Nanotherapeutics for Synergistic Targeting of Myc in Prostate Cancer

c-Myc（Myc）的失调与各种类型癌症的发病机制有关，在许多情况下， 有助于他们的侵略性。人们对开发新的癌症疗法有着极大的兴趣 是针对Myc的已经报道了几种小分子抑制剂。然而，发展 这些化合物受到许多问题的限制，包括快速代谢、生物利用度差或 药物不能在肿瘤部位达到有效浓度。最近我们也发现， Myc的抑制导致谷氨酰胺：果糖-6-磷酸酰胺转移酶-1（GFAT-1）的上调， 几种癌细胞系中己糖胺生物合成途径（HBP）的限速酶。同时 Myc和GFAT-1的抑制导致肿瘤细胞增殖抑制的急剧增加， 提示GFAT-1的上调可能是限制Myc的有效性的另一个障碍， 抑制疗法本申请的重点是开发一种改进的治疗策略 这不仅提高了递送至肿瘤组织的效率，而且同时阻断了Myc， GFAT-1活动。这将通过开发一种多功能纳米载体来实现， 有效地共同递送小分子Myc抑制剂10058-F4和GFAT-1 siRNA。三个具体目标将 在本申请中继续进行。目标1将集中在开发和体外表征 本发明还涉及在共配制10058-F4和GFAT-1 siRNA中有效的多功能载体。目标2将检查 10058-F4和GFAT-1 siRNA在荷瘤小鼠中的药代动力学和生物分布。目标3 将研究通过最佳方法共递送10058-F4和GFAT-1 siRNA的体内治疗效果。 纳米载体人和鼠前列腺癌模型都将用于本申请。成功 这项研究的完成不仅可能导致开发一种新的输送系统， 机制疗法

Deregulation of c-Myc (Myc) is implicated in the pathogenesis of various types of cancers and in many cases contributes to their aggressiveness. There has been enormous interest in developing new cancer therapies that are targeted at Myc. Several small molecule inhibitors have been reported. However, development of these compounds has been limited by a number of issues including rapid metabolism, poor bioavailability, or inability of the drug to reach effective concentrations at tumor sites. Recently, we have also discovered that inhibition of Myc leads to upregulation of glutamine:fructose-6-phosphate amidotransferase-1 (GFAT-1), the rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP) in several cancer cell lines. Simultaneous inhibition of Myc and GFAT-1 results in a drastic increase in the inhibition of the proliferation of tumor cells, suggesting that upregulation of GFAT-1 may represent another barrier that limits the effectiveness of Myc inhibition-based therapy. This application is focused on the development of an improved therapeutic strategy that not only improves the efficiency of delivery to the tumor tissues but also simultaneously blocks Myc and GFAT-1 activities. This will be achieved via the development of a multifunctional nanocarrier that is highly effective in codelivery of a small molecule Myc inhibitor, 10058-F4 and GFAT-1 siRNA. Three specific aims will be pursued in this application. Aim 1 will focus on the development and in vitro characterization of multifunctional carriers that are effective in co-formulating 10058-F4 and GFAT-1 siRNA. Aim 2 will examine the pharmacokinetics and biodistribution of both 10058-F4 and GFAT-1 siRNA in tumor-bearing mice. Aim 3 will investigate the in vivo therapeutic effect of codelivery of 10058-F4 and GFAT-1 siRNA via an optimal nanocarrier. Both human and murine prostate cancer models will be used in this application. Successful completion of this study may lead to not only the development of a new delivery system but also a new mechanism-based therapy.