What is Tumor Hypoxia?

Hypoxia is a condition in which there is a decrease in the oxygen concentration in tissue. In cancer, as a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. This condition is called Tumor Hypoxia.

Several studies have shown that higher levels of tumor hypoxia correlate with poor treatment outcomes for a variety of solid tumors. It is believed that hypoxia may severely limit the curability of tumors. This lack of oxygen in cancer cells compared to normal cells is exploited by Threshold’s Hypoxia-Activated Prodrug (HAP) platform. This technology platform may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse.

A New Class of Drug — TH-302

TH-302 is an anticancer agent in clinical development at Threshold. Preclinically, it is preferentially activated under hypoxic conditions and has demonstrated potent anticancer activity in several preclinical cancer models. TH-302 is converted selectively to the drug’s active form, dibromo isophoramide mustard, a potent DNA alkylator, within hypoxic tumor cells. TH-302 targets levels of hypoxia that are common in tumors but are rare in normal tissues – this is how selective targeting of the tumor occurs. After conversion to the active form of the drug, the more resistant hypoxic cells are exposed to high concentrations of released cytotoxic agent, which can also diffuse into the oxygenated regions of a tumor cell. We believe that TH-302 will be less likely to produce the systemic toxicity caused by most cytotoxic chemotherapies.

In July 2007, we initiated a Phase 1 clinical trial of TH-302, a hypoxia-activated prodrug for the treatment of solid tumors. We expect a number of development candidates to arise from our hypoxia-activate prodrug platform within the next several years.