Translational Research of PT-112, a Clinical Agent in Advanced Phase I Development: Evident Bone Tropism, Synergy in Vitro with Bortezomib and Lenalidomide , and Potent Efficacy in the Vk*MYC Mouse Model of Multiple Myeloma

Introduction: PT-112 is a first-in-class platinum-pyrophosphate agent under advanced Phase I development in solid tumors. PT-112 was rationally designed to circumvent the toxicity and mechanisms of resistance associated with conventional chemotherapy. In previous preclinical models using PT-112, multiple cell signaling effects have been observed: p16 mediated G1/S cell cycle arrest; MDM2/p53 expression modulation; extrinsic apoptosis initiation; and signals indicative of immunogenic cell death (Ames et al., Eur. J. Cancer 2016). In addition, the ongoing first-in-human PT-112-101 Phase I trial in solid tumors has demonstrated a positive therapeutic index, with a range of biological activity observed at well-tolerated dose levels and a lack of severe hematotoxicity (Karp et al., J. Clin. Oncol. 2017).