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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：
10466902
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10466902
关键词：
African American African American population 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 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 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 disease prognosis docetaxel ethnic difference genetic element genome-wide inhibitor 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.

项目摘要/摘要前列腺癌(PCA)是目前诊断最多的癌症，也是第二大癌症美国男性癌症死亡的常见原因。值得注意的是，非裔美国人(AA) 与欧洲相比，发病率和死亡率分别高出1.6倍和2.4倍美国人(EA)。尽管假设有多种社会经济因素可以解释观察到的即使在调整后，PCA差异、更高的复发率和死亡率仍然存在 AAS的社会经济地位，表明内在的生物差异解释了，在最不重要的是，PCA差异的一部分。我们之前的基因组研究表明，在人类和人类之间确实存在内在的基因组差异 AA和EA PCA。这些遗传因素，包括种群特异性和富集性已经确定了microRNAs、mRNAs和选择性剪接变异体，并假设有助于AA和EA之间不同的PCA属性。在试行阶段研究表明，我们的初步结果揭示了大约2,500个差异剪接(DS)事件在AA中发生和EA PCA。在这些DS基因中，70%的基因在功能上与癌症有关疾病。这些结果导致了我们的假设，即异常的mrna剪接可能在但在推动PCA差异方面扮演的角色却鲜为人知。针对这一假设，我们进行了RT-PCR验证和功能分析富含AA的剪接变体(如PIK3CD、FGFR3、TSC2和RASGRP2剪接变体) PCA样本。我们的初步结果证实，这些富含AA的变体是高度在AA-PCa中表达，并有助于更具侵袭性的癌症表型。在这份提案中，我们将重点研究PIK3CD长和短剪接变异体的表达谱 (PIK3CD-L和PIK3CD-S)在一组PCa和其他实体/血液肿瘤细胞系中，以及阐明这些剪接变体在前列腺癌侵袭性和药物中的功能影响抵抗。在强劲的初步数据指导下，我们建议实现三个具体目标： PIK3CD剪接变异体在PCa侵袭性中的分子功能特征：1) 验证PIK3CD剪接变异体在前列腺癌标本和细胞系中的表达谱 2)检测PIK3CD-S表达在AA和EA患者中的功能作用 PCa的疾病侵袭性和耐药性，并评价PIK3CD的可行性。 S/PIK3CD-L比值作为潜在的生物标志物；3)筛选有效的治疗分子 (小分子抑制剂、siRNA和/或剪接开关寡核苷酸)以减少癌症 PIK3CD-S过表达细胞的表型。总而言之，我们提议的研究将对癌症健康领域做出广泛贡献。肿瘤中异常剪接变异体分子特征的差异 (包括前列腺癌和其他实体/血液肿瘤)，并破译其分子机制 Pca侵袭性背后的异常剪接(即增强细胞增殖和侵袭性)和抗药性。这项提案将使我们能够进一步设计剪接变体- 特定的siRNA和筛选可以有效抑制侵袭性剪接形式的SMI PCA中的变种。这些发现和努力可能会促进潜力的开发治疗侵袭性前列腺癌的生物标志物和治疗策略。最后，这次SC1的成功该提案将为PI和他的研究团队进一步研究NIH奠定坚实的基础竞争性拨款(即R01或R21)，用于未来的临床相关研究。