New inhibitor may work against pancreatic adenocarcinoma

Mayo Clinic researchers have opened up a promising front in their search for new ways to increase the effectiveness of chemotherapy against pancreatic adenocarcinoma, one of the deadliest cancers.

Using patient cell lines and tumor-bearing models, the researchers found that inhibition of GSK-3, an enzyme involved in many cancer-promoting processes, sensitizes pancreatic adenocarcinoma cell lines to gemcitabine, the most commonly used chemotherapy. They found that GSK-3 inhibitor treatment prevented the ability of cancer cells to repair single-strand DNA damage induced by gemcitabine.

Their findings suggest that GSK-3 inhibitors may overcome resistance to gemcitabine and other chemotherapies, said Daniel D. Billadeau, Ph.D., an oncology researcher and chair of the Department of Immunology at Mayo Clinic in Rochester, Minnesota, whose work focuses on pancreatic cancer. The findings were published in November 2019 in Clinical Cancer Research, the journal of the American Association for Cancer Research.

"Our study identified a previously unknown role for GSK-3 in the regulation of the cell's ability to respond to and repair its DNA following chemotherapy," Dr. Billadeau said. "The findings suggest that by inhibiting GSK-3, we can impede the cells' DNA damage response, leading to synergistic tumor cell death even in cells that are naturally resistant to chemotherapy."

Pancreatic adenocarcinoma constitutes 95% of pancreatic cancers according to the American Cancer Society, and the five-year relative survival rate is less than 10%.

In this study, pancreatic cancer cell lines and patient-derived tumor samples were treated with a new GSK-3 inhibitor, called 9-ING-41, alone or in combination with chemotherapy. The researchers found that the GSK-3 inhibitor significantly increased pancreatic tumor cancer cell death and prolonged survival in tumor-bearing models when combined with chemotherapy.

"Many pancreatic cancer tumors are resistant to the two most commonly used chemotherapies," said Li Ding, Ph.D., a senior research fellow at Mayo Clinic in Rochester, Minnesota, and the study's lead author. "Thus, identifying ways in which to make resistant tumors sensitive, or to increase the effectiveness of chemotherapy, is vital."

The GSK-3 inhibitor used in this study is in a phase 1a/1b clinical study at Mayo Clinic, and the results from this study are highly relevant to that work, Dr. Ding said.

Related

• Daniel D. Billadeau, Ph.D.
• Gemcitabine (Intravenous Route)
• Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response
• Mayo Clinic Pancreatic Cancer SPORE
• Pancreatic cancer

This article was originally published in Forefront, Mayo Clinic Cancer Center's online magazine, which ceased publication in December 2020.