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）融合基因发生在PCA的50％中，并且具有多种可以促进肿瘤进展的生物学活性。我们已经表明，使用靶向T/E融合基因的基因敲低可以显着降低体内肿瘤的生长。因此，T/E融合基因是PCA中出色的治疗靶标。 T/E mRNA融合连接仅存在于PCA细胞中，因为这两个基因未转录到正常细胞中的单个mRNA中。特异性地使用高度特异性的siRNA靶向这些连接，在正常组织中不应具有任何特定的脱靶效应，因此毒性应很小。我们最近开发了无毒的脂质体纳米型。我们已经使用了这些纳米脂质体载体来提供靶向体内融合连接的基因敲低剂（siRNA），并看到没有毒性的显着抗肿瘤作用。但是，我们需要进一步增强递送，以最大化治疗功效，因为ERG蛋白没有被完全消除，并且肿瘤继续增长，尽管速度较慢。我们将尝试几种增加siRNA输送的方法。首先，将使用纳米脂体的几种化学修饰来提高循环中的稳定性和靶向肿瘤细胞。其次，我们将使用已经常用的药物来增强肿瘤内纳米体递送。多西他赛化疗被广泛用于治疗晚期PCA，但没有治愈。放射疗法也是PCA的主要疗法。我们的初步数据表明，T/E融合的敲低可以在体外增强这些疗法。我们将确定使用无毒siRNA方法在体内对T/E融合基因的优化敲低可以用于增强这些疗法在PCA中的功效。这种靶向辅助治疗的一个重要优点是它将是特定于肿瘤的，从而最大程度地减少了非肿瘤组织中的副作用。最终目标是将这些方法转化为临床实践，这将对PCA男性的生存产生积极影响。作为单一治疗的纳米脂质体siRNA敲低可能对患有晚期PCA的男性有用。每年，成千上万的男性接受多西他赛或PCA的放射疗法，并且失败了此类疗法，因此迫切需要增强这些疗法的临床需求。值得注意的是，在灵长类动物中已经建立了DOPC纳米脂质体的毒性。因此，有一个明确的途径将我们的临床前研究转化为临床实践，以使前列腺癌男性受益。