Understanding the ability of histone deacetylase inhibitors to sensitize renal carcinoma to TRAIL

My research is focused on the immunotherapy of renal carcinoma. I use an adenovirus that encodes for an anti-tumor protein called TRAIL (TNF-related apoptosis inducing ligand). TRAIL alone can induce apoptosis in tumor cells, however large amounts of recombinant TRAIL are necessary. The goal of this research is to use an adenoviral vector to administer TRAIL to renal carcinoma patients. Unfortunately, gene therapy is rather inefficient in delivery of genes, so combination approaches are becoming more common. To enhance the efficacy of gene delivery, histone deacetylase inhibitors (HDACI) are also being studied in combination with Ad5-TRAIL to augment the expression of TRAIL. The advantages of histone deacetylase inhibitors are two-fold, first they can increase adenoviral transgene expression and second, they are capable of sensitizing tumor cells to TRAIL induced apoptosis. Mouse models are also being used to study the combination therapy of HDACI and Ad5-TRAIL and the effects of this therapy on murine renal carcinoma.

Norian LA, Kucaba TA, Earel JK, Knutson T, Vanoosten RL, Griffith TS. Synergistic Induction of Apoptosis in Primary B-CLL Cells after Treatment with Recombinant Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Histone Deacetylase Inhibitors. J Oncol. 2009;2009:408038. Epub 2009 Jun 14. PubMed PMID:19547714; PubMed Central PMCID: PMC2696620.

Griffith TS, Stokes B, Kucaba TA, Earel JK Jr, VanOosten RL, Brincks EL, Norian LA. TRAIL gene therapy: from preclinical development to clinical application. Curr Gene Ther. 2009 Feb;9(1):9-19. Review. PubMed PMID: 19275567; PubMed Central PMCID: PMC2727705.

VanOosten RL, Griffith TS. Activation of tumor-specific CD8+ T Cells after intratumoral Ad5-TRAIL/CpG oligodeoxynucleotide combination therapy. Cancer Res. 2007 Dec 15;67(24):11980-90. PubMed PMID: 18089829.

Griffith TS, Kazama H, VanOosten RL, Earle JK Jr, Herndon JM, Green DR, Ferguson TA. Apoptotic cells induce tolerance by generating helpless CD8+ T cells that produce TRAIL. J Immunol. 2007 Mar 1;178(5):2679-87. PubMed PMID: 17312109.

VanOosten RL, Earel JK Jr, Griffith TS. Histone deacetylase inhibitors enhance Ad5-TRAIL killing of TRAIL-resistant prostate tumor cells through increased caspase-2 activity. Apoptosis. 2007 Mar;12(3):561-71. Epub 2006 Dec 30. PubMed PMID: 17195089.

VanOosten RL, Earel JK Jr, Griffith TS. Enhancement of Ad5-TRAIL cytotoxicity against renal cell carcinoma with histone deacetylase inhibitors. Cancer Gene Ther. 2006 Jun;13(6):628-32. PubMed PMID: 16456549.

Earel JK Jr, VanOosten RL, Griffith TS. Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Res. 2006 Jan 1;66(1):499-507. PubMed PMID: 16397266.

VanOosten RL, Moore JM, Karacay B, Griffith TS. Histone deacetylase inhibitors modulate renal cell carcinoma sensitivity to TRAIL/Apo-2L-induced apoptosis by enhancing TRAIL-R2 expression. Cancer Biol Ther. 2005 Oct;4(10):1104-12. Epub 2005 Oct 13. PubMed PMID: 16096370.

Kemp TJ, Ludwig AT, Earel JK, Moore JM, Vanoosten RL, Moses B, Leidal K, Nauseef WM, Griffith TS. Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood. 2005 Nov 15;106(10):3474-82. Epub 2005 Jul 21. PubMed PMID: 16037389; PubMed Central PMCID: PMC1895062.

Vanoosten RL, Moore JM, Ludwig AT, Griffith TS. Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts. Mol Ther. 2005 Apr;11(4):542-52. PubMed PMID: 15771957.