In this project, we will investigate the role of Ire1, a critical regulator of the unfolded protein response (UPR), in modulating the tumor response to hypoxia and radiation. We have completed a high throughput small molecule screen of >120,000 compounds and identified several classes of lre1 inhibitors. We and other investigators have shown that lre1 endonuclease activity is specific for splicing XBP-1 into its active form and that XBP-1 activation is responsible for mediating survival under hypoxia and ER stress. We will develop small molecule inhibitors for Irel's specific endonuclease activity as a therapeutic strategy for breast and pancreatic cancer. We have also developed an XBP-1-luciferase transgenic reporter mouse in which we can follow Irel activity in tumors in order to optimize the dosing schedules of our Irel inhibitors. These studies will be conducted in an MMTV-Tag breast tumor model as well as a pancreatic cancer orthotopic tumor model as these tumor models reflect important aspects of the tumor microenvironment that more closely resembles human cancer. In addition, because of our data showing that ER stress within the tumor microenvironment may modulate radiation response, we will determine the role of Irel in the radiation response of aerobic and hypoxic cells to radiation. These studies will be performed in tumor cell lines in which Irel has been genetically deleted inhibited as well as in orthotopic pancreas tumors in which Irel is pharmacologically manipulated. These data will help to define the role of Irel in the response of tumors to hypoxia and radiation. This knowledge will further the development of molecular strategies to target Irel for cancer therapy.

Public Health Relevance

Although many tumors rely upon the unfolded protein response (UPR) for survival and proliferation, breast and pancreatic cancers are particularly well adapted to grow because of activation of this pathway. We have developed small molecule inhibitors of Ire1, a critical regulatory protein of the UPR. This proposal will determine the role of Irel in the response of tumors to hypoxia and radiation. Ultimately, we will utilize this knowledge to accelerate the development of cancer therapies targeting this pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA067166-17
Application #
8744823
Study Section
Special Emphasis Panel (ZCA1-RPRB-2)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
$198,153
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Rankin, Erinn B; Fuh, Katherine C; Castellini, Laura et al. (2014) Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A 111:13373-8
Kariolis, Mihalis S; Miao, Yu Rebecca; Jones 2nd, Douglas S et al. (2014) An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis. Nat Chem Biol 10:977-83
Taniguchi, Cullen M; Miao, Yu Rebecca; Diep, Anh N et al. (2014) PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci Transl Med 6:236ra64
Xiao, Nan; Lin, Yuan; Cao, Hongbin et al. (2014) Neurotrophic factor GDNF promotes survival of salivary stem cells. J Clin Invest 124:3364-77
Sun, Ramon C; Denko, Nicholas C (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285-92
Giaccia, Amato J (2014) Molecular radiobiology: the state of the art. J Clin Oncol 32:2871-8
Finger, E C; Cheng, C-F; Williams, T R et al. (2014) CTGF is a therapeutic target for metastatic melanoma. Oncogene 33:1093-100
Kuo, Peiwen; Bratman, Scott V; Shultz, David B et al. (2014) Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clin Cancer Res 20:5558-69
Vilalta, Marta; Rafat, Marjan; Giaccia, Amato J et al. (2014) Recruitment of circulating breast cancer cells is stimulated by radiotherapy. Cell Rep 8:402-9
Razorenova, Olga V; Castellini, Laura; Colavitti, Renata et al. (2014) The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia-inducible factor 1 target gene and promotes survival and proliferation of VHL-deficient renal cancer cells. Mol Cell Biol 34:739-51

Showing the most recent 10 out of 143 publications