The enclosed proposal is a competitive revision of R01-CA120439 "Small Molecule Activators of Procaspases as Anti-Cancer Agents." The broad objectives of parent R01-CA120439 are to investigate the novel anti-cancer agent PAC-1;specifically its mechanism of procaspase-3 activation in vitro, the mechanism by which it induces apoptotic death in vivo, and its efficacy in mouse xenograft models. Through work toward these funded aims of R01-CA120439 we have identified a highly active and non-toxic derivative of PAC-1, called s-PAC-1. We now propose to evaluate s-PAC-1 in a Phase I clinical trial in client-owned dogs (pets) with lymphoma, with the primary endpoint being maximal tolerated dose (MTA), with a secondary endpoint of pharmacokinetic profile, and a tertiary endpoint of efficacy. Importantly, in preliminary results we have given s-PAC-1 to 5 pet dogs with lymphoma, with good results. In the Specific Aim of this competitive revision s-PAC-1 will be assessed in a Phase I clinical trial in 36-72 dogs with spontaneous lymphoma in a dose escalation study. Validation of the safety and efficacy of s-PAC-1 in canines with spontaneously-occurring cancer would validate direct procaspase-3 activation as an anti-cancer strategy, and this compound would then be ready for a fast track Phase I human clinical anti-cancer trial. PUBLIC HEALTH RELEVANCE: PAC-1 is the first small molecule to be described that directly activates procaspase-3 in vitro, and this experimental therapeutic has promise as an anti-cancer agent. In this proposal we seek funds to evaluate a PAC-1 derivative, called s-PAC-1, in a clinical trial with client-owned dogs (pets) with lymphoma.