Pancreatic cancer cells are especially good at repairing their DNA when it’s damaged by chemotherapy and radiation, which is one reason standard treatments for the disease are often ineffective. Now, researchers from the University of Michigan Rogel Cancer Center are reporting promising results from an early trial of a drug that blocks an enzyme cancer cells need to repair their own DNA.
The drug, AstraZeneca’s AZD1775, blocks an enzyme called Wee1 and in so doing prevents pancreatic cancer cells from shielding themselves against radiation and chemo. In a trial combining AZD1775 with radiation and Gemzar (gemcitabine), 34 patients with pancreatic tumors that were too advanced to be removed with surgery had a median overall survival rate of 22 months. That bested a previous trial of Gemzar alone, in which survival was just 12 to 14 months.
The University of Michigan researchers are now planning a phase 2 study of the combination treatment. The results of the phase 1, which was primarily designed to determine the appropriate dose of AZD1775, were published in the Journal of Clinical Oncology.
"If we can disable the DNA damage response in pancreatic cancer cells, it might eliminate treatment resistance and sensitize the cancer to the effects of both radiation and chemotherapy," said lead study author Kyle Cuneo, M.D., associate professor of radiation oncology at Michigan Medicine, in a statement.
AstraZeneca acquired the rights to AZD1775 from Merck in 2013. It is one of 250,000 compounds that are part of AZ’s Open Innovation program—a library of drugs the company makes available to researchers around the world who want to investigate their potential in various diseases.
AZD1775 is currently being tested in ovarian cancer and a variety of solid tumors, both as a solo therapy and in combination with other drugs, according to the company. In 2017, AZ formed a collaboration with Combinations Alliance in the U.K. to test the drug in head and neck cancer. There are currently more than 50 other trials of AZD1775 listed on ClinicalTrials.gov.
Preventing pancreatic cancer cells from repairing their DNA is one of many ideas currently being investigated for combating the disease. Last week, a research team at the Garvan Institute in Australia said it's investigating the potential of reducing levels of the protein perlecan, which facilitates the spread of pancreatic tumors cells to other parts of the body. Combining a perlecan-lowering drug with chemotherapy could stop the spread of the disease, the team suggested.
Several other treatment regimens are being studied, including a combination of Merck’s checkpoint inhibitor Keytruda with GlaxoSmithKline’s RIP1 inhibitor. In mice, that treatment ramped up the activation of immune cells that kill cancer, prompting GSK to launch a clinical trial in people with pancreatic ductal adenocarcinoma.
The University of Michigan team that’s now planning a phase 2 trial of AZD1775 reported that in addition to extending median overall survival, the combination of the drug with Gemzar and radiation staved off progression of pancreatic cancer in the phase 1 trial for a median of nine months and was well tolerated.