A multitargeted nanocarrier inhibitor of undruggable transcription factors for treating castration resistant prostate cancer

Project Summary This project addresses the critical need for treatments of castration resistant prostate cancer (CRPC) by proposing to engineer and develop a novel, nanostructured pharmaceutical (P-TRIS5) which will target tumor cells and deliver two potent, synergistic therapeutics (an siRNA and a small molecule) to inhibit the androgen receptor and RUNX, two commonly implicated transcription factors in CRPC. We will study the new compound using in vitro and in vivo models that are well-established for CRPC and seek to show 1) effective in vitro targeting and cellular uptake, and 2) effective delivery and efficacy in two xenograft mouse models. Parabon NanoLabs has significant experience in the development and validation of rationally designed, nanostructured pharmaceuticals and will leverage existing infrastructure, expertise, and collaborations to investigate the potential for the proposed CRPC targeted drug. Our synthesis methodology begins with the design of P-TRIS5 using Parabon’s Essemblix™ Drug Development Platform, a powerful combination of computer-aided design (CAD) software for designing self-assembling DNA nanocarriers and proprietary nanofabrication methods for their production. Next, the two therapeutics and a targeting peptide will be conjugated to the nanocarrier using commercially available compounds and purified by standard protocols. We will measure the performance of P-TRIS5 by monitoring a fluorescent label on the compound for targeting (via fluorescent confocal microscopy in vitro) and tumor growth via bioluminescent full-body live imaging. Off-target cytotoxicity will also be measured in vivo to demonstrate selective targeting of the tumor. Post-mortem excised tissues will be analyzed to determine the extent of inhibition of downstream targets in the animal model. The success of this project will create new avenues to rationally design nanostructured pharmaceuticals against many kinds of cancer. Our focus on CRPC, a prostate cancer with a critical need for new therapies, is driven by an abundance of knowledge about the molecular biology involved and the synergy formed by a combination of small molecules and siRNA to target drivers of the most dangerous variants of this deadly disease.Project Narrative This NIH STTR Phase I project will create a novel therapeutic for the treatment of castration resistant prostate cancer (CRPC). The proposed therapeutic will incorporate targeting molecules specific to prostate cancer that will enable it to bind and be taken up by prostate cancer cells. The therapeutic will carry a dual payload to inhibit the activity of key CRPC transcription factors, a class of proteins previously considered to be “undruggable.”