CREB1: A Potential Target for Treating Pancreatic Cancer

Preclinical experiments using cell lines, genetic mouse models, and human pancreatic tumor tissue identified the transcription factor CREB1 (for cyclic AMP-responsive element binding protein 1) as a potential therapeutic target for the treatment of pancreatic cancer, according to results presented during Week 1 of the virtual AACR Annual Meeting 2021, held April 10-15. This study is being simultaneously published in Cancer Discovery, a journal of the American Association for Cancer Research.

“Pancreatic cancer is frequently diagnosed after the disease has metastasized, resulting in limited treatment options and subsequent high mortality rates,” said Michael Kim, MD, assistant professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center. “Identifying new therapeutic targets for this deadly cancer represents an urgent unmet need in the field of oncology.”

The oncogene KRAS is mutated in roughly 95 percent of pancreatic tumors, and these mutations co-occur with genetic alterations in the tumor suppressor p53 in nearly 70 percent of patients, said Kim. “The goal of our study was to find a link between these two genetic drivers of pancreatic cancer to better understand how they work together to drive tumor growth and metastasis.”

To identify the relationship between the two cancer driver genes, Kim and colleagues developed a genetically engineered mouse model that expresses both oncogenic KRAS and mutant p53 specifically in pancreas tumor cells, thereby leaving immune cells and fibroblasts within the tumor microenvironment unperturbed. Using this model, along with pancreatic tumors derived from human patients, the researchers found that effectors of oncogenic KRAS activate CREB1, which then interacts with mutant p53 to upregulate the transcription factor FOXA1 (for forkhead box A1), thereby activating prometastatic transcriptional signals that facilitate pancreatic cancer metastasis.

Next, Kim and colleagues evaluated whether inhibiting CREB1 would affect FOXA1 expression and subsequent pancreatic cancer metastasis. They treated pancreatic cancer cells with a potent and selective CREB1 inhibitor and found a dose-dependent reduction in both the expression of FOXA1 and its downstream effector β-catenin. Further, metastasis assays in mice injected with pancreatic cancer cells revealed that the mice treated with the CREB1 inhibitor had significantly reduced lung metastases compared with the mice treated with drug vehicle.   

“Through our work, we’ve shown how two cancer driver pathways can cooperate to amplify myriad downstream targets that are important for pancreatic cancer development and metastasis,” Kim said. “Further, we’ve identified a targetable, cooperative node between these driver pathways that might be therapeutically exploited to improve patient outcomes,” he said.

Mutations in KRAS and p53 are common in many other cancer types in addition to pancreatic cancer.

“We hope that our study will generate increased interest in CREB1 as a therapeutic target and the subsequent development of additional CREB1 inhibitors, which could potentially be used to treat multiple cancer types,” Kim said.

A limitation of this study is its preclinical nature. “Further research is needed to evaluate the safety of CREB1 inhibitors in patients to translate the findings of our study to patients with pancreatic cancer,” noted Kim.

Reference: Kodysh J, Marron T, Rubinsteyn A, et al. Abstract CT173: PGV-001: A phase I trial of a multipeptide personalized neoantigen vaccine in the adjuvant setting. Cancer Res. 2020;80(16 Supplement):CT173-CT173. doi:10.1158/1538-7445.AM2020-CT173

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