The laboratory is focused on the study of cancer and the development of new and improved treatments for currently incurable cancers. The current project is focused on colorectal cancer, a leading cause of cancer death. Recently, we have discovered a vulnerability of colorectal cancer cells and exploited this discovery to develop two experimental drugs that effectively induce cell death in colorectal cancer cells. Briefly, Eph receptors are a family of tyrosine kinase cell surface receptors expressed in colorectal cancer cells. When active, Eph receptors initiate a phosphotyrosine-dependent signaling cascade that sustains colorectal cancer cell survival.  We found that genetic inhibition of Eph tyrosine kinases as well as depletion of EphrinB2 (a ligand for Eph receptors) reproducibly promote colorectal cancer cell death but not the death of control cells. In addition, we have found that a small molecule inhibitor of the Eph kinase, NVP-BHG712 and its regioisomer NVP-Iso, potently inhibit the growth and survival of colorectal cancer cells in vitro. We also found that both compounds reduce significantly the growth of human colorectal cancers established in mice, but do not completely eradicate these cancers.

Future steps are geared towards the identification of new compounds that can eradicate colorectal cancer. These steps include: 1. A more complete biochemical characterization of the Eph tyrosine kinases (colorectal cancer cells express a single or multiple Eph receptors;  the Eph-associated kinases differ biochemically and biologically); 2. Establishment of high throughput assays to quantitatively measure the activity of several Eph tyrosine kinases; 3. Rational design of improved inhibitors of the Eph tyrosine kinases; 4. Characterization of the new compounds for their ability to bind and inhibit the kinase activity; 5. Identification of candidate compounds for further development as colorectal cancer therapeutics.

The laboratory has a solid track-record of research achievements and possesses the technologies necessary to carry out the project. The BESIP student will be involved in defined aspects of this project, commensurate with the candidate expertise, desires, time constrains and probability of success in the experimental part.  In this context, the student will learn various techniques in cell biology, biochemistry, molecular biology and bioinformatics under expert supervision.