Logo for University of Iowa Health Care This logo represents the University of Iowa Health Care

Gregory Thomas


gregory-thomas@uiowa.edu
Mentor: Paloma Giangrande, Ph.D.
Lab Room: 5235 MERF
Lab Phone: 319-384-3243

The effect of synthetic RNA ligands on PSMA-mediated carcinogenesis.

Prostate cancer is the second leading cause of cancer death among men in the United States. Death typically results as the disease becomes metastatic and refractory to hormone treatment. Prostate Specific Membrane Antigen (PSMA) is a type II transmembrane carboxypeptidase glycoprotein expressed predominantly in prostatic epithelium cells and is highly correlated with tumor aggressiveness. This limited tissue expression provides a unique epitope for the therapeutic targeting of malignant cells. That PSMA spontaneously internalizes and shares sequence and domain organization homology with the transferrin receptor is suggestive of ligand transport function, however no endogenous ligand has been identified to date. Functional roles for PSMA remain elusive, however, a role for PSMA in suppressing cellular migration has been described that is associated with the peptidase activity of PSMA. I am interested in using RNA aptamers as synthetic ligands for PSMA to examine the regulation of the functional effects of PSMA stimulation and the pathways involved in these functional outcomes. Understanding the pathways involved will further provide rational targets for specific gene silencing with small interfering RNAs (siRNAs). I plan to utilize PSMA binding aptamers to deliver cytotoxic siRNA targeting pro-survival and anti-apoptotic genes towards the specific induction of apoptosis in malignant cells. The combination of aptamers as regulatory synthetic ligands as well as delivery vehicles for siRNA constructs offers therapeutic potential. Finally, I plan to assess the therapeutic potential of these chimeras in vivo in a mouse model of prostate cancer.

Publications:

Rockey WM, Hernandez FJ, Huang SY, Cao S, Howell CA, Thomas GS, Liu XY, Lapteva N, Spencer DM, McNamara JO, Zou X, Chen SJ, Giangrande PH. Rational truncation of an RNA aptamer to prostate-specific membrane antigen using computational structural modeling. Nucleic Acid Ther. 2011 Oct;21(5):299-314. doi: 10.1089/nat.2011.0313. PubMed PMID: 22004414; PubMed Central PMCID:PMC3198747.

Dassie JP, Liu XY, Thomas GS, Whitaker RM, Thiel KW, Stockdale KR, Meyerholz DK, McCaffrey AP, McNamara JO 2nd, Giangrande PH. Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol. 2009 Sep;27(9):839-49. Epub 2009 Aug 23. PubMed PMID: 19701187; PubMed Central PMCID: PMC2791695.



Honors and Awards

  • 2009 MCB Retreat Travel Award for Poster Presentation