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.
This application is aimed at developing a novel strategy for synergistic targeting of Myc. Successful completion of this study may lead to the development of a novel therapy that will advance the treatment of various types of cancers including prostate cancer.
| Xu, Jieni; Zhao, Whenchen; Sun, Jingjing et al. (2018) Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents. J Control Release 288:212-226 |
| Wang, Yue; Wang, Zehua; Xu, Jieni et al. (2018) Systematic identification of non-coding pharmacogenomic landscape in cancer. Nat Commun 9:3192 |
| Li, Zuojun; Sun, Jingjing; Huang, Yixian et al. (2018) A Nanomicellar Prodrug Carrier Based on Ibuprofen-Conjugated Polymer for Co-delivery of Doxorubicin. Front Pharmacol 9:781 |
