Novel TAK-1 Inhibitor Reduces Resistance of Pancreatic Cancer Cells to Chemotherapy

Pancreatic cancer is one of the most difficult malignancies to treat and invariably fatal because pancreatic cancer cells are highly resistant to most therapies. For some time, gemcitabine (Gemzar) has been the gold standard for treating inoperable pancreatic cancer and has shown promise as adjuvant therapy. Yet, despite its widespread use, the majority of patients with pancreatic cancer survive less than 1 year. Dr David Melisi, National Cancer Institute, Naples, Italy, and colleagues presented data at the ECCO 15 - ESMO 34 Joint Congress today identifying the transforming growth factor (TGF) beta-activated kinase-1 enzyme, known as TAK-1, as a possible target in pancreatic cancer.

As a researcher for the past few years at the MD Anderson Cancer Center in Houston, Texas, Dr Melisi, along with his colleagues, studied the role that TGF beta plays in the formation of malignant tumors of the pancreas. TGF beta activates the TAK-1 enzyme, which the investigators believe moderates the “extreme drug resistance” seen in pancreatic cancer. They developed a drug to inhibit TAK-1, which they first tested in vitro against pancreatic cancer cell lines, alone and in combination with either gemcitabine, oxaliplatin, or the irinotecan metabolite SN-38. Explaining the findings in a press release, Dr Melisi said, “By combining it with classic anti-cancer drugs, we were able to use doses of drugs up to 70 times lower in comparison with the control to kill the same number of cancer cells.”

Encouraged by the activity of the TAK-1 inhibitor, they proceeded to test it together with gemcitabine in mice with pancreatic cancer. It proved successful here, as well, according to Dr Melisi. “In mice, we were able to reduce significantly the tumor volume, to prolong the mice survival, and to reduce the toxicity by combining the TAK-1 inhibitor with very low doses of a classic chemotherapeutic drug, gemcitabine, that would have been ineffective otherwise,” he said. Specifically, the combination reduced tumor volume in the mice by 78% and increased survival by nearly 50% compared with gemcitabine alone (82 days vs. 122 days, respectively). The rate of survival with the TAK-1 inhibitor plus gemcitabine was nearly double the rate seen with no treatment, and mice that received only TAK-1 actually survived a median of 5 days longer than those treated only with gemcitabine.

“Pancreatic cancer is an incurable malignancy, resistant to every anti-cancer treatment. Targeting TAK-1 could be a strategy to revert this resistance, increasing the efficacy of chemotherapy,” Dr Melisi said. The team plans to study whether the TAK-1 inhibitor can also increase the efficacy of other chemotherapeutic agents in mice with pancreatic cancer. Dr Melisi said the group eventually hopes to conduct a clinical trial to demonstrate the safety and efficacy of the novel TAK-1 inhibitor, combined with gemcitabine, in humans with pancreatic cancer.

ECCO/ESMO Abstract O-1002