A New Application of Metabolic Targeting

Tumor hypoxia, a region of very low oxygen concentration in solid tumors, was first characterized a half-century ago. Abnormal or poor blood vessel growth, a fundamental hallmark of tumors, was later shown to be the cause of tumor hypoxia. Many solid tumors have significant hypoxic regions, and because these regions have limited access to the blood supply and oxygen, the cells in them divide slowly, making them resistant to traditional chemotherapy and radiation treatment, which target rapidly dividing cells. Moreover, many scientists now believe that hypoxia can accelerate tumor invasiveness and metastatic potential. Thus, therapeutics that specifically target resistant hypoxic zones could provide significant additional anti-tumor activity and clinical benefit over current chemotherapeutic and radiation therapies.

Threshold has been developing new drugs to target the hypoxic regions of tumors. Threshold’s research has focused on prodrugs that are activated only in the hypoxic regions of tumors (Hypoxia-Activated Prodrugs or HAPs). A prodrug is an inactive compound that is converted in the human body by enzymatic processes to form an active drug. The prodrug concept is well established in chemotherapy, but initially employed only to modify the pharmacokinetic properties of compounds. More recently, the prodrug concept been applied to the design of agents that are selectively activated in tumor tissues by specific activation processes.

Threshold’s lead HAP prodrug TH-302 consists of two distinct parts, a toxic portion and an attached molecular trigger. To prevent general toxicity, the molecular trigger keeps the toxin inactive until the prodrug is in the hypoxic region of the tumor, where it is then activated by low oxygen concentration. Once activated, the toxin kills cells in its vicinity. Threshold filed an IND with the FDA in April 2007 and started a Phase 1 clinical trial in solid tumors in July 2007.