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.
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.
|Yuan, William; Jiang, Dadi; Nambiar, Dhanya K et al. (2017) Chemical Space Mimicry for Drug Discovery. J Chem Inf Model 57:875-882|
|Kariolis, Mihalis S; Miao, Yu Rebecca; Diep, Anh et al. (2017) Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. J Clin Invest 127:183-198|
|Castellini, Laura; Moon, Eui Jung; Razorenova, Olga V et al. (2017) KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic Acids Res 45:3674-3692|
|VandeKopple, Matthew J; Wu, Jinghai; Baer, Lisa A et al. (2017) Stress-responsive HILPDA is necessary for thermoregulation during fasting. J Endocrinol 235:27-38|
|Aguilera, Todd A; Giaccia, Amato J (2017) Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion-A New Role for the AXL Receptor Tyrosine Kinase. Clin Cancer Res 23:2928-2933|
|Bobko, Andrey A; Evans, Jason; Denko, Nicholas C et al. (2017) Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models. Cell Biochem Biophys 75:247-253|
|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|
|Johnson, Rachelle W; Sowder, Miranda E; Giaccia, Amato J (2017) Hypoxia and Bone Metastatic Disease. Curr Osteoporos Rep 15:231-238|
|Chiou, Shin-Heng; Risca, Viviana I; Wang, Gordon X et al. (2017) BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer. Cancer Discov 7:1184-1199|
|Sun, Ramon C; Koong, Albert; Giaccia, Amato et al. (2016) Measuring the Impact of Microenvironmental Conditions on Mitochondrial Dehydrogenase Activity in Cultured Cells. Adv Exp Med Biol 899:113-20|
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