Date of Defense

4-25-2013

Date of Graduation

4-2013

Department

Biological Sciences

First Advisor

Christine Byrd-Jacobs

Second Advisor

Douglas Coulter

Abstract

Crizotinib is a small molecule tyrosine kinase inhibitor that is currently being marketed by Pfizer under the trade name Xalkori®. After its development in 2005, an appropriate target was discovered in 2007. By 2011 the FDA had approved crizotinib for use in patients with ALK+ non small cell lung cancer (NSCLC). ALK+ NSCLC is caused by a genetic mutation that truncates and flips a section of the EML4 gene and attaches it to a section of the ALK gene. The result is the EML4-ALK oncogene. The resulting protein from this mutation is capable of undergoing ligand independent dimerization, triggering a variety of second messenger signaling cascades. These second messenger systems trigger pro-survival systems such as decreased apoptosis, increased growth and increased proliferation. Crizotinib acts on this oncoprotein by competitively binding to the ATP binding site. By removing the protein’s access to ATP, crizotinib effectively shuts it down. The removal of the protein from its active state shuts down the aforementioned second messenger systems, retuning the cell to a near normal life cycle.

In clinical trials, crizotinib has seen great initial success. Through two studies, its objective response rate averaged about 55% with minimal side effects. Unfortunately, resistance developed in 100% of cases with an objective response in an average of 42 weeks. This was done mainly through secondary mutations in the tyrosine kinase domain of the ALK portion of the EML4-ALK gene. This drug has shown that medicine designed for a very specific disease has the potential to be effective.

Comments

Powerpoint accompanying.

Access Setting

Honors Thesis-Open Access

Additional Files
2013-McLaren- Powerpoint.pdf (577 kB)
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