Activity of Py-Im Polyamides in Anti-Androgen Resistant Prostate Cancer Models

Author: Kurmis, Alexis Anna

Year: 2019

Degree: Dissertation (Ph.D.)

Advisor: Dervan, Peter B.

Committee Members: Tirrell, David A.; Campbell, Judith L.; Ondrus, Alison E.; Dervan, Peter B.

Option: Chemistry

DOI: 10.7907/HC6V-FV39

Abstract

The antiproliferative effects of Py-Im polyamides have been evaluated in several cancer models. The work presented here focuses on prostate cancer and the application of Py-Im polyamides targeted to the sequence 5′-WGWWCW-3′, which is found in a subset of androgen response elements. We begin by exploring the effect of a Py-Im polyamide in the VCaP model, which overexpresses wildtype AR and is genomically unstable due to ERG overexpression caused by the TMPRSS2-ERG translocation. In this model, Py-Im polyamide treatment reduces ERG protein level and DNA fragmentation, and reduces VCaP xenograft growth. Transcriptomic analysis of Py-Im polyamide treated VCaP cells provides a novel potential mechanism of blockage of topoisomerase I and II activity by polyamides. We next evaluate the activity of a second generation Py-Im polyamide in two models of anti-androgen resistant prostate cancers, and demonstrate growth inhibition in both cell culture and tumor models. Transcriptomic analysis of the model cell lines revealed suppression of androgen receptor signaling. Further, expression profiles are consistent with transcription inhibition in both cell samples and tumor samples. Finally, we examine the effect of a Py-Im polyamide on the AR cistrome in prostate cancer cells. We find through ChIP-Seq analysis that loci differentially affected by Py-Im polyamide treatment are enriched for potential ARE half-sites consistent with the polyamide target site. In summary, we find that Py-Im polyamides interfere with several DNA dependent processes, similar to other DNA minor groove binders, and we show through AR cistromic analysis that Py-Im polyamides reduce AR occupancy in a pattern that is predicted by Py-Im polyamide pairing rules.

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