Clinical Newswire, Sep 24, 2009 (Berlin, Germany) -Inhibiting the enzyme TAK-1 makes pancreatic cancer cells sensitive to chemotherapy, opening ways for the development of a new drug to treat the disease, researchers show for the first time in a study presented at the Joint ECCO15-34th ESMO Congress.
Pancreatic cancer is presently considered an incurable disease, and its resistance to chemotherapeutic drugs poses a great challenge to treatment. In the past few years, researchers at M.D. Anderson Center in Houston (Texas, USA) have been studying the role played by a regulatory protein called Transforming Growth Factor beta (TGFbeta) in the development of pancreatic cancer. A unique enzyme activated by TGFbeta, TAK-1 (TGFbeta-Activated Kinase-1), has recently been implicated as a mediator of the extreme drug resistance of pancreatic cancer cells.
Study presenter Dr Davide Melisi (currently working at the National Cancer Institute in Naples, Italy) and his colleagues investigated the expression of TAK-1 in pancreatic cancer cell lines, which was found to be overexpressed in all pancreatic cancer lines studied but not in normal pancreatic ductal epithelial cells. They also developed a drug that was capable of inhibiting TAK-1, and tested its activity on its own and in combination with the chemotherapeutic agents gemcitabine, oxaliplatin and SN-38 (a metabolite of irinotecan) in vitro. In vivo activity of the TAK-1 inhibitor alone or in combination with gemcitabine was also tested against panreatic cancer in mice.
In vitro, the TAK-1 inhibitor alone demonstrated potent cytotoxic activity, and in combination it increased the sensitivity of pancreatic cells to all three chemotherapeutic drugs. “By combining it with classic anti-cancer drugs, we were able to use doses of drugs up to 70 times lower in comparison with control to kill the same number of cancer cells,” said Dr Melisi. In mice, oral administration of the TAK-1 inhibitor in combination with very low doses of gemcitabine led to a 78% reduction of tumor volume, whereas the use of gemcitabine on its own was ineffective because of the drug resistant nature of the disease. Survival was also prolonged in the combination group, with median average survival for the control, TAK-1 inhibitor, gemcitabine on its own, or TAK-1 inhibitor combined with gemcitabine at 68, 87, 82 and 122 days respectively. Treatment-related toxicity was also reduced in the combination group.
“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.The TAK-1 inhibitor used in this study is an exciting drug that warrants further development for the treatment of pancreatic cancer”, said Dr Melisi. The researchers are planning to study it in combination with other chemotherapeutic agents, such as oxaliplatin, 5-FU, or irinotecan, in mice models of pancreatic cancer, aiming at eventually conducting a clinical trial to demonstrate the safety and efficacy of the TAK-1 inhibitor in combination with gemcitabine in pancreatic cancer patients.
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