Targeting BET Bromodomain in Pancreatic Cancer

Project: Research project

Description

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.
StatusFinished
Effective start/end date9/15/148/31/19

Funding

  • National Cancer Institute (3R01CA186885-04S1)

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Pancreatic Neoplasms
Adenocarcinoma
Collagen
varespladib methyl
Fibrosis
Small Interfering RNA
Protein Domains
Drug Therapy
Neoplasms
Growth Inhibitors
Proteins
Neoplastic Stem Cells
Therapeutics
Acetylation
Growth
Research
Gold
Nanoparticles
Population
Chromatin