Deregulation of the Myc oncogene promotes tumorigenesis in most if not all cancers and is often associated with poor prognosis. However, targeting Myc has long been considered impossible because of potential catastrophic side effects in normal tissues. Despite this general assumption, we showed that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer, and caused only mild, well-tolerated and reversible side effects in normal tissues. For these studies we have employed a dominant negative of Myc, called Omomyc, which we designed and validated, and that is able to inhibit Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as gene therapy and served the purpose of pre-clinically validating the therapeutic impact of systemic Myc inhibition. In this proposal we intend to push such a therapeutic approach further towards the clinic, making use of1. Omomyc-based Cell Penetrating Peptides (CPPs): a novel, state-of-the-art potential method for directly utilising Omomyc itself (or a similar peptide) as a drug;2. A new generation of Myc inhibitory small molecules generated by our collaborators at the Roswell Park Cancer Center.Our study in different mouse models of cancer will provide a comprehensive preclinical validation of such innovative therapies and will potentially boost our therapeutic arsenal against the majority of human cancers