Abstract 1764: Galeterone and its novel analogs induce profound anti-cancer activities in human pancreatic cancer cell lines: Implications for pancreatic cancer therapy
Authors: Kwegyir-Afful Andrew K. , Purushottamachar Puranik , Martin Marlena S. , Njar Vincent C.o. 
Published: August 2015

Pancreatic cancer is a lethal disease with a 3-5% survival rate. Histologically, 90% of human pancreatic cancer is presented as pancreatic ductal adenocarcinoma (PDAC). The aggressive nature of the disease and its high metastatic potential makes the development of efficacious therapeutic strategies very significant.

Current therapeutic strategies are ineffective as the deregulated RAS/MAPK and PI3K/AKT/mTOR pathways to enhance drug resistance. Gemcitabine alone or in combination with erlotinib, the currently used drugs for PDAC, elicit only marginal survival benefits. The modest efficacy of gemcitabine therapy has been attributed to activation of the NF-κB pathway which activates genes involved in gemcitabine resistance. Recent studies have implicated the eIF4F (specifically, eIF4E-Mnk1/2 axis) that control gene expression at the translational level towards PDAC gemcitabine drug resistant. Several groups have also implicated the androgen receptor in PDAC progression/metastasis and have investigated the use anti-androgens in several in vitro and vivo models of PDAC and in a few clinical trials with mixed results.

In the course of our studies to develop more potent androgen receptor degrading agents (ARDAs), we discovered that galeterone (gal) and its novel analogs also effectively target oncogenic eukaryotic protein translation. These novel small molecule inhibitors significantly depleted Mnk1/2 protein expression and decreased eIF4E phosphorylation. Interestingly, our studies revealed that the phosphorylation level of Nf-kB (p65) was significantly decreased after exposing pancreatic cancer cells to ARDAs. We note that these targets are implicated in PDAC progression and drug resistance.

Here we report for the first time, the efficacy of galeterone and its lead ARDA analogs in inhibiting cell viability of both gemcitabine-naïve and gemcitabine/erlotinib-resistant human pancreatic cancer cells in vitro. Gal/ARDAs alone or in combination with gemcitabine significantly reduced the colony forming potential of gemcitabine-naïve and gemcitabine resistant pancreatic cancer cells. Decreased invasive potential of PDAC cells was shown through wound-healing and matrigel-coated Boyden chambers assays. Gal/ARDAs also caused significant depletion of matrix metalloproteinases (MMPs). Ezh2, a prominent metastatic enhancing gene in pancreatic cancer was also downregulated at the protein level. Immunoblot analysis of treated lysates also revealed induction of apoptosis via caspase 3 and PARP cleavage. Flow cytometric analysis showed that gal/ARDAs did not only deplete cyclins but also inhibited cell cycle progression. Our results highlight the unique ability of gal and its novel analogs to inhibit the growth, colonization and metastatic potential of a variety of PDAC cells through modulation of several oncogenic targets.

Citation Format: Andrew K. Kwegyir-Afful, Puranik Purushottamachar, Marlena S. Martin, Vincent C.o. Njar. Galeterone and its novel analogs induce profound anti-cancer activities in human pancreatic cancer cell lines: Implications for pancreatic cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1764. doi:10.1158/1538-7445.AM2015-1764