Enhanced antitumor activity of the HIF-1 inhibitor PX-478 combined with radiation and chemotherapy in pancreatic cancer

Growing tumors respond to hypoxic stress through increased expression of the HIF‐1α transcription factor resulting in an adaptive switch to glycolytic metabolism, angiogenic signaling, survival, and metastasis. HIF‐1α expression is associated with tumor resistance to cytotoxic therapy and inferior clinical outcomes. Pancreatic cancer is frequently associated with extensive desmoplasia, hypovascularity, and hypoxia, and is resistant to chemotherapy and radiation treatment. We have observed that HIF‐1α is increased compared to normal pancreatic tissue in 24/32 (75%) of patent pancreatic ductal carcinoma samples, while 43% of the surrounding stromal tissue also showed elevated HIF‐1α. Distal stroma showed no increase in HIF‐1α. We have investigated the effects of the novel selective HIF‐1α inhibitor PX‐478 currently in Phase I clinical trial, on the in vitro and in vivo radiation response of human pancreatic cancer models. In pancreatic cancer cell lines, inhibition of HIF‐1α by PX‐478 was associated with increased cell killing by radiation with a radiation enhancement factor at 0.2 surviving fraction (SF2) in hypoxia (1% O 2 ) of between 1.3 and 1.4. In mice with Panc‐1 xenografts, 1 Gy QD alone × 5 yielded a tumor inhibition T/C at 70 days of 65% (with no regression), PX‐478 20mg/kg po QD × 5 yielded a T/C of 14% (with 41% tumor regression) and the combination of 20mg/kg po PX‐478 given daily 4 hr before 1 Gy × 5 provided a T/C of 8% (with 81% tumor regression). In CF‐PAC‐1, or SU.86.86 sc pancreatic xenografts, concurrent administration of 10 mg/kg PX‐478 potentiated the antitumor effects of fractionated radiation and 5FU 20 mg/kg iv QD × 5 with a T/C of up to 3%, and with 66% tumor regression. In Panc‐1 and SU.86.86 xenografts 20 mg/kg PX‐478 potentiated the antitumor effects of radiation in combination with gemcitabine 120 mg/kg ip Q3D given one week later with a T/C of up to 8%, and with 80% tumor regression. Early tumor responses to combined PX‐478/radiation treatment could be rapidly quantified by clinically relevant vascular imaging biomarkers. DCE‐MRI and ultrasound imaging reproducibly discriminated tumor responses to PX‐478 alone or combined with radiation as early as 10 days post‐treatment, before differences in anatomic tumor size could be detected. Therefore, PX‐478 is a mechanistically appealing and potentially clinically relevant enhancer of pancreatic cancer radiosensitivity, inhibiting tumor and stromal HIF‐1 pro‐angiogenic signaling and reducing the innate radiation resistance of hypoxic tumor cells. Supported by CA CA109552‐05. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B194.