8:00 AM Abstract No. 4 - Selective hypoxia-activated intraarterial therapy in a rabbit liver tumor model

Abstract

Tumor hypoxia has been shown to correlate with treatment failure and progression to a more aggressive cancer phenotype. Hypoxia resulting from embolization also contributes to chemoresistance after TACE. TH302, a nontoxic prodrug, has been shown to be selectively activated by hypoxia resulting in DNA damage and tumor cell death. The study aim was to evaluate the feasibility, safety and efficacy of hepatic hypoxia-activated intraarterial therapy (HAIAT) in a rabbit model. 28 VX2 tumor-bearing rabbits were assigned to 4 intraarterial therapy (IAT) regimens: 1) saline (control group); 2) TH302; 3) doxorubicin-Lipiodol emulsion followed by embolization with 100-300μm beads (conventional, cTACE); or 4) a combination of TH302 and cTACE (TH302-cTACE). Blood work was performed pre-IAT and 24/48 hours, 7/14 days post-IAT. Antitumor efficacy was assessed quantitatively on CT (24h pre-, 7/14 days post-IAT). Pathologic tumor necrosis was quantified by slide-by-slide segmentation. Hypoxic fraction (HF) and compartment (HC) were determined by immunohistochemistry (IHC) and morphometrics of pimonidazole staining. Endogenous hypoxia and cell death were evaluated by specific markers including HIF1-α, TUNEL, caspase-3, annexin V and γ-H2AX. AST/ALT were similarly elevated in TH302-cTACE and cTACE except at day 7 where ALT was higher in the former (median, 211 vs 113; P=.03) with normalization by day 14. All treated tumors were significantly smaller at 7 and 14 days vs control. At 14 days, the TH302 group had bigger tumors compared to TH302-cTACE and cTACE (median, 2.3 vs 0.24cm3 and 2.3 vs 0.8cm3, respectively; P=.03). The TH302-cTACE group had smaller tumors (P=.03), lower growth rate (-69% vs 17%; P=.03) and higher median necrotic fraction (96 vs 39%) compared to cTACE. TH302 resulted in a reduction in the HF and HC (P<.05). IHC data showed that TH302 or TH302-cTACE promoted antitumor effects as evidenced by caspase-3 activation, TUNEL, annexin V and γ-H2AX staining. TH302 showed a bystander effect with apoptosis and DNA damage extending beyond hypoxic areas. HAIAT with TH302 was feasible, safe, and demonstrated antitumor activity by selective targeting of hypoxic tumor tissues.