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Stanford Molecular and Cellular Characterization Laboratory

斯坦福大学分子和细胞表征实验室

基本信息

批准号：
9769651
负责人：
JAMES D. BROOKS
金额：
$ 98.35万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-16 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769651
关键词：
Address Basement membrane Biological Biological Markers Biology Biopsy Cancer Patient Carcinoma Cell Lineage Cells Clinical Clinical Trials DNA Sequence Alteration DNA copy number Data Death Rate Detection Development Diagnosis Drops Early treatment Epithelial Event Evolution Financial cost Formalin Freezing Gene Expression Gene Expression Profiling Genetic Diseases Genetic Transcription Genomics Gleason Grade for Prostate Cancer Glycoproteins Growth Heterogeneity Histologic Histology Indolent Laboratories Lesion Malignant Neoplasms Malignant neoplasm of prostate Molecular Molecular Genetics Morbidity - disease rate Morphology Nature Neoplastic Epithelial Cell Organ Outcome Ovary Paraffin Embedding Pathway interactions Patient-Focused Outcomes Patients Phenotype Phylogenetic Analysis Phylogeny Physicians Prostate Prostate-Specific Antigen Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Protein Glycosylation Proteins Proteome Proteomics Radical Prostatectomy Recurrence Sampling Screening for Prostate Cancer Screening procedure Sensitivity and Specificity Serum Specimen Technology Testing Tissue Embedding Tissues Transcript Trees Uncertainty adverse outcome base biological heterogeneity body system candidate marker clinical effect clinically relevant clinically significant cohort glycoproteomics improved men overtreatment prognostic prostate carcinogenesis protein expression public health relevance screening success tool transcriptome tumor

项目摘要

DESCRIPTION (provided by applicant): Recent suggests that in the U.S. prostate cancer is over-detected and over-treated resulting in significant morbidity and financial costs. These problems are the product of poor sensitivity and specificity serum Prostate Specific Antigen (PSA) as a screening tool, leading to many unnecessary biopsies that find small and predominantly indolent prostate tumors. While many prostate cancers should be managed with active surveillance, uncertainties surrounding available clinical tools of aggressiveness (such as PSA, Gleason score and clinical stage) will often drive patients and physicians to treatment. Attempts to improve prognostication using candidate biomarkers, mostly discovered from genomic analyses of large pieces of cancers, have had few successes, and available molecular tools provide only modest prediction at best. Clearly, a better understanding of the early molecular genetic events in prostate cancer is desperately needed. We hypothesize that early prostate cancer arises from definable molecular alterations in precursor lesions and progresses as a result of acquired lesions that confer aggressive features in a subpopulation of cells in precursor lesions and/or early tumors. In addition, we hypothesize that at each step, there are downstream molecular alterations that confer, in a probabilistic sense, the ability for some lesions to grow and spread and in others an indolent phenotype (dead end lesions). As such, defining the earliest genomic events, the evolutionary pathways to invasive carcinoma, the final constellation of genomic alterations, and the extent of genomic heterogeneity (the building blocks for evolution), should illuminate the key genomic features distinguishing good and bad outcome prostate cancer. In depth characterization of early lesions has been constrained by limitations of conventional histology tools (prostate cancer precursors can only be reliably identified in fixed tissues) and of available genomic and proteomic technologies (which do not work well on fixed tissues). To address the challenges we wil take advantage of technologies we have developed to analyze small samples in both fixed and frozen tissue to provide a complete picture of the early events in prostate carcinogenesis. We propose 1) to investigate the early genomic evolution of good and bad outcome prostate cancer in histologically defined prostate cancers and precursor lesions in fixed tissues; and 2) to define the genomic heterogeneity of good and bad outcome prostate cancer and the downstream consequences in transcript, protein and glycoprotein expression in frozen tissues. An integrated approach using fixed and frozen tissues will allow us to delineate the early genomic lesions in prostate cancer, define which are selected to evolve into more aggressive and which end up as non-aggressive (dead end) lesions, and characterize the downstream effects of these selected changes in cellular transcription, protein expression and protein glycosylation. A systematic study of the events in prostate cancer during its development and evolution will help address the issues of over- treatment by providing prognostic features and biomarkers that help select men for definitive treatment or observation.