Cancer is a significant health burden in the US and across the globe, representing the second leading cause of death in the US. Cancer cells have metabolic pathways that are altered significantly compared to normal cells. As a result, the pathways involved (lipid biosynthesis for example) are considered excellent targets for therapeutic intervention. The levels of ether lipids have been found elevated in cancer cells, but it was not until late 2013 that a specific role in cancer was described. Historically, these important signaling molecules were investigated in peroxisomal disorders, where decreased levels result in assorted diseases that often cause death before the age of twenty. The 2013 report revealed an important role for ether lipids in tumor cell growth. The precursor for all ethe lipids is produced in cells by the enzyme alkyldihydroxyacetone phosphate synthase (ADPS), also called alkylglycerone phosphate synthase (AGPS). The report mentioned above described that elevated levels of ADPS result in proliferation of cancer cells, while reduction of ADPS levels accomplished by shRNA resulted in decreased growth of cancer cells and reduction in levels of numerous lipids involved in oncogenic signaling. While this report is an exciting development for identification of a new therapeutic target for cancer, broad investigation is hampered by the lack of any commercially-available research tools. In fact, even the enzyme and substrates are only available if prepared by individual research laboratories. Assays for ADPS activity rely on the use of radioactive substrates (which are not suitable for high throughput or widespread utility), monitoring the change in redox state of the flavin cofactor (which suffers from a lack of sensitivity and selectivity) or a complex assay coupled to additional enzymes. Echelon Biosciences, Inc. has extensive experience developing research tools including enzymes, substrates (natural and fluorescent analogs) and assay kits to facilitate investigation of biological pathways, elucidating their role(s) in diseases and the discovery/advancement of inhibitors targeting them. Representative examples include suites of tools developed for phoshpoinositide 3-kinase and autotaxin which utilize smart-probes activated by their respective enzyme, various assay platforms for use in biological samples and inhibitor screening, ELISAs for determining levels of each protein and an in vivo imaging agent for use in live animals. This Phase I project will develop research tools to enable widespread investigation of ADPS and ultimately identify novel therapeutic candidates.
Aim 1 will develop chemical tools to study ADPS.
Aim 2 will determine factors for rational probe design and produce novel fluorescent probes to monitor ADPS activity while Aim 3 will establish an assay platform for detecting ADPS activity in a plate-based assay format. Phase II will expand upon Phase I by adapting the assay for use with biological samples, screening inhibitors that will be advanced as new therapeutic candidates and construct new derivatives for in vivo imaging.
A recent report revealed that an exciting metabolic pathway to exploit for cancer-directed therapies, as well as a host of additional diseases, is that of ether lipid biosynthesis. Elevated ether lipids had been found in a number of cancer cells but a role in pathology had not been defined. This project will develop novel tools for studying ether lipid biosynthesis that will enable new therapeutic development and further elucidation of their roles in biological processes.