Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and truly devastating disease with an overall five- year survival rate of about 5%. It is expected to become the second leading cause of cancer deaths by 2020. Oncogenic RAS signaling is almost universally a marker of poor prognosis in three of the most deadly cancers in the United States - lung (30%), colon (50%) and pancreatic (95%) carcinomas. Unfortunately, pharmacological targeting of Kras has been clinically unsuccessful. Thus, its downstream pathways have been examined as new potential therapeutic targets. We evidenced that human pancreatic tumor tissues, PDAC cells and pancreatic tumor cell lines from genetically engineered mouse model (GEMM), displays hyperactive CREB signaling in comparison with normal ductal cells; raising the intriguing hypothesis that CREB, an effector of RAF-MEK-ERK and PI3K-AKT-mTOR pathways plays a critical role in PDAC pathogenesis. Moreover, activated cyclic AMP response element-binding (CREB) signaling is induced by granulocyte macrophage colony-stimulating factor (GM-CSF). Therefore, we are arguing for the crucial role of CREB in the PDAC progression, metastasis, survival, and hypothesize, that CREB signaling pathway represents a novel target and therapeutic intervention opportunity yielding a greater anti-tumor effect. We hypothesize that hyper activation of CREB signaling significantly contributes to carcinogenesis, oncogenic transformation, and PDAC progression. Consequently, targeting the oncogenic Kras signaling downstream effector CREB will improve overall survival. To achieve this goal, the following specific aims will test this hypothesis:
Aim 1. To investigate the functional role and targeting of activated CREB in PDAC. We provide evidence that CREB activity is elevated in PDAC, supporting our hypothesis that blocking CREB activation can therapeutically prevent PDAC progression.
Aim 1 a will determine the biologic effects of CREB inhibition and silencing on fundamental target genes.
Aim 1 b will demonstrate the therapeutic efficacy of CREB inactivation using pre- clinical mouse model.
Aim 2. To determine whether GM-CSF is necessary for CREB-dependent PDAC formation. We hypothesize that smoking activates GM-CSF, which mediates activation of CREB signaling.
Aim 2 A will determine whether GM-CSF induces CREB signaling pathways and modulates TSN-induced PDAC carcinogenesis in vitro.
Aim 2 b will determine the promotion of GM-CSF induced CREB signaling in driving PDAC in vivo using Ptf1aCreER;LSL-KrasG12D (PK) mouse model. These studies will provide fundamental basic and translational insights on initiating events of cellular carcinogenesis and facilitate therapeutic interventions downstream of Kras. The mouse models provide a clinically and molecularly relevant tool to probe the mechanism of therapeutics in PDAC.
Among all human cancers, pancreatic cancer has the highest frequency (>90%) of mutated forms of Kras proto-oncogene. Despite great efforts, we have failed to target Kras with any of our therapies. In an attempt to overcome this problem, we sought to block specific proteins that are abnormally activated when there is a mutation in Kras, namely CREB. We have designed the experimental arms to test the efficacy of treatments at the early pancreatic cancer developmental as well as at the late pancreatic cancer stages evaluating tumor behavior and designing biological approaches to improve overall survival.
| Totiger, Tulasigeri M; Srinivasan, Supriya; Jala, Venkatakrishna R et al. (2018) Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. Mol Cancer Ther : |
| Srinivasan, Supriya; Totiger, Tulasigeri; Shi, Chanjuan et al. (2018) Tobacco Carcinogen-Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer. Cancer Res 78:6146-6158 |
| Messaggio, Fanuel; Mendonsa, Alisha M; Castellanos, Jason et al. (2017) Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth. Oncotarget 8:85378-85391 |
| Nagathihalli, Nagaraj S; Castellanos, Jason A; VanSaun, Michael N et al. (2016) Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget 7:65982-65992 |
