NFAT Transcription Factors as Therapeutic Targets in Pancreatic Cancer
Despite tremendous scientific efforts aimed at understanding the molecular biology of pancreatic cancer, conventional treatment approaches have had little impact on the course of pancreatic cancer.
Thus, studies identifying key determinants in pancreatic cancer and pancreatic cancer stem cells can provide both biomarkers of pancreatic ductal adenocarcinoma (PDAC) aggressiveness and potential optimal targets to overcome chemoresistance.
SPORE researchers have found that the nuclear factor of activated T cells (NFATc1 and NFATc2, or NFATc1/c2), were ectopically expressed in PDAC samples, respectively, and that pharmacologic inhibition or RNAi toward NFATc1/c2 reduced PDAC cell growth in vitro and in vivo.
Researchers showed that expression of a constitutive nuclear NFATc1 in the developing mouse pancreas using p48-cre along with KRasG12D developed invasive PDAC by 16 to 20 weeks of age. These results demonstrated that that NFATc1 was a potent oncogene in pancreatic ductal adenocarcinoma.
Investigators performed NFATc1 ChIP-seq in order to gain insight into the transcriptional network driven by this oncogenic/inflammatory transcription factor. They identified nearly 1,800 NFATc1-target genes, two-thirds of which were dependent on an interaction with STAT3.
Project results showed that most of the NFAT/STAT3-regulated gene networks were involved in inflammation, proliferation and metastasis.
SPORE investigators demonstrated that NFATc1 was enriched in pancreatic cancer stem cells generated from PDAC cell lines and cancer stem cell self-renewal was inhibited by pharmacologically targeting NFAT nuclear activity through the use of cyclosporine A.
However, the mechanisms by which NFATs regulated cancer stem cell self-renewal or chemoresistance, or both, were unclear. Researchers also showed that PDAC cell lines, which expressed NFATc1/c2, were sensitive to cyclosporine A and synergized with gemcitabine to kill tumor cells in vitro and limit tumor growth in vivo.
Despite these preliminary observations, information regarding NFATc1/c2 target genes in human pancreatic ductal adenocarcinoma is lacking, and mechanisms by which NFATc1/c2 regulate pancreatic cancer cell growth remain to be determined.
It's also unknown whether ectopic expression of NFATc1/c2 correlates with specific clinical features of the disease, participates in pancreatic cancer stem cell biology or represents a therapeutic target in the clinic. These outstanding questions will be addressed.
NFATs are important transcriptional regulators in pancreatic cancer, and their expression correlates with high-grade tumors, facilitates tumor cell growth and contributes to pancreatic cancer stem cells characteristics.
Aims of the NFAT Transcription Factors as Therapeutic Targets in Pancreatic Cancer research project are to:
- Identify NFATs and NFAT-dependent target genes in pancreatic cancer
- Determine the role of NFATs in the acquisition of pancreatic cancer stem cell properties
- Start a phase I trial with an expansion cohort for cyclosporine A and gemcitabine-paclitaxel in untreated patients with metastatic pancreatic cancer with metastases amenable to biopsy
Leaders of this Pancreatic Cancer SPORE project are:
The project collaborator is: