Pancreatic ductal adenocarcinoma is a highly malignant form of cancer and the most common form of pancreatic cancer. It most often is only diagnosed at advanced stages, leaving dismal outlooks. Chemotherapy for this cancer has centered around gemcitabine for several decades. Unfortunately, the cancer is quick to develop resistance to gemcitabine and then the drug fails to remain effective.
To improve treatment efficacy, combination therapy is often the next step. However, combination therapies are often even more toxic overall. Because of increased toxicity, another desired improvement is the ability to deliver the chemical directly to the tumor, with less impact on the healthy cells and tissues. Unfortunately, conventional nanocarrier systems tend to result in severe hepatotoxicity and inadequate delivery to the tumor site.
Recently, researchers at Zhejiang University School of Medicine attempted to treat pancreatic cancer by targeted delivery using vesicles containing combination treatment of gemcitabine and RP-6306. Working with a mouse model they found that this method of drug delivery was effective. The drugs were delivered to the tumor microenvironment as intended, while successfully avoiding inducing cytotoxic effects.
While gemcitabine disrupts DNA synthesis, RP-6306 disrupts the G2/M checkpoint by silencing PKMYT1, thereby inducing PANoptosis. This combination effectively targeted the cancer cells without inducing organ damage. The use of vesicles showed superior biocompatibility and minimal toxicity. Further studies of this combination are warranted as the current work shows great promise.
Chen J, Ren J, Zhang C, et al. Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe. Cell Death Dis. 2025 Jul 15;16(1):526. PMID: 40664640