Trials in mice show that adding inhibitor to gemcitabine leads to dramatic tumor shrinkage and increased survival.
Scientists report a new approach to rendering pancreatic cancer susceptible to chemotherapy. The method involves inhibiting TGFbeta-activated kinase -1 (TAK-1) in pancreatic tumor cells, explains lead researcher David Melisi, M.D., at the National Cancer Institute in Naples, Italy. The research was reported at ECCO 15 ESMO 34 meeting in Berlin.
The scientists had been studying the role of TGF-beta on the development of pancreatic cancer and subsequently shifted their focus to the role of TAK-1, which is activated by TGF-beta, as a potential mediator in the extreme drug resistance displayed by pancreatic cancer, Dr. Melisi reports. The team developed a compound capable of inhibiting TAK-1 and tested it both on its own and in combination with gemcitabine, oxaliplatin, and SN-38 (a metabolite of irinotecan) in pancreatic cell lines. They also tested it in combination with gemcitabine in mice with pancreatic cancer.
The TAK-1 inhibitor increased the sensitivity of pancreatic cells to all three chemotherapeutics investigated. In comparison with using chemotherapy alone, adding the inhibitor allowed the use of up to 70 times lower doses of the chemotherapeutic drugs to kill the same number of cancer cells, Dr. Melisi continues.
Moreover, while gemcitabine therapy alone was ineffective in pancreatic cancer-bearing mice, adding the TAK-1 inhibitor led to a 78% reduction in tumor volume and increased median average survival from 82 days to 122 days.
“This is the first time that TAK-1 has been indicated as a relevant target for the treatment of a solid tumor and that it is a valid approach to reverting the intrinsic drug resistance of pancreatic cancer,” Dr. Melisi stresses. “The TAK-1 inhibitor used in this study is an exciting drug that warrants further development for the treatment of pancreatic cancer. In the near future, we will study whether it is also possible to make other chemotherapeutic agents such as oxaliplatin, 5-FU, or irinotecan work against pancreatic cancer in mice.”