Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer - PubMed (original) (raw)

Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer

David L Schwartz et al. Mol Cancer Ther. 2010 Jul.

Abstract

Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1alpha (HIF-1alpha) transcription factor, resulting in an adaptive switch to glycolytic metabolism, angiogenic signaling, survival, and metastasis. HIF-1alpha expression is associated with tumor resistance to cytotoxic therapy and inferior patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1alpha in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1alpha in 43% of cases. We investigated the novel selective HIF-1alpha inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1alpha by PX-478 increased cell killing by radiation. In mice with Panc-1, CF-PAC-1, or SU.86.86 pancreatic xenografts, concurrent administration of PX-478 potentiated the antitumor effects of fractionated radiation, with or without combined treatment with 5-fluorouracil or gemcitabine. Alternative sequencing of PX-478 with fractionated radiotherapy suggests optimal radiosensitization with concurrent or neoadjuvant administration of drug. Early tumor responses to combined PX-478/radiation treatment could be rapidly and repeatedly quantified by vascular imaging biomarkers. Dual-tracer dynamic contrast enhanced-magnetic resonance imaging and ultrasound imaging discriminated response to combined treatment prior to detection of differences in anatomic tumor size at 10 days posttreatment. Therefore, PX-478 is a mechanistically appealing and potentially clinically relevant enhancer of pancreatic cancer radiosensitivity, inhibiting tumor and stromal HIF-1 proangiogenic signaling and reducing the innate radiation resistance of hypoxic tumor cells.

(c)2010 AACR.

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Figures

Figure 1

Figure 1

Immunohistochemistry of HIF-1 in patient tumors and PX-478 potentiation of the antitumor activity of fractionated radiation in Panc-1 tumor xenografts. A, typical staining of cytokeratin and HIF-1α. Left to right, two moderately well-differentiated ductal carcinomas and a moderately differentiated acinar carcinoma. The numbers are HIF-1α staining on a scale of 0 to 3 for the pancreatitis/tumor and for the adjacent stroma. B, histogram showing numbers of tumors in each staining range. Open bars, PDC (42 evaluable); filled bars, normal pancreas (42 evaluable); rough cross hatching, stroma adjacent to tumor (32 evaluable); fine cross hatching, stroma distant to tumor (30 evaluable). Stroma did not include blood vessel staining. C, female SCID mice with Panc-1 pancreatic tumor xenografts, 8 mice per group, were treated with vehicle alone (●);1 Gy radiation daily for 5 days (□); PX-478 10 mg/kg orally daily for 5 days (△); PX-478 20 mg/kg orally daily for 5 days (▲); PX-478 10 mg/kg orally daily for 5 days 1 hour before Gy radiation daily 1 for 5 days (◇); and PX-478 20 mg/kg orally daily for 5 days 1 hour before 1 Gy radiation daily for 5 days (◆). Arrows, daily dosing and/or radiation treatment. Values are the mean of 8 mice per group; bars, SE of mean.

Figure 2

Figure 2

PX-478/radiation sequencing study treatment cohorts. Female SCID mice with Panc-1 pancreatic tumor xenografts, 8 mice per group, were treated with single-modality treatment or concurrent PX-478 25 mg/kg orally and 2 Gy radiation daily for 5 days per the indicated sequences. Timing of serial MRI and ultrasound measurements of each cohort is also indicated.

Figure 3

Figure 3

Tumor growth curves, DCE-MRI permeability/vascular volume fraction measurements, and power Doppler ultrasound measurements of tumor blood flow. Female SCID mice with Panc-1 pancreatic tumor xenografts, 8 mice per group, were treated with single-modality treatment or concurrent PX-478 25 mg/kg orally and 2 Gy radiation daily for 5 days (A, C, E), or over two weeks with sequenced PX-478 and radiation (XRT; B, D, F), as indicated. Statistical comparisons of results at each time point are with untreated controls, as reported as mean values ± SD; *, P < 0.05; **, P < 0.01.

Figure 4

Figure 4

Representative serial DCE-MRI permeability/vascular volume fraction maps for indicated PX-478/radiation sequencing study treatment cohorts. Female SCID mice with Panc-1 pancreatic tumor xenografts were treated with single-modality treatment or concurrent PX-478 25 mg/kg orally and 2 Gy radiation daily for 5 days (A) or over two weeks with sequenced PX-478 and radiation (B).

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