The bromodomain (BRD) and extra terminal domain (BET) family of proteins, which function as 'readers'of histone acetylation marks, mediate growth of pancreatic ductal adenocarcinoma (PDAC) cells in 3D collagen. Additionally, PDAC cells in 3D collagen demonstrate chemoresistance through increased expression of high mobility group A2 (HMGA2), an architectural protein that regulates chromatin structure. The long-term goal is to help develop novel mechanism-based targeted therapies for the treatment of PDAC. The objective in this application is to determine how BET proteins mediate chemoresistance and contribute to fibrosis in vivo. The central hypothesis is that BET protein inhibition will decrease PDAC tumor growth and increase chemosensitivity by decreasing the cancer stem cell population and HMGA2 protein function, respectively. A second hypothesis is that BET inhibition will lead to an attenuation of fibrosis in PDAC tumors. These hypotheses are based on strong preliminary data demonstrating that BET inhibitors decrease growth of PDAC and stellate cells in 3D collagen. In addition, treatment of PDAC cells with BET inhibitors decreases cancer stem cell population and represses HMGA2. The rationale is that a determination of the role and underlying mechanism of BET proteins in PDAC progression in vivo is likely to contribute substantively to a conceptual framework whereby new clinically effective targeted therapies can ultimately be developed.
Three specific aims are proposed: 1) Determine the role of BET proteins in PDAC progression in vivo;2) Evaluate the ability of BET protein inhibition to increase chemotherapy sensitivity;and 3) Evaluate the ability of BET protein inhibition to attenuate fibrosis. Under the first aim, the effect of BET inhibitors on PDAC progression will be determined in mouse models. Further, the extent to which BET inhibitors decrease PDAC stem cell population in vivo will be evaluated. Also, the ability of gold nanoparticles (Au-NPs) coupled with BRD4 siRNA to inhibit tumor growth will be determined. For the second aim, the ability of BET inhibitors to increase chemotherapy efficacy will be evaluated in 3D collagen and in mouse models. Additionally, the role of BET proteins in DNA damage response and the contribution of HMGA2 to BET protein regulation of chemoresistance will be assessed. In the third aim, the mechanism by which BET inhibitors regulate stellate cell activation and collagen production will be determined. The effectiveness of BET inhibitors and Au-NPs functionalized with BRD4 siRNA to attenuate fibrosis in mouse models will also be evaluated. The research proposed is innovative because it utilizes complex models of pancreatic cancer, including in vitro organotypic cultures and in vivo orthotopic and transgenic mouse models to determine the role of BET proteins in PDAC progression. An additional innovation is the use of Au-NPs functionalized with siRNAs to downregulate BRD4 expression in the model systems. This proposed research is significant because it is expected to provide strong scientific justification for the continued development and future clinical trials of BET inhibitors in PDAC.

Public Health Relevance

The proposed research is relevant to public health because characterizing the mechanisms that mediate growth and chemoresistance in pancreatic cancer is ultimately expected to help identify novel targets and approaches for the treatment of this highly lethal malignancy. Thus, the proposed research is relevant to the mission of the NIH that pertains to improving the health of the Nation by supporting research in the cure/treatment of human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA186885-01
Application #
8737723
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2014-09-15
Project End
2018-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$316,064
Indirect Cost
$108,564
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Principe, Daniel R; DeCant, Brian; Diaz, Andrew M et al. (2016) PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction. Oncotarget 7:28218-34
Chow, Christina R; Ebine, Kazumi; Knab, Lawrence M et al. (2016) Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling. J Biol Chem 291:1605-18
Ebine, Kazumi; Chow, Christina R; DeCant, Brian T et al. (2016) Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia. Sci Rep 6:29133
Principe, Daniel R; DeCant, Brian; Mascariñas, Emman et al. (2016) TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res 76:2525-39
Abedin, Sameem M; Boddy, Craig S; Munshi, Hidayatullah G (2016) BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects. Onco Targets Ther 9:5943-5953
Kumar, Krishan; Chow, Christina R; Ebine, Kazumi et al. (2016) Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer. Mol Cancer Res 14:216-27
Wang, Xiaoyun; Chow, Christina R; Ebine, Kazumi et al. (2016) Interaction of tRNA with MEK2 in pancreatic cancer cells. Sci Rep 6:28260
Kumar, Krishan; Raza, Sania S; Knab, Lawrence M et al. (2015) GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. Sci Rep 5:9489
Sahai, Vaibhav; Kumar, Krishan; Knab, Lawrence M et al. (2014) BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen. Mol Cancer Ther 13:1907-17