CombinatoRx Announces the Identification of Synergistic Enhancers of TRAIL-Mediated Apoptosis

CombinatoRx, Incorporated has announced data from its first biologic/small molecule combination High Throughput Screening (cHTS™) effort identifying drug classes that synergistically enhance the activity of the oncology-relevant cytokine TNF-related apoptosis inducing ligand (TRAIL) to overcome a common mechanism of TRAIL resistance.

The data were presented in a poster entitled “Synergistic Enhancers of TRAIL-Mediated Apoptosis: A Quantitative Parallel Comparison of TRAIL-Small Molecule Synergies using cHTS™” at the 98th Annual Meeting of the American Association for Cancer Research in Los Angeles, CA.

Utilizing its cHTS™ technology, CombinatoRx conducted an analysis of 122 different TRAIL-small molecule combinations across TRAIL-sensitive and insensitive non-small cell lung carcinoma (NSCLC) cell lines. The resulting synergies were then compared to identify a subset of compounds that synergistically enhance TRAIL-mediated apoptosis (cell death).

While certain compounds were synergistic, few were capable of overcoming TRAIL resistance. Of the classes studied, certain cytostatic agents, DNA cross-linking agents, and topoisomerase inhibitors were found to be particularly efficacious in overcoming TRAIL resistance while maintaining selectivity toward NSCLC cell lines.

TRAIL is an extensively studied biologic cytokine known to selectively induce apoptosis (cell death) in a variety of cancer cell lines through the activation of an apoptotic signaling cascade. Although TRAIL is regarded as a potentially useful anti-cancer therapeutic, many tumor cell lines display partial or complete resistance to TRAIL treatment.

“As the largest reported parallel comparison of TRAIL-mediated synergies, these data demonstrate the power of cHTS™ to quantitatively screen and compare large numbers of biologic/small molecule combinations to select drug combinations with the greatest potential efficacy,” commented Curtis Keith, Ph.D., Senior Vice President, Research of CombinatoRx.

“Our cHTS™ technology could prove to be extremely valuable in identifying biologic/small molecule combinations that have the potential to provide therapeutic benefit for severe life threatening diseases such as NSCLC,” Keith continued.