The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects.
Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 97, 1515 Holcombe Boulevard, Houston, TX 77030, USA. docdls@mdanderson.org
David L
DL
Schwartz
Garth
G
Powis
Arun
A
Thitai-Kumar
Yi
Y
He
James
J
Bankson
Ryan
R
Williams
Robert
R
Lemos
Junghwan
J
Oh
Andrei
A
Volgin
Suren
S
Soghomonyan
Ryuichi
R
Nishii
Mian
M
Alauddin
Uday
U
Mukhopadhay
Zhenghong
Z
Peng
William
W
Bornmann
Juri
J
Gelovani
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009150:Mustard Compounds / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D010666:Phenylpropionates / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D017154:Stromal Cells / Q000528:radiation effects*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014916:Whole-Body Irradiation
C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010666:Phenylpropionates; D042461:Vascular Endothelial Growth Factor A