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.
Schwartz
David L
DL
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
Powis
Garth
G
Thitai-Kumar
Arun
A
He
Yi
Y
Bankson
James
J
Williams
Ryan
R
Lemos
Robert
R
Oh
Junghwan
J
Volgin
Andrei
A
Soghomonyan
Suren
S
Nishii
Ryuichi
R
Alauddin
Mian
M
Mukhopadhay
Uday
U
Peng
Zhenghong
Z
Bornmann
William
W
Gelovani
Juri
J
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