Biology of the OGF-OGFr Axis

Dr. McLaughlin's laboratory centers on the OGF-OGFr axis. Initially, the laboratory, in collaboration with Dr. Ian Zagon, utilized a multifaceted approach to identify, isolate, and understand the individual components of the OGF-OGFr axis - that is, the pentapeptide OGF and its receptor, OGFr. [Met5]-enkephalin (OGF) has been identified to be the most potent opioid inhibitor; OGFis an autocrine and paracrine produced inhibitory peptide whose action is receptor mediated. The laboratories have identified, isolated, and characterized the OGFr, and determined its cDNA and gene in mouse, rat, and human. Because of the unique molecular structure and dissimilarity with classical opioid receptors, the receptor was termed opioid growth factor receptor, OGFr, located on chromosome 20q13.3 in humans.
The laboratory focuses on translational research and understanding the OGF-OGFr axis and its mechanisms of action in both normal and disease states. Currently, we are focused on understanding the OGF-OGFr axis in cancer development, progression, and treatment. A recent discovery suggests that it is not the loss of OGF, but rather a defect in the receptor number, that is characteristic of advanced stages of SCCHN. Building upon the requisite in vitro and in vivo animal model studies, the laboratory has recently been involved in assaying tumor samples, as well as pathologically normal specimens (i.e., tumor margins) from patients with SCCHN for both gene and peptide expression. Using quantitative Northern blot studies to examine for the OGFr mRNA, as well as binding assays, western blot analysis, and IHC to assess protein levels, we have documented that OGF receptors decrease significantly in tumor tissue in comparison to normal epithelia. Moreover, and perhaps the most provocative, is that the pathologically normal tumor margins are in fact, defective in their number of OGF receptors, suggesting that OGFr levels decline with cancer progression. Thus, OGFr assays could be used as a prognosticator of recurrent neoplasia. Our approach is unique and novel in that we are examining negative modulators of cancerous growth, not promoters and attempting to understand the negative signaling pathways mediated by the OGF-OGFr axis during cancer cell cycle progression. Further studies will target use of gene therapy for re-introduction of OGFr into neoplastic tissues, as well as preclinical and clinical trials using OGF as a biotherapy, alone, and in combination with other chemotherapies.