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
Vilalta, Marta; Brune, Jourdan; Rafat, Marjan et al. (2018) The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration. Clin Exp Metastasis 35:247-254
Tandon, Neha; Thakkar, Kaushik N; LaGory, Edward L et al. (2018) Generation of Stable Expression Mammalian Cell Lines Using Lentivirus. Bio Protoc 8:
Yang, Zhifen; Zhang, Jing; Jiang, Dadi et al. (2018) A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1?-XBP1 Activation. Mol Cancer Res 16:745-753
Benej, Martin; Hong, Xiangqian; Vibhute, Sandip et al. (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115:10756-10761
Rafat, Marjan; Aguilera, Todd A; Vilalta, Marta et al. (2018) Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients. Cancer Res 78:4241-4252
Saiki, Julie P; Cao, Hongbin; Van Wassenhove, Lauren D et al. (2018) Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proc Natl Acad Sci U S A 115:6279-6284
Olcina, Monica M; Kim, Ryan K; Melemenidis, Stavros et al. (2018) The tumour microenvironment links complement system dysregulation and hypoxic signalling?. Br J Radiol :20180069
Peinado, H├ęctor; Zhang, Haiying; Matei, Irina R et al. (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17:302-317
Vilalta, Marta; Hughes, Nicholas P; Von Eyben, Rie et al. (2017) Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location. Mol Imaging Biol 19:215-224
Boyko, Tatiana V; Bam, Rakesh; Jiang, Dadi et al. (2017) Inhibition of IRE1 results in decreased scar formation. Wound Repair Regen 25:964-971

Showing the most recent 10 out of 203 publications