Invited Speaker

Translational Research from a Basic Science Perspective - Development of Novel Therapeutics for Cancer, Diabetes and Obesity
Thomas E. Adrian
UAE


Translational research involves taking findings from the laboratory to the clinical setting or in the other direction. Many academic physicians focus their research careers on basic science problems. In contrast, I have focused on clinical problems because I view that as the role of a scientist in a Medical School. Over the years this work has spanned gastrointestinal disease, cancer and diabetes and this has provided several opportunities for translation of laboratory finding into potential therapeutics.

One example was our work unraveling the importance of the inflammatory lipoxygenase (LOX) pathways in cancer. The enzymes in the 5-LOX and 12-LOX pathways are not expressed in normal epithelial tissues but are upregulated early in the development of malignancy. The products of these pathways trigger growth responses through mitogen-activated protein kinase pathways. The LOX pathways allow cancer cells to escape normal cellular growth restraints, to avoid apoptosis and to enhance angiogenesis, invasion and formation of metastases. These processes are suppressed by inhibitors of the LOX pathways. Study of potential therapeutic interventions led to the discovery of the potent anti-cancer effects of the leukotriene B4 receptor antagonist, LY293111. Promising results from the phase 1 trial led Eli Lilly to take this drug to phase 2 clinical trials for pancreatic and lung cancer both in the USA and Europe.

A long-term collaboration with Peter Collin from Coastside Bio Resources has led to the identification of several potent anti-cancer compounds from marine sources, in particular from the edible Atlantic sea cucumber, Cucumaria frondosa. One such compound, a triterpenoid called Frondoside A is under development by the RAPID program at the National Cancer Institute. Frondoside A, induces apoptosis and inhibits invasion in a wide variety of cancer cells but has no effect on normal cell function.

Several years ago at Yale University, we were investigating the physiological role of a newly discovered polypeptide hormone from the distal GI tract called peptide YY (PYY). My group had shown that PYY inhibited upper GI secretions and slowed transit through the alimentary canal in humans. PYY levels were found to be massively elevated in different disorders that produced malabsorption, including sprue, chronic pancreatitis and short bowel syndrome. We found that this peptide was co-produced in the same cells (L cells) that produced the glucagon-related peptides in the distal gut. What we did not know was how these peptides were released from the L cells which are predominantly in the distal colon. We persuaded patients that were undergoing endoscopy examinations to allow us to perfuse different nutrient solutions into the colon. We identified the release mechanism. Subsequent work has shown that glucagon-like peptide 1 (GLP-1) has valuable insulin releasing properties and also improves the peripheral tissue responses to circulating insulin. GLP-1 and the major circulating form of PYY both have inhibitory effects on food intake. Indeed, therapeutics that prevent the metabolism of native GLP-1 and a long active analogue of GLP-1 have recently been marketed for treatment of type II diabetes mellitus and weight loss. Based on our mechanistic studies, in collaboration with the San Diego, California-based Satiogen Pharmaceuticals, Inc. we are currently developing a simple way of releasing these hormones from the distal bowel as a treatment for diabetes and obesity.