Novel nanotechnology approach to target prostate cancer

针对前列腺癌的新型纳米技术方法

• 批准号: 7795937
• 负责人: ALEXANDER V KAZANSKY
• 金额: $ 9.44万
• 依托单位: UNIV/TEXAS BROWNSVILLE & SOUTHMOST COLL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795937
• 关键词: Address; Adenocarcinoma; Aggressive behavior; Agreement; Alternative Splicing; Applications Grants; Appointment; Biological Models; Biological Sciences; Biomedical Research; C-terminal; Cancer cell line; Cell Cycle Progression; Clinical; Collaborations; Copyright; DNA; Development; Disease; Dominant-Negative Mutation; Ectopic Expression; Educational process of instructing; Extramural Activities; Faculty; Family; Fred Hutchinson Cancer Research Center; Funding; Future; Genes; Goals; Grant; Growth; Human; In Vitro; Intervention; Knowledge; Laboratories; Laboratory Research; Laws; Lead; Legal patent; Length; Letters; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Manuscripts; Medicine; Messenger RNA; Minority; Mus; Nanotechnology; Nude Mice; Oligonucleotides; Peptides; Principal Investigator; Prostate; Protein Isoforms; Proteins; Proto-Oncogenes; Protocols documentation; Public Health; RNA Splicing; Recruitment Activity; Regulation; Research; Research Project Grants; STAT3 gene; STAT5A gene; STAT5B gene; Science; Secure; Students; Technology; Testing; Texas; Therapeutic; Time; Trademark; Training; Transactivation; Transgenic Organisms; Translational Research; Tumor Suppressor Proteins; United States National Institutes of Health; Universities; Validation; Wages; Work; Writing; base; cancer cell; carcinogenesis; career; college; design; factor C; falls; graduate student; in vivo; innovation; mRNA Precursor; men; model development; mouse model; neoplastic; neoplastic cell; novel; novel strategies; novel therapeutic intervention; preclinical study; professor; programs; research study; targeted delivery; tool; transcription factor; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): In many cases malignant transformation can be directly linked to activation of the STAT family of transcription factors. Two major STAT isoforms have been characterized: the full-length transcription factor and C-terminal truncated isoforms that lack the transactivation domain. Constitutive activation of STAT5 proteins has been demonstrated in many diverse human cancer cell lines and clinical tumors including those of the prostate. Furthermore, our studies provide evidence that STAT5B, but not STAT5A, contributes to tumor progression. Increased activation of STAT5 correlates with aggressive behavior of prostate cancer while the naturally occurring dominant-negative truncated isoform, STAT5?B blocks tumorigenic abilities cancer cells. Therefore, the overall hypothesis of this proposal is that ectopic expression of the dominant-negative truncated isoform STAT5?B, a tumor suppressor, in place of the proto-oncogene STAT5B reverses carcinogenesis. The rationale of this study is that validation of this hypothesis can lead to novel approaches and the development of disease-intervention strategies in the treatment of prostate cancer and likely, other malignances. We propose to substitute expression of STAT5B (proto-oncogene) with the dominant-negative truncated isoform STAT5?B (tumor suppressor) applying pHLIP nanotechnology for delivery of splice-switching oligonucleotides to block alternative splicing. The proposed work combines recently acquired knowledge on regulation and action of specific genes involved in prostate cancer progression with a novel nanotechnology-based approach for targeted delivery of DNA specifically in tumors. Aim1: To investigate the efficacy of the steric-blocking by splice-switching oligonucleotide (SSO) conjugates with pH insertion peptide (pHLIP) to block alternative splicing of STATs mRNA in vitro. The hypothesis of this aim is that pHLIP is well suited to target delivery of splice switching DNA into tumor cells. The rationale of this aim is that optimization of SSO delivery employing pHLIP is necessary to attempt this strategy in vivo. Aim2: To test the ability of pHLIP-SSOs directed to induce expression of STAT5?B to block prostate cancer in vivo. The hypothesis of this aim is that application of the pHLIP-SSO technology will induce ectopic expression of STAT5?B (tumor suppressor) in place of STAT5B (proto-oncogene) in the Athymic Nude Mouse Model System. The rationale of this aim is based on the overall hypothesis of this proposal that ectopic expression of the dominant-negative truncated isoform STAT5?B in place of the proto-oncogene STAT5B can reverse carcinogenesis. The modulation of STAT5B isoform expression represents a model for the development of a novel therapeutic approach not only for prostate cancer but also for other diseases caused by defective pre-mRNA splicing. The successful completion of this work is anticipated to open new avenues for chemotherapeutic disease intervention strategies based on the proposed combination of pHLIP nanotechnology and a novel approach to switching expression from a proto- oncogene to a tumor suppressor. RELEVANCE TO PUBLIC HEALTH: This project aims to develop an innovative strategy for therapeutic approaches not only for prostate cancer but also for other diseases caused by defective pre-mRNA splicing. Completion of this proposal may open new avenues for chemotherapeutic disease intervention strategies based on the proposed combination of pHLIP nanotechnology and a novel approach to switching expression from a proto-oncogene to a tumor suppressor.

描述（由申请人提供）：在许多情况下，恶性转化可能与转录因子 STAT 家族的激活直接相关。两种主要的 STAT 同工型已得到表征：全长转录因子和缺乏反式激活结构域的 C 端截短同工型。 STAT5 蛋白的组成型激活已在许多不同的人类癌细胞系和临床肿瘤（包括前列腺肿瘤）中得到证实。此外，我们的研究提供的证据表明 STAT5B 而不是 STAT5A 有助于肿瘤进展。 STAT5 激活的增加与前列腺癌的侵袭行为相关，而自然发生的显性失活截短亚型 STAT5?B 可阻断癌细胞的致瘤能力。因此，该提议的总体假设是，显性失活截短亚型 STAT5?B（一种肿瘤抑制因子）的异位表达代替原癌基因 STAT5B 可逆转癌发生。这项研究的基本原理是，验证这一假设可以带来治疗前列腺癌和其他可能的恶性肿瘤的新方法和疾病干预策略的发展。我们建议用显性失活截短亚型 STAT5?B（肿瘤抑制基因）替代 STAT5B（原癌基因）的表达，应用 pHLIP 纳米技术传递剪接转换寡核苷酸以阻断选择性剪接。这项拟议的工作将最近获得的有关前列腺癌进展中特定基因的调控和作用的知识与一种基于纳米技术的新型方法结合起来，用于在肿瘤中特异性靶向递送 DNA。目的1：研究剪接转换寡核苷酸（SSO）与pH插入肽（pHLIP）缀合物的空间阻断在体外阻断STATs mRNA选择性剪接的功效。该目标的假设是 pHLIP 非常适合将剪接转换 DNA 靶向递送至肿瘤细胞中。这一目标的基本原理是，为了在体内尝试这种策略，需要使用 pHLIP 优化 SSO 递送。目的2：测试pHLIP-SSOs定向诱导STAT5?B表达以阻断体内前列腺癌的能力。该目标的假设是，pHLIP-SSO 技术的应用将诱导 STAT5?B（肿瘤抑制基因）异位表达，以代替无胸腺裸鼠模型系统中的 STAT5B（原癌基因）。这一目标的基本原理是基于该提案的总体假设，即显性失活截短亚型 STAT5?B 的异位表达代替原癌基因 STAT5B 可以逆转癌发生。 STAT5B 同工型表达的调节代表了开发新治疗方法的模型，该方法不仅适用于前列腺癌，还适用于由有缺陷的前 mRNA 剪接引起的其他疾病。这项工作的成功完成预计将为化疗疾病干预策略开辟新的途径，该策略基于所提出的 pHLIP 纳米技术和将表达从原癌基因转换为肿瘤抑制基因的新方法的组合。与公众健康的相关性：该项目旨在开发一种创新策略，不仅用于治疗前列腺癌，还用于治疗由前 mRNA 剪接缺陷引起的其他疾病。该提案的完成可能会为化疗疾病干预策略开辟新的途径，该策略基于所提出的 pHLIP 纳米技术和将表达从原癌基因转换为肿瘤抑制基因的新方法的组合。