Pancreatic cancer is one of the most lethal cancers in both men and women. Because it is usually diagnosed at an advanced stage, the survival rate is extremely poor. While developing better therapeutic modality is key to improving the treatment outcome of patients diagnosed with pancreatic cancer, it is highly imperative to identify individuals at high risk of pancreatic cancer and provide active screening for early detection. Known risk factors for pancreatic cancer include cigarette smoking, obesity, chronic pancreatitis, diabetes, and family history of genetic syndromes associated with increased pancreatic cancer risk, including BRCA2 gene mutation, Lynch syndrome, familial atypical multiple mole melanoma syndrome (caused by mutations in p16/CDKN2A), Peutz-Jeghers syndrome, and Von Hippel-Lindau syndrome. While active screening and monitoring of high risk individuals should allow early detection of pre-invasive pancreatic lesions, effective interventional modalities to prevent progression of precursor lesions to pancreatic cancer are virtually non-existent, except for surgical resection, which is not always curative and can be associated with a significant risk of morbidity. Safe and effective preventive measures are urgently needed to reduce morbidity and mortality associated with this highly deadly disease. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and accounts for more than 85% of cases. More than 90% of PDAC are known to harbor mutationally activated KRAS (e.g. G12D). KRAS mutations are one of the earliest genetic alterations believed to drive pancreatic tumorigenesis and frequently detected in pancreatic intraepithelial neoplasia (PanIN), the most common precursor lesion of PDAC. Mutated oncogenic driver genes, such as KRAS, known to be involved in early tumorigenic process are ideal targets for preventive interventions. However, there are no small molecule agents targeting oncogenic KRAS presently available for clinical translation. Another approach to targeting oncogenic KRAS may be through boosting the host?s immune defense through vaccination. Recent advances in the understanding of immune regulatory mechanisms and the characteristics of innate and adaptive antitumor immune responses have uncovered the host immune system?s remarkable ability to counter tumor growth. When tumor-derived immune suppression is blocked by immune checkpoint inhibitors, the immune system can unleash more robust antitumor immune responses, leading to tumor clearance. Tumor antigens (TA) targeted by the host immune system can range from tumor-driving oncoproteins, tumor-associated mutant neo-antigens or self-antigens overexpressed in tumors. It is highly conceivable that if antitumor immunity can be elicited by TA-specific vaccines before or early in the tumorigenic process, the host may be able to mount more robust antitumor immunity and protect itself from emerging malignant tumors, as tumor-associated immunosuppressive mechanisms should have negligible effects on the host?s immune function. A recent study carried out by Dr. Ming You from Medical College of Wisconsin in collaboration with the DCP PREVENT Program has identified novel KRAS peptides, which had 100% sequence identity to human KRAS and were found to promote Th1 immune responses in immune-competent mice. Vaccination with a mixture of the immunogenic KRAS peptides conferred significant tumor preventive effects in a genetically engineered mouse model of mutant KRAS-driven lung tumorigenesis. It is highly conceivable that similar effects can be attained with the identified multipeptide KRAS vaccine in other KRAS-driven tumors such as pancreatic cancer. Given the high degree of homology between human and mouse KRAS, the KRAS vaccine holds a great potential for clinical translation in the prevention setting. The current study aims to examine the cancer preventive efficacy of the multipeptide KRAS vaccine and establish immune correlates of protection against KRAS-induced pancreatic cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Medical College of Wisconsin
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