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2.
Cell ; 174(3): 758-769.e9, 2018 07 26.
Article in English | MEDLINE | ID: mdl-30033370

ABSTRACT

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.


Subject(s)
Genomic Structural Variation/genetics , Prostatic Neoplasms/genetics , Aged , Aged, 80 and over , BRCA2 Protein/metabolism , Cyclin-Dependent Kinases/metabolism , DNA Copy Number Variations , Exome , Gene Expression Profiling/methods , Genomics/methods , Humans , Male , Middle Aged , Mutation , Neoplasm Metastasis/genetics , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Tandem Repeat Sequences/genetics , Tumor Suppressor Protein p53/metabolism , Whole Genome Sequencing/methods
3.
J Nucl Med ; 56(3): 354-60, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25635138

ABSTRACT

UNLABELLED: (18)F-fluoride PET quantitatively images bone metabolism and may serve as a pharmacodynamic assessment for systemic therapy such as dasatinib, a potent SRC kinase inhibitor, with activity in bone. METHODS: This was an imaging companion trial (American College of Radiology Imaging Network [ACRIN] 6687) to a multicenter metastatic castration-resistant prostate cancer (CRPC) tissue biomarker-guided therapeutic trial (NCT00918385). Men with bone metastatic CRPC underwent (18)F-fluoride PET before and 12 weeks after initiation of dasatinib (100 mg daily). Dynamic imaging was performed over a 15-cm field of view for trial assessments. The primary endpoint was to determine whether changes in (18)F-fluoride incorporation in tumor and normal bone occurred in response to dasatinib. Other endpoints included differential effect of dasatinib between (18)F-fluoride incorporation in tumor and normal bone, (18)F-fluoride transport in bone metastases, correlation with progression-free survival (PFS), prostate-specific antigen, and markers of bone turnover. RESULTS: Eighteen participants enrolled, and 17 underwent interpretable baseline (18)F-fluoride PET imaging before initiation of dasatinib. Twelve of 17 patients underwent on-treatment PET imaging. Statistically significant changes in response to dasatinib were identified by the SUVmaxavg (average of maximum standardized uptake value [SUVmax] for up to 5 tumors within the dynamic field of view) in bone metastases (P = 0.0002), with a significant differential (18)F-fluoride PET response between tumor and normal bone (P < 0.0001). Changes in (18)F-fluoride incorporation in bone metastases had borderline correlation with PFS by SUVmaxavg (hazard ratio, 0.91; 95% confidence interval, 0.82-1.00; P = 0.056). Changes by SUVmaxavg correlated with bone alkaline phosphatase (P = 0.0014) but not prostate-specific antigen (P = 0.47). CONCLUSION: This trial provides evidence of the ability (18)F-fluoride PET to delineate treatment response of dasatinib in CRPC bone metastases with borderline correlation with PFS.


Subject(s)
Antineoplastic Agents/therapeutic use , Fluorine Radioisotopes , Positron-Emission Tomography , Prostatic Neoplasms, Castration-Resistant/diagnostic imaging , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Biopsy , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Bone and Bones/pathology , Dasatinib , Disease-Free Survival , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Neoplasm Metastasis , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Kinase Inhibitors/therapeutic use , Receptors, Androgen/metabolism , Tomography, X-Ray Computed , Treatment Outcome
4.
Mol Cancer Ther ; 11(7): 1500-1509, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22351745

ABSTRACT

Despite advances in contemporary chemotherapeutic strategies, long-term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. To validate our oxaliplatin sensitivity signature, patient-derived colorectal cancer explants (PDCCE) were developed in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (sensitivity = 87.5%; specificity = 100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Organoplatinum Compounds/pharmacology , Animals , Cell Line, Tumor , Cluster Analysis , Disease Models, Animal , Gene Expression Profiling , Humans , Mice , Oxaliplatin , Prognosis , Transplantation, Heterologous
5.
Urology ; 66(2): 386-91, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16098367

ABSTRACT

OBJECTIVES: To test the hypothesis that chromogranin A (CgA) levels are prognostic in patients with metastatic hormone-refractory prostate cancer (HRPC). The extent of neuroendocrine differentiation in prostate cancer correlates with aggressive disease and with progression to HRPC. Plasma CgA levels in patients with prostate cancer may reflect the extent of the tumor neuroendocrine phenotype. METHODS: Pretreatment plasma was collected from 390 patients with metastatic HRPC enrolled in the Cancer and Leukemia Group B (CALGB) 9480 trial, a study of three different doses of suramin. Plasma CgA levels were determined in 321 samples in duplicate using a quantitative sandwich immunoassay. The proportional hazards model was used to assess the prognostic significance of CgA in predicting overall survival. RESULTS: The median plasma CgA level was 12 U/L (interquartile range 7.7 to 19.3). In univariate analysis, plasma CgA correlated inversely with survival times, with a survival time of 17 months for low CgA (less than 12 U/L, 95% CI 14 to 19) compared with 11 months for high CgA (95% CI 8 to 14, P = 0.014) and at all exploratory cutpoints, including CgA of 9.5 U/L or less versus greater than 9.5 U/L, with survival of 19 months compared with 12 months (P = 0.0015). In multivariate models (adjusting for performance status, prostate-specific antigen, and lactate dehydrogenase), the plasma CgA levels remained predictive of overall survival. CONCLUSIONS: These results support the hypothesis that serum CgA levels correlate with outcome in patients with HRPC, although the clinical significance needs to be established in confirmatory studies before incorporation of CgA measurements in clinical practice.


Subject(s)
Adenocarcinoma/blood , Adenocarcinoma/mortality , Chromogranins/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/mortality , Adenocarcinoma/drug therapy , Aged , Chromogranin A , Clinical Trials, Phase III as Topic , Hormones/therapeutic use , Humans , Male , Prognosis , Prostatic Neoplasms/drug therapy , Randomized Controlled Trials as Topic , Survival Rate
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