Highly specific targeting of the TMPRSS2/ERG fusion gene in prostate cancer

TMPRSS2/ERG 融合基因在前列腺癌中的高度特异性靶向

• 批准号: 8732393
• 负责人: Michael M Ittmann
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732393
• 关键词: Adjuvant Therapy; Adverse effects; Androgens; Binding; Biological; Blood Circulation; Blood flow; Cancer Etiology; Cessation of life; Charge; Chemicals; Clinical; Combined Modality Therapy; Data; Diagnostic Neoplasm Staging; Disease; Drug usage; Endothelial Cells; Fibroblast Growth Factor Receptors; Folic Acid; Gene Silencing; Gene Targeting; Genes; Genetic; Glutamate Carboxypeptidase II; Goals; Hematopoiesis; In Vitro; Integrin Binding; Liposomes; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Modality; Modification; Nanotechnology; Normal Cell; Normal tissue morphology; Oncogenes; Outcome; Peptides; Permeability; Play; Primates; Prostate Cancer therapy; Proteins; RGD (sequence); Radiation therapy; Resistance; Reticuloendothelial System; Role; Second Primary Neoplasms; Small Interfering RNA; TMPRSS2 gene; Therapeutic; Tissues; Toxic effect; Translating; Treatment Efficacy; Tumor stage; United States; VCaP; Veterans; Visceral; antitumor effect; base; chemotherapy; clinical practice; design; docetaxel; effective therapy; fusion gene; improved; in vivo; men; nanoliposome; nanovector; neoplastic cell; particle; preclinical study; pressure; prostate cancer cell; prostate cancer model; public health relevance; receptor binding; small hairpin RNA; standard of care; therapeutic target; tumor; tumor growth; tumor progression; uptake; vector

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the second leading cause of cancer deaths in US men. The TMPRSS2/ERG (T/E) fusion gene occurs in 50% of PCas and has multiple biological activities that can promote tumor progression. We have shown using gene knockdown targeting the T/E fusion gene can markedly decrease tumor growth in vivo. Thus the T/E fusion gene is an outstanding therapeutic target in PCa. The T/E mRNA fusion junctions are present only in PCa cells since these two genes are not transcribed into a single mRNA in normal cells. Specifically targeting these junctions using highly specific siRNAs should not have any specific off-target effects in normal tissues so toxicity should be minimal. We have recently developed non-toxic liposomal nanovectors. We have used these nanoliposomal vectors to deliver gene knockdown agents (siRNAs) targeting the fusion junctions in vivo and seen significant anti-tumor effects without toxicity. However, we need to further enhance delivery in order to maximize therapeutic efficacy since the ERG protein was not completely eliminated and tumors continue to grow, although at slower rates. We will try several approaches to increasing siRNA delivery. First, several chemical modifications of the nanoliposome will be used to both increase stability in the circulation and target tumor cells. Second, we will use drugs that are already in common use to enhance intratumoral nanoliposome delivery. Docetaxel chemotherapy is widely used to treat advanced PCa but is not curative. Radiation therapy is also a major therapy for PCa. Our preliminary data indicates that knockdown of the T/E fusion can enhance these therapies in vitro. We will determine if the optimized knockdown of the T/E fusion gene in vivo using non-toxic siRNA approaches can be used to enhance the efficacy of these therapies in PCa. A significant advantage of such targeted adjuvant therapy is that it will be tumor specific and thus minimize side effects in non-tumor tissues. The ultimate goal is to translate these approaches into clinical practice that will positively impact survival for men with PCa. As a monotherapy nanoliposomal SiRNA knockdown may be useful in men with advanced PCa. Every year tens of thousands of men receive docetaxel or radiation therapy for PCa and fail such therapies and thus there is a pressing clinical need to enhance these therapies. Significantly, the lack of toxicity of DOPC nanoliposomes has already been established in primates. Thus there is a clear path forward to translate our preclinical studies into clinical practice to benefit men with prostae cancer.

描述（由申请人提供）： 前列腺癌（PCa）是美国男性癌症死亡的第二大原因。 TMPRSS2/ERG (T/E)融合基因存在于50%的PCas中，具有多种可促进肿瘤进展的生物活性。我们已经证明，使用针对 T/E 融合基因的基因敲低可以显着减少体内肿瘤的生长。因此T/E融合基因是PCa的一个突出的治疗靶点。 T/E mRNA 融合连接仅存在于 PCa 细胞中，因为这两个基因在正常细胞中不会转录成单个 mRNA。使用高度特异性的 siRNA 专门针对这些连接点，不应在正常组织中产生任何特定的脱靶效应，因此毒性应最小。我们最近开发了无毒的脂质体纳米载体。我们使用这些纳米脂质体载体来递送靶向体内融合连接的基因敲除剂（siRNA），并观察到显着的抗肿瘤作用且无毒性。然而，我们需要进一步增强递送，以最大限度地提高治疗效果，因为 ERG 蛋白并未完全消除，肿瘤仍在继续生长，尽管速度较慢。我们将尝试多种方法来增加 siRNA 的递送。首先，纳米脂质体的几种化学修饰将用于增加循环和靶向肿瘤细胞的稳定性。其次，我们将使用已经常用的药物来增强肿瘤内纳米脂质体的递送。多西他赛化疗广泛用于治疗晚期 PCa，但不能治愈。放射治疗也是前列腺癌的主要治疗方法。我们的初步数据表明，T/E 融合的敲低可以增强这些体外疗法。我们将确定使用无毒 siRNA 方法体内 T/E 融合基因的优化敲低是否可用于增强这些疗法在 PCa 中的疗效。这种靶向辅助治疗的一个显着优点是它具有肿瘤特异性，从而最大限度地减少非肿瘤组织的副作用。最终目标是将这些方法转化为临床实践，从而对男性前列腺癌患者的生存产生积极影响。作为单一疗法，纳米脂质体 SiRNA 敲低可能对患有晚期 PCa 的男性有用。每年都有数以万计的男性接受多西紫杉醇或放射治疗治疗 PCa，但这些治疗失败，因此临床迫切需要加强这些治疗。值得注意的是，DOPC 纳米脂质体在灵长类动物中已被证实无毒性。因此，我们有一条明确的道路可以将我们的临床前研究转化为临床实践，使前列腺癌患者受益。