Abstract 5054: Hypoxia-activated prodrug TH-302 enhances antitumor activity of antiangiogenics in preclinical models

Antiangiogenics have revolutionized cancer therapy. Angiogenesis is a critical step in the establishment, growth, and metastasis of solid tumors. However, relative to other cancer drugs, the dramatic delays in disease progression after antiangiogenic therapy are tempered by the smaller differences in overall survival time. Such differences have led to the hypothesis that antiangiogenic therapy increases tumor hypoxia and leads to the emergence of an aggressive cancer phenotype. TH-302, a 2-nitroimidazole triggered hypoxia-activated prodrug, releases bromo-isophosphoramide mustard (Br-IPM), which induces DNA crosslinking in hypoxic cells. TH-302 has been shown in human tumor xenograft models to target the hypoxic compartment selectively and reduce its volume. A series of studies have been conducted to investigate whether TH-302 and antiangiogenic combination have improved efficacy. Xenograft models were established by s.c. implantation of 4 x106 786-O human renal cell carcinoma (RCC) or 1×106 H460 human non-small cell lung cancer (NSCLC) cells into the flanks of nude mice. Tumor hypoxia was detected by pimonidazole immunostaining, and morphometric analysis was performed to determine the hypoxic fraction. When tumor size was approximately 100-150mm3, sunitinib or sorafenib was administered daily. TH-302 administration began one week after antiangiogenics administration. Sunitinib and sorafenib increased hypoxia in both the RCC and NSCLC xenografts in a dose- and time-dependent manner. In the RCC model, sunitinib activity was potentiated with TH-302: TGI increased from 38% with 40mg/kg sunitinib monotherapy to 75% with 50 mg/kg TH-302. In the NSCLC model, sunitinib (20, 40 or 80mg/kg QDx21) activity was potentiated with TH-302 (50mg/kg, QDx5 x2wk) from 78% TGI (sunitinib monotherapy) to 97% TGI with TH-302 combination therapy. In another study, sunitinib was administered for 33 days, and TH-302 was administered for 4 weeks. With this longer dosing regimen, antitumor activity increased. Medium dose sunitinib (40mg/kg) in combination with TH-302 reached 99% TGI and delayed tumor growth to 500mm3 for 29 days. A complementary effect of TH-302 in combination with sorafenib was also observed (94% TGI for combination therapy versus less than 80% TGI for either monotherapy in the NSCLC model). Importantly, body weight loss, a toxicity indicator, was not significantly increased with TH-302 in combination with any of the antiangiogenics in these studies. In summary, TH