Inhibition of ERBB2 expression by polyamides in NSCLC
Initial Award Abstract
Cigarette smoke is a major cause of lung cancer, which is the leading form of cancer deaths worldwide. The most common form of clinically treated lung cancer is non-small cell lung cancer. Despite advances in modern medicine, prognosis remains poor for the disease due to high recurrent rates and limited treatment options. Thus, there is an urgent need for the development of new treatments for non-small cell lung cancer (NSCLC).
A common trait among many forms of cancer, including NSCLC, is the over-abundance of the ERBB2 protein on the cell surface. The ERBB2 protein belongs to a class of signaling receptors known as the epidermal growth factor (EGF) receptors. Together, these proteins regulate cellular differentiation, growth, and migration in normal tissue cells. However, the over production of the ERBB2 protein, which is usually caused by amplification of the ERBB2 gene at the DNA level, triggers uncontrolled cell growth leading to tumor formation and metastasis.
Instead of blocking the function of the ERBB2 protein like most drugs on the market, we propose a new mechanism of treatment which blocks the production of ERBB2 at the RNA level, thus eliminating the root of the problem. The ERBB2 gene is turned on by two DNA binding transcription factors ETS1 and AP-2. By using a class of programmable sequence-specific DNA-binding molecule known as polyamides we can target the DNA sites where ETS1 and AP-2 regulate the ERBB2 gene and prevent them from turning the gene on. This type of approach is known as anti-transcription factor therapy. Towards this goal, we have designed polyamides to target the ETS1 and AP-2 binding sites, and we have shown these polyamides are able to prevent ETS1 and AP-2 from binding to the ERBB2 gene. Further work will address the ability of the polyamides to turn off the ERBB2 gene in NSCLC cell lines that display an over abundance of ERBB2 protein. Should our experiments prove successful, we hope to establish a polyamide based therapy that can be applied to other forms of cancer. |