An estimated 10-15% of pancreatic adenocarcinomas are attributed to genetic causes (Klein 2012). Germline mutations in the BRCA1 and BRCA2 genes are the most common, occurring in 13-19% of families (Lal et al. 2000). The PALB2 and ATM genes are also some that are commonly mutated in hereditary pancreatic adenocarcinomas (Jones et al. 2009). These mutations could be further examined in an effort to detect pancreatic adenocarcinoma earlier in those that are at higher risk. An early screening mechanism of detecting pancreatic adenocarcinoma in patients, regardless of family history, would be significantly beneficial in increasing survivability.
In terms of resistance to the developed ONC201 liposome treatment, a fluorinated-ONC201 analogue, ONC212, has been developed and has shown preclinical efficacy in melanomas and hepatocellular models. A study demonstrated ONC212’s efficacy in in vivo models with ONC201-resistant tumors (Lev et al. 2017). The researchers found an effective combination of ONC212 with the inhibitor AG1024 in vivo for pancreatic adenocarcinoma. ONC212 is effective in pancreatic adenocarcinomas alone and in combination with other drugs such as 5-fluorouracil, irinotecan, oxaliplatin, and RTK inhibitor crizotinib (Lev et al. 2017). This may serve as a backup treatment if resistance to ONC201 develops, and another synergistic combination may be developed from these drugs.
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