Abstract 366: Novel self-folding tricyclic cholic acid-peptide hybrids as nanotherapeutic ligands targeting prostate and breast cancers and human embryonic stem cells

Abstract

Abstract Prostate cancer is the second leading cause of death in American men accounting for 10% of all cancer-related mortalities. According to NCI statistics from 2005-2007, 1 in 6 men will be diagnosed with prostate cancer during their lifetime. Despite the use of chemotherapy for the treatment of advanced or metastatic disease, cellular resistance to anticancer drugs and adverse side effects to healthy organs limit therapeutic efficacy. A targeted pro-apoptotic drug delivery system has been developed for the selective destruction of malignant tumors and tumorigenic stem cells. A novel self-folding tricyclic branched library was synthesized. Fixed hydrophobic amino acids near the N-terminus (position 5) of twin branched peptide arms fold back onto the hydrophobic face of the planar cholic acid molecule to form a compact tricyclic molecule. The novel bracelet library was screened using a One Bead Two Compounds (OB2C) combinatorial chemistry approach. Receptors expressed on cancerous cells serve as the targets for the tricyclic molecules to induce apoptotic signaling. Receptors for LDO 18, found on prostate cancer and stem cells, serve as the carrier vector, enabling the targeted delivery of the anticancer drug to the tumor mass. This approach spares normal tissues from toxic side effects of the peptidomimetic compounds. Preliminary studies suggest that tumors of ovarian and breast origin can also be targeted using LDO18. Lead therapeutic compounds will be conjugated to LDO18 nanocarriers along with LHRH analogues to evaluate the efficacy and combined potency to prostate, ovarian, and breast cancer xenografts in nude mice and orthotropic models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2011-366