Highly specific targeting of the TMPRSS2/ERG fusion gene in prostate 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，具有促进肿瘤进展的多种生物学活性。我们已经证明，使用针对T/E融合基因的基因敲除可以显著减少体内肿瘤的生长。因此，T/E融合基因是治疗前列腺癌的良好靶点。T/E基因融合连接只存在于前列腺癌细胞中，因为这两个基因在正常细胞中不转录成单一的mRNA。具体地说，使用高度特异的siRNAs靶向这些连接，在正常组织中不会有任何特定的脱靶效应，因此毒性应该是最小的。我们最近开发了无毒的脂质体纳米载体。我们已经使用这些纳米脂质体载体在体内运送针对融合连接的基因敲除剂(SiRNAs)，并看到了显著的抗肿瘤作用而没有毒性。然而，我们需要进一步加强递送，以最大限度地发挥治疗效果，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。我们将尝试几种方法来增加siRNA的递送。首先，将对纳米脂质体进行几次化学修饰，以增加循环和靶向肿瘤细胞的稳定性。其次，我们将使用已经普遍使用的药物来增强纳米脂质体在肿瘤内的输送。多西紫杉醇化疗被广泛用于治疗晚期前列腺癌，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，在体外，T/E融合基因的敲除可以加强这些治疗。我们将确定是否可以使用无毒的siRNA方法在体内优化敲除T/E融合基因，以提高这些疗法在PCa中的疗效。这种靶向辅助治疗的一个显著优点是它将是肿瘤特异性的，从而将非肿瘤组织的副作用降至最低。最终目标是将这些方法转化为临床实践，这将对患有前列腺癌的男性患者的存活率产生积极影响。作为一种单一疗法，纳米脂质体siRNA敲除对晚期前列腺癌患者可能有用。每年，数以万计的男性接受多西紫杉醇或放射疗法治疗前列腺癌，但这些疗法失败，因此迫切需要加强这些疗法。值得注意的是，DOPC纳米脂质体在灵长类动物中的毒性已经得到证实。因此，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。

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.