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

David Schwartz, James A. Bankson, Robert Lemos, Stephen Y. Lai, Arun K. Thittai, Yi He, Galen Hostetter, Michael J. Demeure, Daniel D. Von Hoff, Garth Powis

Research output: Contribution to journalArticle

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Abstract

Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1α (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 patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1α in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1α in 43% of cases. We investigated the novel selective HIF-1α inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1α 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.

Original languageEnglish (US)
Pages (from-to)2057-2067
Number of pages11
JournalMolecular Cancer Therapeutics
Volume9
Issue number7
DOIs
StatePublished - Jan 1 2010

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Hypoxia-Inducible Factor 1
Pancreatic Neoplasms
Drug Therapy
Pancreatic Ductal Carcinoma
Radiation
Neoplasms
gemcitabine
Radiation Tolerance
Radiation Effects
Chemoradiotherapy
Therapeutics
2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
Heterografts
Fluorouracil
Blood Vessels
Pancreas
Ultrasonography
Transcription Factors
Radiotherapy
Biomarkers

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. / Schwartz, David; Bankson, James A.; Lemos, Robert; Lai, Stephen Y.; Thittai, Arun K.; He, Yi; Hostetter, Galen; Demeure, Michael J.; Von Hoff, Daniel D.; Powis, Garth.

In: Molecular Cancer Therapeutics, Vol. 9, No. 7, 01.01.2010, p. 2057-2067.

Research output: Contribution to journalArticle

Schwartz, David ; Bankson, James A. ; Lemos, Robert ; Lai, Stephen Y. ; Thittai, Arun K. ; He, Yi ; Hostetter, Galen ; Demeure, Michael J. ; Von Hoff, Daniel D. ; Powis, Garth. / Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 7. pp. 2057-2067.
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AU - Lai, Stephen Y.

AU - Thittai, Arun K.

AU - He, Yi

AU - Hostetter, Galen

AU - Demeure, Michael J.

AU - Von Hoff, Daniel D.

AU - Powis, Garth

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AB - Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1α (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 patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1α in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1α in 43% of cases. We investigated the novel selective HIF-1α inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1α 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.

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