Abstract 2428: Translational regulation as a therapeutic target of prostate cancer metastasis to bone
Authors: Adams Lisa K. , Young James , Williams Briana Jill 
Published: June 2012

Eighty-five percent of men who die from prostate cancer have disease that has metastasized to the bone. Many changes in gene expression are acquired to allow cancer cells to gain metastatic potential. While many are changes in mRNA levels, certain translation initiation factors like eukaryotic initiation factors 4E and 4G, eIF4E binding protein-1, and mTOR are reportedly overexpressed or dysregulated in many progressive cancers_implicating them as a mechanistic feature for transformation of proliferative cancer cells into invasive and metastatic cells. Our hypothesis is that a distinct subset of mRNA that promotes cancer cells to specifically metastasize to bone is regulated at the level of translation. To support this hypothesis, we have found components of the translation machinery which are preferentially upregulated in a panel of cell lines that metastasize to bone. We also identified a novel subset of actively translated mRNA differentially expressed in either osteolytic or osteoblastic bone metastatic prostate cancer cell lines versus those that do not metastasize to bone. We used shRNA to test the effect of eIF4E on properties of bone metastasis, and found significantly reduced motility and invasion in eIF4E-knockdown cell lines and changes in tumor cell:osteoblast adhesion. When we co-cultured eIF4E-knockdown PC-3 prostate cancer cells with osteoclasts, significant differences in growth and osteoclast activation were observed. Cap-dependent translation is a desirable therapeutic target since there is potential to simultaneously affect many progression-related proteins. We screened the NIH Clinical Collection library of 450 FDA-approved drugs for inhibitors of translation. The goal of the screen was to identify a drug with an acceptable safety profile that could be quickly repositioned into clinical trials as an anti-cancer drug targeting translation. In PC-3 cells, our lead candidate drug, LS1553, inhibited phosphorylated, i.e., activated, eIF4E, 4EBP-1, S6K, and Akt levels. LS1553 is currently used to treat heart disease and is well-tolerated in patients. Other commonly prescribed drugs in its class did not inhibit components of the translational machinery, making LS1553 uniquely suited to reposition to an anti-cancer application. Additionally, LS1553 significantly inhibited key elements of cancer progression: proliferation, motility/invasion, and expression of MMP-9 and VEGF, both of which are translationally-regulated. Translational regulation is a novel mechanism of action for LS1553 and along with clinical safety and demonstrated anti-tumor efficacy, provides an exciting rationale for repositioning LS1553 to treat a variety of metastatic cancer types in which protein synthesis is dysregulated.

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 2428. doi:10.1158/1538-7445.AM2011-2428