James Norris

Background

About James Norris

For patients who present with many types of malignancies where the cancers were not diagnosed early allowing successful surgical intervention or had already metastasized, a successful therapeutic outcome diminishes significantly. Little improvement of this has been observed since the 1950’s. There are many reasons for this including development of cancer cell resistance to therapy or that have developed resistance as a consequence of treatment. This situation is hard to overcome and treat which results in poor outcomes. Development of new therapeutic approaches are urgently needed to improve this situation. Dr. Norris’ laboratory is studying the development and utilization of a new class of drugs that specifically intervene in an enzymatic pathway which is responsible for disruption of a variety of signaling events required for normal homeostatic function which leads to chemo and radiation resistance. Specifically, acid ceramidase (AC) is the major enzyme that regulates a signaling pathway known as the ceramide-Sphingosine, Sphingosine-1-Phosphate (S1P) rheostat. AC is upregulated in 67% of primary cancer cells that have been tested (94/139). When this occurs, increased catabolism of ceramide shifts the pathway to the right increasing the amount of anti-apoptotic S1P. S1P counteracts many of the roles of ceramide and leads to increased angiogenesis and tumor growth. The small molecules being studied interrupt the enzymatic function of AC, and restores the normal balance between apoptosis and anti-apoptosis in the cancer cell. This work demonstrates that better preclinical therapeutic outcomes can be achieved using gene, chemo- and radiation therapies combined with small molecule AC inhibitors. Results indicate the utility of modifying sphingolipid metabolism to improve clinical outcomes with therapies currently in the clinic. This work is being performed with the intent of developing clinical trials to test the validity of this approach in patients.