New frontiers of CRISPR/Cas۹ system in pancreatic cancer therapy: the current status and future perspectives

As a predominant type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) is characterized by a dismal prognosis and a considerably high mortality rate. However, the aggressive nature of pancreatic cancer renders it a highly malignant and incurable disease. Estimates indicate that PDAC will be the second most common cause of cancer-related mortality by ۲۰۳۰ due to the fact that the majority of PDAC patients have locally advanced or obvious metastatic disease, which eliminates any remedy opportunities. Furthermore, the paucity of obvious early symptoms and diagnostic biomarkers, as well as the difficult-to-access anatomical pancreas location for routine screening, play a critical role in late diagnosis, resulting in only about ۱۲% of patients surviving beyond ۵ years. Surgical intervention and chemotherapy are the main therapeutic approaches for PDAC. Nevertheless, only about ۱۵%–۲۰% of patients meet the clinical criteria for surgery following diagnosis. Unfortunately, even in surgical resection cases, patients are still susceptible to developing micro-metastatic disease, and approximately ۷۵% of them will experience a recurrence within ۲ years. Although existing chemotherapeutic regimens based on ۵-fluorouracil or gemcitabine have shown gradual improvements by extending survival within several months, there are essentially no FDA-approved targeted therapies for PDAC. For therapeutic purposes, advanced and controlled DNA manipulation strategies are vital. The CRISPR/Cas system, as a gift from nature, plays an essential role in prokaryotic adaptive immunity that allows cells to recognize and destroy foreign DNA and facilitates genome editing and therapies. The CRISPR/Cas۹ system is extensively employed in clinical trials for the treatment of various cancer types and centered around specifically targeting cancer-related genes and cancer immunotherapy. This gene editing technique is characterized by its simplicity, rapid development, and higher accuracy compared to previous methods. In such a system, Cas۹ endonuclease can be efficiently designed to target any gene sequence by modifying a small guide RNA sequence. This versatility has greatly facilitated sequence-specific gene editing for repair disease-causing genes, deactivate oncogenes, or enhance specific traits. The present article reviews the current landscape of CRISPR/Cas۹ applications for molecular gene therapy and immunotherapy in pancreatic cancer as the basis for further studies. Additionally, some issues regarding cancer treatment using translational CRISPR-Cas۹ therapeutics are also discussed. Taken together, CRISPR/Cas۹-based targeted and personalized therapy has the potential to significantly influence future advances in pancreatic cancer therapy.

کلیدواژه ها:

CRISPR/Cas۹ ، Pancreatic cancer ، Genome editing ، Targeted therapy