An Ultrasound-Activated Nanoparticle Vehicle for Selective Imaging and Drug Delivery
July 22, 2011
Targeting the Mildly Acidic Tumor Microenvironment using pH-sensitive Recombinant Peptide Nanoconstructs
July 22, 2012
An Ultrasound-Activated Nanoparticle Vehicle for Selective Imaging and Drug Delivery
July 22, 2011
Targeting the Mildly Acidic Tumor Microenvironment using pH-sensitive Recombinant Peptide Nanoconstructs
July 22, 2012

Telomerase Reprogramming Nanoparticles (TeRN): Design and Validation of a Universal Cancer Therapeutic

Cancer is a major health concern worldwide, accounting for millions of deaths and untold pain and suffering each year. There is an urgent need for new therapeutic strategies with greater efficacy, fewer toxicities, and – ideally – activity against many types of cancer. Although the development of such a universal cancer therapeutic is highly challenging due to the enormous phenotypic heterogeneity of cancer, one emerging possibility involves the enzyme telomerase. Whereas benign, terminally differentiated tissues have extremely low telomerase levels, over 90% of all human cancers have high levels of telomerase and rely on its activity for continuing proliferation. Indeed, telomerase is virtually unmatched as a therapeutic target that is both universal in malignant cells and unique to them, a profile which contributed to the recent awarding of the 2009 Nobel Prize to Blackburn, Greider and Szostak, the discoverers of this enzyme. However, despite early hopes, most efforts to inhibit telomerase have not been successful.

We have recently been pursuing a novel therapeutic strategy based on “telomerase reprogramming” which – rather than inhibiting the enzymatic function of telomerase – harnesses and reprograms its activity to induce rapid cell death in cancer cells. This approach has been highly effective across a broad spectrum of cancer types, but its development has been limited to in vitro models, because the plasmids used to reprogram telomerase are not suited for systemic delivery. Here, for the first time, we propose to surmount this challenge by rationally designing, synthesizing, and testing a Telomerase Reprogramming Nanoparticle (TeRN) capable of efficiently entering cancer cells and reprogramming their telomerase to induce cell death.

Innovation and Significance
• Telomerase reprogramming is a novel therapeutic strategy which exploits the telomerase activity present in >90% of all malignancies yet absent from normal tissues. Hence, it holds tremendous potential as a highly efficacious, non-toxic universal cancer treatment.

• Telomerase Reprogramming Nanoparticles (TeRN) offer a highly innovative implementation of this approach, transitioning telomerase reprogramming from its current in vitro stage to a potentially viable therapeutic agent capable of systemic delivery against cancer cells.

• The project is a highly collaborative, inter-departmental endeavor leveraging the strengths of a translational oncologist from the USC Keck School of Medicine (Goldkorn) and a synthetic/medicinal chemist from the USC Dornsife College (Petasis).

• The proposal constitutes a stepwise translational progression from nanoparticle design through chemical and biological validation, culminating in a novel therapeutic with major clinical impact that will be highly competitive for subsequent peer reviewed funding.