Inhibition of MYC-activated gene expression by polyamides

Institution:	California Institute of Technology
Investigator(s):	Daniel Harki, Ph.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16FT-0055	Award: $71,330
Subject Area:	General Biomedical Science
Award Type:	Postdoctoral Fellowship Awards

Abstracts

Initial Award Abstract

The largest single cause of cancer death in the United States is tobacco use. It is estimated that approximately 1.4 million people will be newly diagnosed with cancer in 2006; with California residents encompassing 10% of those affected. In both men and women, mortality rates are the highest in patients suffering from lung cancer- a disease which has been unambiguously linked to tobacco smoking. In fact, a recent analysis of small cell lung cancer patients revealed more than 95% were tobacco smokers. Consequently, new and more efficacious treatments for lung and related cancers are highly warranted. A common defect found in small cell lung cancer, and many other cancers, is deregulated activity of a gene termed MYC (also know as MYC oncogene). The MYC oncogene encodes the MYC protein; hence, a high level of MYC oncogene activity yields a high level of MYC protein in cells. Elevated MYC protein levels are present in many small cell lung cancers and increasingly prevalent during progression of the disease following chemotherapy. Unfortunately, elevated MYC protein levels are deleterious to cells. The MYC protein functions in cells as a transcription factor- a protein involved in "turning on" other genes. Hence, high levels of MYC protein facilitates "turning on" a bevy of other genes. Such actions are harmful to cells in a variety of ways, such as promoting uncontrolled cell growth- a hallmark trait of cancer. In this proposal we aim to circumvent the effects of elevated MYC protein levels in cells with a designed molecule- a polyamide. Polyamides are small molecules (like drugs) that enter into cells and influence cellular processes by interacting with DNA. In this application, a small family of related polyamides has been designed to: (i) enter into cells, (ii) find the region of DNA that MYC binds to "turn on" genes, and (iii) block the ability of MYC to "turn on" genes, thereby regulating its activity. Unlike other approaches that abolish the formation of functional MYC protein in cells, our approach simply inhibits the ability of MYC to haphazardly "turn on" genes. We hypothesize this may be therapeutically useful since some genes require functional MYC protein to repress (instead of activate) their activity. In addition to preparing the proposed polyamides, we will evaluate their ability to block gene activation by MYC, and study their potential in cells as anticancer therapeutics. If successful, this project has the potential to uncover a new avenue in the development of novel, targeted cancer therapies for treating human cancer.

Publications

In vivo imaging of pyrrole-imidazole polyamides with positron emission tomography .
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Harki DA, Satyamurthy N, Stout DB, Phelps ME, Dervan PB				ART
Yr: 2008	Vol:	Nbr: 105	Abs:	Pg: 13039-13044

Solution-phase synthesis of pyrrole-imidazole polyamides
Periodical: Journal American Chemicaal Society			Index Medicus:
Authors: Chenoweth DM, Harki DA, Dervan PB				ART
Yr: 2009	Vol:	Nbr: 131	Abs:	Pg: 7175-7181

Cyclic pyrrole-imidazole polyamidestargee to the androgen response element
Periodical: Journal American Chemicaal Society			Index Medicus:
Authors: Chenoweth DM, Harki DA, Phillips JW, Dose C, Dervan PB				ART
Yr: 2009	Vol:	Nbr: 131	Abs:	Pg: 7182-7188

In vivo imaging of pyrrole-imidazole polyamides with positron emission tomography .
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Harki DA, Satyamurthy N, Stout DB, Phelps ME, Dervan PB				ART
Yr: 2008	Vol:	Nbr: 105	Abs:	Pg: 13039-13044

Solution-phase synthesis of pyrrole-imidazole polyamides
Periodical: Journal American Chemicaal Society			Index Medicus:
Authors: Chenoweth DM, Harki DA, Dervan PB				ART
Yr: 2009	Vol:	Nbr: 131	Abs:	Pg: 7175-7181

Cyclic pyrrole-imidazole polyamidestargee to the androgen response element
Periodical: Journal American Chemicaal Society			Index Medicus:
Authors: Chenoweth DM, Harki DA, Phillips JW, Dose C, Dervan PB				ART
Yr: 2009	Vol:	Nbr: 131	Abs:	Pg: 7182-7188