastases. Through generation mouse models with a targeted deletion Tmprss2, we demonstrate that activity this regulates cell invasion metastasis to distant organs. By screening combinatorial peptide libraries, identified spectrum substrates include pro-hepatocyte growth factor (HGF). HGF activated by...
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of progression and mechanisms therapeutic resistance. We conducted deep phenotypic characterization CRPC metastases patient-derived xenograft (PDX) lines using whole genome RNA sequencing, gene set enrichment analysis immunohistochemistry. Our analyses revealed five mCRPC phenotypes based on the expression well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: (i) AR-high...
Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression (PC) tissue.Following generation validation of a potentially novel antibody for IHC, protein was determined 358 primary samples 293 metastatic biopsies. Associations disease...
Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that frequently disrupted in tumorigenesis and acts multiple cell types to suppress cycle progression. The role of RB progression, however, poorly defined. Here, we have identified critical for protecting against progression through regulation targets distinct from control. In analyses human prostate cancer samples, loss was infrequently observed primary disease predominantly associated with transition the incurable,...
A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression ETS transcription factor, ERG; however, functional significance this event is poorly understood. We report here that up-regulation ERG transcript sufficient for initiation neoplasia. In agreement with measurements transcripts, we found protein expressed neoplastic epithelium. Overexpression cell lines increased invasion. Moreover, targeted expression vivo luminal epithelial...
BACKGROUND Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long-term durable remissions. Clinically relevant preclinical models needed to increase our understanding of biology this malignancy evaluate new agents might provide effective treatment. Our objective was establish characterize patient-derived xenografts (PDXs) from advanced (PC) investigation evaluation treatment modalities. METHODS Samples PC obtained primary at...
To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing 23 derived from 16 different lethal tumors three high-grade primary carcinomas. All were propagated in mice as xenografts, designated LuCaP series, model phenotypic variation, such responses cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, able take...
Abstract A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 60) cancers are hypermutated, all mismatch repair gene mutations microsatellite instability (MSI). Mutations frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels differences in the hypermutation compared with other MSI-associated cancers.
Abstract Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript protein abundance in spatially-distinct regions mPCs. By assessing multiple discrete areas across metastases, find high level intra-patient homogeneity with respect tumor phenotype. there are notable exceptions including tumors comprised low androgen...
Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. also influence cell plasticity are frequently lost in PCs neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant urgently needed. Using deep genomic profiling 410 metastatic biopsies, we determine relationships between combined PC phenotypes. Notably, 40% TP53/RB1-deficient tumors classified as AR-active adenocarcinomas, indicating NE differentiation...
Abstract Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism adaptive resistance targeted therapy in cancer. An archetypal example development neuroendocrine prostate cancer (NEPC) after treatment adenocarcinoma (PRAD) with inhibitors androgen signaling. NEPC aggressive variant that aberrantly expresses genes characteristic (NE) tissues and no longer depends on androgens. Here, we investigate epigenomic basis this by profiling histone...
Abstract Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes a range human NECs show convergence to activation common epigenetic program. With particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), analyze cell lines, patient-derived xenograft (PDX) models samples existence two distinct NEPC...
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface for therapeutic targeting in cancer. Here, we report broad expression STEAP1 relative to prostate-specific membrane (PSMA) lethal metastatic cancers and development STEAP1-directed chimeric receptor (CAR) T therapy. CAR cells demonstrate reactivity low density, antitumor activity across cancer models, safety human knock-in mouse model. escape recurrent mechanism treatment resistance associated with diminished...
Adenocarcinomas of the prostate can be categorized into tumor grades based on extent to which cancers histologically resemble normal glands. Because are surrogates intrinsic behavior, characterizing molecular phenotype grade is potential clinical importance. To identify alterations underlying cancer grades, we used microdissection obtain specific cohorts cells corresponding most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each sample with...
Expression levels of mRNA and protein by cell types exhibit a range correlations for different genes. In this study, we compared abundance several cluster designation (CD) genes determined gene arrays using magnetic sorted laser-capture microdissected human prostate cells with expression the respective CD proteins immunohistochemical staining in major – basal epithelial, luminal stromal fibromuscular, endothelial precursor/stem carcinoma cells. Immunohistochemical stains tissues from more...