Race-related alternative splicing: novel targets in prostate cancer

种族相关的选择性剪接：前列腺癌的新靶点

基本信息

批准号：
10153715
负责人：
STEVEN R PATIERNO
金额：
$ 34.75万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-05 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153715
关键词：
Address Affect African American Alternative Splicing Automobile Driving Biological Biological Markers Biology Biopsy Cancer Biology Cancer Patient Castration Cell Line Cellular biology Characteristics Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Computer Analysis Data Data Set Development Diagnosis Disease Resistance Elements Event Exhibits Exons Frequencies Genetic Growth Health Services Accessibility Hormone Receptor Incidence Inflammation Intervention Maintenance Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of prostate Metastatic to Methods Modeling Molecular Oligonucleotides Oncogenic Outcome Pathway interactions Patients Pattern Pharmacology Population Prevention Prostatic Neoplasms RNA Splicing Race Reporter Research Scientist Signal Pathway Signal Transduction Small Interfering RNA Specimen Spliced Genes Testing Therapeutic Therapeutic Agents Time Tissues Variant Work base cancer health disparity castration resistant prostate cancer cohort differential expression effective therapy expectation health disparity improved malignant breast neoplasm men mortality novel novel strategies overexpression patient subsets population based pre-clinical precision medicine prostate cancer cell prostate cancer cell line prostate cancer progression racial diversity screening social health determinants tool tumor tumorigenesis

项目摘要

African American (AA) men exhibit 1.6-fold higher incidence and 2.4-fold higher mortality rates from prostate cancer (PCa) compared to white men. Although much of this disparity remains after controlling for factors related to social determinants of health, very few studies have used this population-based difference to identify molecular mechanisms of tumor aggressiveness. The proposed work addresses the urgent need to interrogate the molecular mechanisms driving the more aggressive PCa biology in AA men across the PCa progression continuum and to modulate such mechanisms for therapeutic application. Our data from evaluating PCa biopsy tissue from AA and white patients has led to the discovery of alternative splicing as a novel molecular mechanism underlying more aggressive PCa in AA men. Preliminary analysis has indicated that several of these race-related alternative splicing events track with increased growth and more aggressive invasion characteristics of PCa in AA men. Additional preliminary work has demonstrated our capability to generate the first significant collection of PCa patient-derived explants and the first establishment of PCa patient-derived explants from AA patients. We aim to extend our preliminary findings by 1) determining the pattern and frequency of candidate race- related splice variants across the PCa progression continuum, from localized PCa of varying degrees of aggressiveness to metastatic castration-resistant PCa, and defining the relationship between these variants and PCa cell biology, 2) assessing the effects of expression of particular race-related splice variants on mechanistic and functional biology in population-specific PCa cell lines and developing tools to pharmacologically modulate race-related oncogenic splice variants for therapeutic application using AA and white PCa cell lines and AA and white PCa patient-derived explants generated for this study and 3) defining the biological significance of cis- acting splicing elements and/or trans-acting splicing factors to driving the alternative splicing events specific to AA PCa. The rationale for and impact of this study are that it will further our understanding of the molecular mechanisms driving PCa disparities and aid in development of novel precision biomarkers for prostate tumor aggressiveness and/or therapeutic agents against aggressive PCa. Such precision medicine interventions will reduce PCa disparities for AAs and will likely have impact on a subset of patients of all races with aggressive PCa. New AA and white PCa bio-specimens, AA and white PCa patient-derived explants and derivative cell lines and splicing-related materials and methods and tools resulting from the proposed work will be available to the nationwide cohort of scientists conducting research on PCa disparities.

非裔美国人（AA）男性的发病率高1.6倍，死亡率高2.4倍与白人相比，前列腺癌（PCA）。尽管在控制之后，大部分差异仍然存在与健康有关的因素有关的因素，很少有研究使用这种基于人群的差异确定肿瘤侵袭性的分子机制。拟议的工作解决了迫切需要询问驱动PCA中AA男性更具侵略性PCA生物学的分子机制进展连续性并调节这种机制以进行治疗。我们评估来自AA和白人患者PCA活检组织的数据导致发现替代剪接是AA男性中更具侵略性PCA的一种新型分子机制。初步的分析表明，其中一些与种族有关的替代剪接事件跟踪随着增长的增加而 PCA在AA男子中的更具侵略性的入侵特征。其他初步工作已经证明我们能够产生第一个重要的PCA患者衍生的外植体的能力和第一个建立来自AA患者的PCA患者衍生的外植体。我们的目标是将初步发现扩展到1）确定候选人种族的模式和频率 - 从不同程度的局部PCA跨PCA进展连续体的相关剪接变体对转移性cast割PCA的侵略性，并定义这些变体与 PCA细胞生物学，2）评估特定种族相关剪接变体表达对机理的影响和人群特异性PCA细胞系中的功能生物学以及开发药理调节的工具使用AA和白色PCA细胞系以及AA和AA和AA和AA和为这项研究生成的白色PCA患者衍生的外植体和3）定义顺式的生物学意义作用拼接元件和/或反式拼接因子，以驱动特定于 AA PCA。这项研究的基本原理和影响是，它将进一步了解分子驱动PCA差异的机制并有助于开发前列腺肿瘤的新型精确生物标志物侵略性和/或针对侵略性PCA的治疗剂。这种精确的医学干预将减少AAS的PCA差异，并可能会影响所有种族的患者的一部分 PCA。新的AA和白色PCA生物特异性，AA和白色PCA患者衍生的外观和衍生细胞系以及与剪接相关的材料以及拟议工作产生的方法和工具全国范围内的科学家研究PCA差异研究。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Corrigendum: Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer.

DOI：
10.1038/ncomms16161
发表时间：
2017-09-27
期刊：
Nature communications
影响因子：
16.6
作者：
Wang BD;Ceniccola K;Hwang S;Andrawis R;Horvath A;Freedman JA;Olender J;Knapp S;Ching T;Garmire L;Patel V;Garcia-Blanco MA;Patierno SR;Lee NH
通讯作者：
Lee NH

Differential alternative RNA splicing and transcription events between tumors from African American and White patients in The Cancer Genome Atlas.

DOI：
10.1016/j.ygeno.2021.02.020
发表时间：
2021-05
期刊：
Genomics
影响因子：
4.4
作者：
Al Abo M;Hyslop T;Qin X;Owzar K;George DJ;Patierno SR;Freedman JA
通讯作者：
Freedman JA

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

DOI：
10.1002/cncr.33589
发表时间：
2021-08-15
期刊：
Cancer
影响因子：
6.2
作者：
通讯作者：

Changing the landscape of non-small cell lung cancer disparities.

DOI：
10.46439/cancerbiology.2.020
发表时间：
2021
期刊：
Journal of cancer biology
影响因子：
0
作者：
Odera, Joab O;Abo, Muthana Al;Patierno, Steven R;Clarke, Jeffrey M;Freedman, Jennifer A
通讯作者：
Freedman, Jennifer A

A widespread length-dependent splicing dysregulation in cancer.

癌症中广泛存在的长度依赖性剪接失调