Cancers, Treated with VEGF and HER 2/neu Receptor Tyrosine Kinase Inhibitors
There are more than 2.5 million cancer patients in India at any given time, of which the frequency of breast and ovarian cancer cases has increased. Although there are many possible reasons, reversible phosphorylation of proteins, mediated by receptor tyrosine kinases (RTK) such as VEGF and HER2/neu receptors play a crucial role on different cellular processes associated with cancer pathogenesis. Small molecule anticancer drugs that target VEGF and HER2/neu receptors have been developed and are currently in use for the treatment of many forms of cancers. Identification of surrogate tyrosine phosphoprotein markers to evaluate actions of these drugs will be of greater use in the subsequent patient selection for a specific treatment or exclusion of patients who are unlikely to get any clinical benefit from a particular drug.
This project exploits the unique capability of current day mass spectrometers and its fragmentation techniques in phosphoproteomics research and determines the effect of few recently marketed small molecule receptor tyrosine kinase inhibitor drugs on VEGF and HER2/neu signaling pathways. Differentially expressed tyrosine phosphoproteins (surrogate markers) before and after drug treatment is analyzed in cancer cell lines and the study is then extended to body fluids collected from cancer patients. The work also addresses quantitative changes associated with tyrosine protein phosphorylation, with the help of a novel chemical labeling strategy coupled to mass spectrometry.
The project involves:
- Using cancer cell lines, investigate role of tyrosine phosphorylation in cancer pathogenesis and identify differentially expressed tyrosine phosphoproteins by iTRAQ chemical labeling strategy.
- Determine quantitative changes associated with tyrosine phosphoproteomics in cancer cell lines before and after treatment with receptor tyrosine kinase inhibitor drugs such as Sunitinib, Sorafenib, Vatalanib, and Lapatinib.
- Extend the study to ascites or pleural effusions obtained from cancer patients and identify surrogate tyrosine phosphoprotein markers.