Faculty Biosketch  -                        Milton S. Hershey Medical Center
                                                                       Penn State College of Medicine
                                                                       P.O. Box 850, 
                                                                       500 University Drive
                                                                       Hershey, PA 17033-2390

Dr. Zagon, in a collaboration with Dr. Patricia J. McLaughlin, Associate Professor of Neuroscience and Anatomy, discovered that opioids can act as growth factors in neural and nonneural cells and tissues.  One native opioid peptide, methionine enkephalin, was found to exert a negative influence on growth; this peptide was termed Opioid Growth Factor (OGF) to signify its role as a growth factor and to distinguish it from its neuromodulatory function.  Subsequent work with receptor binding analysis revealed a nuclear-associated receptor for OGF, OGFr.  Biochemical, cellular, and molecular work on the receptor, particularly in collaboration with Dr. Michael F. Verderame in the Department of Medicine, resulted in the cloning and sequencing the cDNA for OGFr in rat, mouse, and human, along with the chromosomal identity on human chromosome 20q13.3.  The OGF-OGFr axis has been studied in vivo and in vitro, and the interaction of OGF-OGFr defined in development, homeostatic renewal, neoplasia, and injury.  OGF serves as a tonically active, constitutively expressed, inhibitory growth factor, and displacement of OGF-OGFr interfacing using opioid antagonists, antibodies to OGF, and antisense technology with OGFr, accelerates growth.

Basic Science studies on the biology of OGF and OGFr continue (e.g., trafficking of the peptide and receptor, targeting of the cell cycle, characterizing the receptor).  However, a long-range intent of our research program has been to translate scientific discoveries from the laboratory to the bedside.  Our medical center- with patients, facilities such as the General Clinical Research Center (GCRC), and clinical faculty, is the perfect environment to achieve this goal.  Some current projects include: 1) The treatment of pancreatic cancer with OGF.  Working with Dr. Jill P. Smith and Dr. Harold Harvey in the Department of Medicine, Dr. David Mauger in the Department of Health Evaluation, and Dr. Larry Demers from the Department of Pathology, we have recently been successful in completing phase I trials using OGF in pancreatic cancer patients.  While funding for Phase II trials is being sought, we already have data showing that some of these patients may live twice as long with OGF administration in comparison to standard of care treatments.  2) The pathogenesis of squamous cell carcinoma of the head and neck is related to a defect in the OGF-OGFr axis.  In a team effort with Dr. Brendan Stack of the Department of Surgery, we have learned that the OGF receptor (OGFr) is progressively disabled thereby providing a growth advantage to these neoplasias, and the loss of OGFr may serve as a marker for these cancers.  Phase II trials are now being initiated to supplement OGF in order to augment growth inhibition early in these neoplasias, and preclinical experiments using gene therapy to add OGFr to these cells - and reinstate the OGF-OGFr intracellular growth regulatory pathway - are now underway.  3) Homeostasis and wound healing of the corneal epithelium in diabetes can be restored to normal by blocking OGF-OGFr interactions with the opioid antagonist, naltrexone.  These preclinical studies have been conducted in a collaborative effort with Dr. Joseph W. Sassani of the Department of Ophthalmology.  Phase I trials with topical application of naltrexone in patients will be undertaken following investigations concerning the safety and toxicity of naltrexone applied to the ocular surface. 4) The use of low-dose naltrexone therapy as a therapeutic agent in colorectal cancer.  Earlier studies have shown that daily intermittent opioid receptor blockade from endogenous opioids has a remarkable antitumor effect, markedly reducing the incidence of - and delaying the growth - some gastrointestinal cancers.  In collaboration with Dr. Jill P. Smith, phase II studies using a low-dose naltrexone regimen are now being constructed.  5) OGF is known to target the cell cycle.  However, the specific pathway of this influence on OGF as to cell replication is unknown.  Currently, a predoctoral student in Cell and Molecular Biology is performing research to elucidate this pathway.  6) Some information about the trafficking of OGF and OGFr in cells has been reported using confocal microscopy and immunoelectron microscopy; this work was performed by an M.S. degree student.  Using probes for OGF and OGFr, including green fluorescent technology and labeled OGF, the dynamic relationship of OGF and OGFr and being investigated.  7) A great deal of knowledge would come from the generation of transgenic animals that over-express OGFr. Currently, we are working on generating transgenic mice that over-express OGFr in the cerebellum, heart, and the cornea.

Zagon, I.S., M.F. Verderame, W.E. Zimmer, and P.J. McLaughlin. 2000.  Molecular characterization and distribution of the opioid growth factor receptor (OGFr) in mouse.  Molecular Brain Res. 84:106-114.

Zagon, I.S., M.F. Verderame, and P.J. McLaughlin. 2002.  The biology of the opiod growth factor receptor (OGFr) Brain Res. Rev. 38-351-376.

Zagon, I.S., J.B. Jenkins, J.W. Sassani, J.D. Wylie, T.B. Ruth, J.L. Fry, C.M. Lang, and P.J. McLaughlin. 2002.  Naltrexone, an opioid antagonist, facilitates re-epithelialization of the cornea in diabetic rat.  Diabetes 51:3055-3062.

Zagon, I.S., F.M. Essis, M.F. Verderame, D.A. Healy, R.G. Atnip and P.J. McLaughlin. 2004. Opioid growth factor inhibits intimal hyperplasia in ballon-injured rat carotid arter.  J. Vasc. Surg 37: 636-643.

Zagon, I.S., T.B. Ruth, A.E. Leure-duPree, J.W. Sassani and P.J. McLaughlin.  2003.  Immunoelectron microscopic localization of the opioid growth factor receptor (OGFr) and OGF in the cornea.  Brain Res. 967:37-47.

Zagon, I.S. and P.J. McLaughlin. 2003. Opioids and the apoptotic pathway in human cancer cells. Neuropeptides 37:79-88.

Zagon, I.S., M.F. Verderame and P.J. McLaughlin.  2003.  The expression and function of the OGF-OGFr axis-a tonically active negative regulator of growth - in COS cells.  Neuropeptides 37:290-297.

McLaughlin, P.J., B.C. Stack, K.M. Braine, J.D. Ruda and I.S. Zagon. 2004. Opioid growth factor (OGF) inhibition of a human squamous cell carcinoma of the head and neck in nude mice:  Dependency on the route of administration.  Int. J. Oncol. 24:227-232.

Smith, J.P., M. Ahmad, R. Conter, S. Bingaman, J.Harvey, D. Mauger, L. Demers, PJ. McLaughlin, W. Stanley, and I.S. Zagon. 2004.  Treatment of advanced pancreatic cancer with opioid growth factor: Phase 1.  Anti-Cancer Drugs 15:203-209.

Zagon, I.S., P.J. McLaughlin. 2004. Opioid growth factor (OGF) inhibits anchorage-independent growth in human cancer cells.  Int. J. Oncol. 24: 1443-1448.

Zagon, I.S., and P.J. McLaughlin.  2004. Gene expression of OGFr in the developing and adult rat brain and cerebellum.  Brain Res. Bull. 63:57-63.

Zagon, I.S., T.B. Ruth and P.J. McLaughlin. 2005.  Nucleocytoplasmic distribution of opioid growth factor (OGF) and its receptor (OGFr) in tongue epithelium. 
The Anatomical Record 282A:24-37.

Jagowski, J.R., I.S. Zagon, B.C. Stack, M.F. Verderame, A.E. Leure-duPress, J.D. Manning and P.J. McLaughlin.  2005.  Opioid growth factor (OGF) enhances tumor growth inhibition and increases the survival of paclitaxel-treated mice with squamous cell carcinoma of the head and neck. Cancer Chemother. Pharmacol., in press.

Zagon, I.S., J.W. Sassani, M.F. Verderame and P.J. McLaughlin. 2005. Particle-mediated gene transfer of OGFr cDNA regulates cell proliferation of the corneal epithelium. Cornea, in press.

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