Targeting protein translation for anticancer therapies; CD59 and diabetes
Employ the preclinical resources of the Laboratory for Translational Research to develop new therapies and diagnostics in oncology and diabetes
Novel small molecules for antagonizing cancer cell growth; diagnostic tests to screen for persons at risk for developing diabetes and its associated vascular disturbances
Dr. Halperin’s lab is geared toward developing clinical applications from their biological findings. They have advanced their development of novel small molecule inhibitors that target protein complexes required for protein translation initiation, and their data is very encouraging. Their results continue to strongly support the contention that a subset of growth-promoting mRNAs such as oncogenes are more susceptible to translation inhibition by agents that disrupt translation initiation, due to the distinct nature of their 5´ UTRs. Consequently, cancer cells, which display unrestrained growth as their hallmark, are differentially affected by these inhibitors as compared to normal differentiated cells. These drug discovery efforts have the potential to open up new avenues for anticancer drug development.
The chronic elevated glucose levels in diabetics can damage blood vessels (that is, angiopathy) and lead to serious vascular complications, including organ deterioration (e.g., kidney and heart), retinopathy, and led and feet disorders. Dr. Halperin’s studies on CD59 as a biomarker for diabetes and vascular diseases should lay the groundwork for the development of new diagnostic clinical tests.
Dr. Halperin built the Laboratory for Translational Research as a means of converting basic biological knowledge into practical benefit, otherwise described as the “bench-to-bedside” process. The lab has the technological resources, including robotics, to undertake assay development, medicinal chemistry, primary and secondary screens, high throughput screening, and in vivo studies employing mouse models of disease.
For the anticancer investigations, the lab is extending its earlier observations on the targeting of initiation of translation for attenuating cancer cell growth. Published data from multiple labs have reinforced the validity of this approach, for it has been demonstrated that mRNAs possessing long 5´UTRs, which typically encode proteins that promote cell growth, require efficient translation initiation. The lab is developing small molecule inhibitors displaying increased potency and selectivity for two different multiprotein entities that participate in the protein translation initiation process: (1) the ternary complex, consisting of eIF2 bound to initiator methionyl tRNA and GTP; and (2) the eIF4F complex, containing eIF4A, eIF4E (which binds the 5´ mRNA cap motif), and eIF4G. The lab is collaborating with Dr. Gerhard Wagner on high resolution NMR structural studies to facilitate the development of novel compounds that disrupt the protein-protein interactions that comprise these multimers.
The lab is also exploring the relationship of glycated CD59 to vascular disease in diabetics. Glycation of the complement inhibitor CD59 presages vascular complications in diabetic patients, and the lab has developed the first informative animal models for diabetes-related vascular abnormalities by making transgenic mice harboring the wild-type or mutant human CD59 gene. These mouse models are being utilized to explore the etiology of vascular disease and to develop diagnostic tests for predicting the onset of vascular pathophysiology in diabetics.
Dr. Halperin has made important scientific findings in cancer and diabetes. Dr. Halperin illuminated the cancer-fighting properties of clotrimazole, routinely used to combat fungal infections. He demonstrated that clotrimazole modulates intracellular calcium levels, leading to a series of reactions that culminates with inhibition of protein translation at the initiation stage. This finding spurred subsequent cancer therapeutic studies, focusing on targeting protein translation initiation as a key nodal point. Dr. Halperin’s lab also showed that naturally occurring molecules such as the omega-3 unsaturated fatty acid eicosapentaenoic acid (EPA), commonly found in fish, blocks cancer cell growth by disrupting translation initiation. These data have important ramifications, since they implicate the initiation phase of protein translation as a valid target for developing cancer therapeutics. Moreover, these results help explain why diets high in fish have been linked to a reduced cancer incidence. Recent studies in the lab have investigated small molecule inhibitors of protein translation initiation, in collaboration with Dr. Gerhard Wagner.
Diabetes is another major area of interest in the lab. Based on their study of vascular abnormalities in diabetic patients, the lab proposed that glycation (that is, glucose covalently bound to a lysine residue) of the membrane complement regulatory protein CD59 inactivates CD59. By abolishing CD59 activity, activation of the complement cascade and formation of the membrane attack complex is promoted, eliciting proinflammatory alterations in endothelial cells which line blood vessels. This proposed sequence of events may contribute to the vascular complications commonly found in diabetic patients. These data suggest new methods for diagnosing persons at risk for developing diabetes and diabetes-associated vascular disease.