Tumor Hypoxia?
Tumor hypoxia, or low oxygen concentration, is a result of the disordered vasculature found in all solid tumors and represents a compelling target for anti-cancer intervention. Conventional anti-cancer therapies typically target actively dividing cells in close proximity to the vasculature. But solid tumors also have zones in which the vasculature is disordered and chaotic. There are many irregularities and abnormalities in tumor vasculature including a wide variation in the distance between the blood vessels that carry oxygen and other vital nutrients to tissues. In normal tissues, the distance between blood vessels is carefully regulated by several processes. However, in tumors the growth of malignant cells is unregulated and some cells or regions literally outgrow their blood supply, leading to severe deficiencies in the perfusion of oxygen and nutrients. Also, the blood vessels in tumors are often abnormal with “blind-ends” and temporary occlusions. Together, the abnormalities in tumor vasculature and the exaggerated intercapillary spacing lead to distinctive microenvironments that do not exist in normal tissues and to which neither oxygen nor many traditional anti-cancer agents can penetrate. Furthermore, cells in these hypoxic zones are relatively quiescent which renders them refractory to most cancer chemotherapies that target the rapidly proliferating cells which are the hallmark of cancer. And finally, it has been demonstrated that cells kept under a hypoxic constraint accumulate genetic mutations which can ultimately lead to resistance to the same drugs that so effectively targeted their progenitors and which otherwise enhance their metastatic potential, ultimately contributing to treatment relapse. TH-302 has been designed to be selectively activated within these hypoxic cells, killing them as well as those in close proximity via a bystander effect. Preclinical as well as early clinical data suggest that TH-302 exerts significant anti-tumor activity both alone as well as in combination with other therapies that target the rapidly proliferating cells found in normally oxygenated compartments of solid tumors.
What is TH-302?
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 many 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 surrounding oxygenated regions of the tumor, exerting what is referred to as a bystander effect. In this way, TH-302 can kill more of the tumor than can otherwise be accounted for by the hypoxic fraction alone. Because of its selective activation in the hypoxic regions of solid tumors, we believe that TH-302 will be less likely to produce the systemic toxicity caused by most cytotoxic chemotherapies.
