Alterations in oncogenic RAS have been identified in nearly thirty percent of all cancers with a high frequency in numerous cancers including non-small cell lung carcinomas (NSCLC). Despite significant effort in developing specific therapeutic agents, RAS remains an elusive target. Much of the focus has shifted to blocking downstream effectors of RAS signaling. RAS signaling is disseminated downstream through at least three major networks including the mitogen-activated protein kinase (MAPK), phosphoinostide 3-kinase (PI3K), and the Ras-like small GTPases RalA and RalB. Significant progress has been made in the development of agents that target multiple key components of MAPK and PI3K signaling. Despite this, none of these agents have progressed beyond early phase trials in any RAS associated cancers. We have identified that the RAS effectors RalA and RalB are vital components of RAS signaling in NSCLC. Presently, specific inhibitors of RalA or RalB have not been developed.
We are currently employing a novel approach to generate RalA and RalB directed pharmacological agents. Traditional methods of developing drugs involve large chemical library screens and have typically been reserved for large pharmaceutical companies. Newer methods involving computer aided design based on known structure data has led to the development of several kinase inhibitors. As Ral is not a kinase like many signaling mediators, the development of RalA or RalB specific inhibitors has not materialized. Our innovative approach exploits the ability of peptides to recognize and block the ability of active Ral from projecting a signal to downstream effectors. Ral has two switch conformations; GDP-bound inactive and GTP-bound active. Each is three dimensionally distinct allowing for the development of antibodies that recognize and interfere with the active switch state. Utilizing an in vitro Ral activity assay under development in our lab allows us to rapidly identify clones capable of blocking RalA and/or RalB. Promising peptides will then be assessed for their ability to inhibit Ral signaling in vivo. These peptidomimetics can then be modified for enhancement, specificity and deliverability or serve as a blueprint in developing non-peptide small molecule inhibitors. Our long term goal is to further develop these tools and evaluate them clinically in NSCLC and other Ral associated tumors.