Tumors often contain hypoxic regions resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-activated prodrug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. This study evaluated the efficacy and safety profile of combining T with gemcitabine (G) and nab-paclitaxel (nP) in human pancreatic ductal adenocarcinoma (PDAC) xenograft models in mice. Antitumor activity of the G + nP + T triplet was assessed and compared with T-alone or the G + nP doublet in the Hs766t, MIA PaCa-2, PANC-1, and BxPC-3 PDAC xenograft models. Efficacy was assessed by tumor growth kinetic analysis. Body weight, blood cell counts, blood chemistry, and the von Frey neuropathy assay were analyzed to evaluate safety profiles. Pharmacodynamic changes after the treatment were determined by immunohistochemistry of cell proliferation, DNA damage, apoptosis, hypoxia, and tumor stroma density. The G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP doublet. Compared with vehicle (V), G + nP induced body weight loss, reduced neutrophil and lymphocyte counts, increased the levels of liver function parameters, and induced neurotoxicity. However, when T was added to G + nP, there was no statistically increased impairment compared to G + nP. The triplet significantly increased DNA damage, apoptosis, and tumor necrosis. Furthermore, the triplet further inhibited cell proliferation and reduced stroma density and intratumoral hypoxia. The triplet combination of G + nP + T exhibited superior efficacy but additive toxicity was not evident compared to the G + nP doublet in this study. This study provides a translational rationale for combining G, nP, and T in the clinical setting to assess efficacy and safety. A Phase I clinical trial of the triplet combination is currently underway (NCT02047500).
Keywords: BW, body weight; Br-IPM, a brominated analog of isophosphoramide mustard; CAF, cancer-associated fibroblast; CAIX, carbonic anhydrase IX; CR, complete response; EMT, epithelial to mesenchymal transition; G, gemcitabine; HF, hypoxic fraction; ILS, increased life span; MT, median time to reach the size of 1000 mm3; MTD, maximum tolerated dose; NF, necrotic fraction; PDAC, pancreatic ductal adenocarcinoma; T, TH-302; TGD1000, tumor growth delay compared to Vehicle reaching the size of 1000 mm3; TGI, tumor growth inhibition; TH-302; V, vehicle; gemcitabine; hypoxia; hypoxia-activated prodrug; nP, nab-paclitaxel; nab-paclitaxel; pancreatic cancer; pharmacodynamics, biomarker; smooth muscle actin; xenograft; α-SMA, α.