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Aberrant Splice Variants as Potential Precision Biomarkers for Aggressive Prostate Cancers in African American Patients

异常剪接变异作为非洲裔美国患者侵袭性前列腺癌的潜在精确生物标志物

基本信息

批准号：
10252790
负责人：
Bi-Dar Wang
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MARYLAND EASTERN SHORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252790
关键词：
African American Alternative Splicing American Automobile Driving Biologic Characteristic Biological Biological Assay Biological Markers Biopsy Specimen Breast Cancer Etiology Cancer cell line Carcinoma Catalytic Domain Cell Line Cell Proliferation Cells Cessation of life Classification Clinical Colon DU145 Data Development Discrimination Disease Disease Progression Drug resistance Environmental Risk Factor European Evaluation Event Exhibits FGFR3 gene Fluorescent in Situ Hybridization Foundations Future Genes Genomics Goals Grant Hematologic Neoplasms Human Immunohistochemistry In Vitro Incidence Individual LNCaP Lead Length Link Malignant Neoplasms Malignant neoplasm of prostate Messenger RNA MicroRNAs Modeling Molecular Molecular Profiling Neoplasm Metastasis Neuroblastoma Oligonucleotides Oncogenic Oncoproteins PC3 cell line Patients Pharmaceutical Preparations Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphotransferases Pilot Projects Play Population Prognosis Property Prostate Protein Isoforms Proteins RNA Splicing Race Recurrence Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Sensitivity and Specificity Series Small Interfering RNA Socioeconomic Factors Socioeconomic Status Solid Solid Neoplasm Specimen Spliced Genes Structure TSC2 gene Testing Therapeutic Time Transcription Process Transfection Tumor Cell Line United States United States National Institutes of Health VCaP Validation Variant Western Blotting advanced prostate cancer cancer biomarkers cancer diagnosis cancer health disparity cytotoxicity design docetaxel ethnic difference genetic element genome-wide inhibitor/antagonist leukemia leukemia/lymphoma mRNA Precursor men migration mortality neoplastic cell novel novel marker novel therapeutic intervention overexpression potential biomarker precision medicine prostate cancer cell prostate cancer cell line racial and ethnic responders and non-responders small molecule inhibitor success therapeutic target therapeutically effective tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Prostate cancer (PCa) is now the most frequently diagnosed cancer and the second most common cause of cancer deaths in men in United States. Notably, African Americans (AAs) exhibited 1.6-fold higher incidence and 2.4-fold higher mortality rates compared to European Americans (EAs). Despite multiple socioeconomic factors postulated to explain the observed PCa disparities, higher recurrence and mortality rates remained even after adjustment of socioeconomic status in AAs, suggesting that intrinsic biological differences account for, at least, part of PCa disparities. Our previous genomic studies have revealed that intrinsic genomic differences do exist between AA and EA PCa. These genetic elements, including population-specific and -enriched microRNAs, mRNAs and alternative splicing variants, have been identified and were hypothesized to contribute to the differential PCa properties between AA and EA. In the pilot study, our preliminary results revealed ~2,500 differential splicing (DS) events occurring in AA and EA PCa. Among these DS genes, >70% of the genes were functionally linked to cancer diseases. These results lead to our hypothesis that aberrant mRNA splicing may play a critical but largely unknown role for driving the PCa disparities. Towards this hypothesis, we have performed RT-PCR validations and functional analyses of AA-enriched splice variants (such as PIK3CD, FGFR3, TSC2 and RASGRP2 splice variants) in PCa samples. Our preliminary results confirmed that these AA-enriched variants were highly expressed in AA PCa and contributed to more aggressive cancer phenotypes. In this proposal, we will focus on investigating the expression profiles of PIK3CD long and short splice variants (PIK3CD-L and PIK3CD-S) in a panel of PCa and other solid/hematologic tumor cell lines, and elucidating functional impacts of these splice variants in PCa aggressiveness and drug resistance. Guided by strong preliminary data, we propose to pursue three Specific Aims to character molecular functions of the PIK3CD splice variants underlying PCa aggressiveness: 1) Validate the expression profiles of PIK3CD splice variants in PCa specimens and cell lines derived from AA and EA patients; 2) Determine the functional roles of PIK3CD-S expression in disease aggressiveness and drug resistance in PCa and evaluate the feasibility of PIK3CD- S/PIK3CD-L ratios as potential biomarker; and 3) Screen for the effective therapeutic molecules (small molecule inhibitors, siRNAs and/or splice switching oligos) to reduce the cancer phenotypes in PIK3CD-S overexpressing cells. Collectively, our proposed research will broadly contribute to the field of cancer health disparities by characterizing the molecular signatures of aberrant splice variants in cancers (including PCa and other solid/hematologic tumors), and deciphering the molecular mechanisms of aberrant splicing underlying PCa aggressiveness (i.e. enhanced cell proliferation and invasion) and drug resistance. This proposal will allow us to further design for splice variant- specific siRNAs and screen for SMIs that can effectively inhibit the aggressive form of splice variants in PCa. These findings and efforts may facilitate the development of potential biomarkers and therapeutic strategy to treat aggressive PCa. Finally, the success of this SC1 proposal will set a strong foundation for the PI and his research team to further pursue a NIH competitive grant (i.e. R01 or R21) for future clinically-related studies.

项目总结/文摘