Pancreatic cancer is one of the most fatal cancers in the United States and is rapidly advancing up the ranks. The best treatment available is the removal of the tumor through surgery. Many patients see recurrence post-operation, however, and rush to get treated with chemo and radiotherapies that have serious side effects. Even then, many patients develop resistance to these therapies. The need for an alternative treatment was evident, and it would have to be creative.
A team from the Human BioMolecular Research Institute stepped up to the task, with cancer stem cells (CSCs) as their proposed treatment. CSCs are a type of persistent cancer cell that can survive post-treatment and initiate recurrence in a patient. They are identified by testing for distinctive biomarkers. Integrin β3 is one such biomarker and is a known indicator of an increased chance of metastasis in many cancers. The team utilized a new CSC experimental cell line to investigate how they might prevent CSC dependent recurrence in pancreatic cancer patients. They then focused on the compound PAWI-2, and its ability to inhibit CSC cells with high Integrin β3 levels to determine if PAWI-2 was a viable alternative treatment for pancreatic cancer.
They began by taking their CSC experimental line, as well as another control CSC cell line without elevated integrin β3 expression and treated both with PAWI-2. The compound turned out to be twice as potent against the integrin cell line, reducing cell viability two-fold compared to the control. PAWI-2 seemed to cause apoptosis, or cell death, through a mitochondrial-controlled pathway. PAWI-2 also dysregulated the KRAS-RalB-NF signaling pathway, the primary path that CSCs utilize to generate resistance and other CSC properties.
A common method of cancer is to use two treatments in combination. The two treatments together would have a greater anti-cancer effect than either alone. Running with this logic, the team began to examine how PAWI-2 might enhance the effects of the commercially available inhibitor erlotinib. Compared to the control of erlotinib/bortezomib, PAWI-2/erlotinib managed to show a significantly higher anti-cancer effect. It managed to reduce the cell viability and self-renewal capacity of CSCs to a much greater extent than the control. Comparing it to another standard combination treatment for pancreatic cancer, gemcitabine/paclitaxel, the PAWI-2/erlotinib combination seemed to have a greater effect on CSCs with elevated integrin β3. Against the standard CSC control line, however, the two treatments showed similar results. PAWI-2 continues to prove effective against CSCs with elevated integrin β3.
The team concludes, “Selective pharmacological potency of PAWI-2 in CSCs (e.g., FGβ3 cells versus FG cells) showed the utility of PAWI-2 to inhibit CSCs versus bulk cancer cells.” PAWI-2 proved to be unique among KRAS inhibitors by inhibiting downstream phosphorylation events, rather than the origin events themselves. In combination with erlotinib, it also proved to be quite effective in reducing pancreatic CSCs in vitro and could be utilized to prevent recurrence in patients in the future. As with most of these works, further study is still required. PAWI-2 has proven itself to be a worthy contender for a role in the future of cancer treatment.
Sources: Nature, IFOM
