Pancreatic cancer, among the deadliest tumors, has a particularly effective weapon in its arsenal: its resistance to chemotherapy that allows it to quickly repair damaged cells wrought by the drugs.
But trials are underway to target this advantage – and one drug shows some promise in the laboratory: 9-ING-41. One of the lead researchers, Daniel Billadeau, PhD, told Cancer Network™ it was a “completely unexpected finding for the compound” to potentially prove to be a fundamental breakthrough in battling some pancreatic cancers.
“We went into it with a different idea of how the compound worked,” said Billadeau, a professor of immunology, biochemistry and molecular biology at the Mayo Clinic College of Medicine and Science. “Through a lot of hard work, from my senior fellow who’s the lead author on the paper, Li Ding, MD, we figured out this drug can actually sensitize the tumors to chemotherapies such as gemcitabine and also irinotecan.
The researchers hypothesized that by inhibiting the enzymes that allow the tumor to repair its DNA after chemotherapy, the cancer cells themselves will die.
Phase I and II trials are ongoing in the Actuate Therapeutics 1801 study, using intravenous administration of the small molecule both alone and in combination with gemcitabine chemotherapy. Currently more than 50 participants have been enrolled, and 7 have undergone treatment since trials began at the beginning of this year.
The latest evidence, both in vitro and in vivo, has also shown promise with GSK-3, a serine threonine kinase which is a natural regulator of metabolism. The natural enzyme’s beta isoform variant has shown that it can be particularly helpful to cancer growth and progression when overexpressed.
“Aberrant overexpression of GSK-3βhas been shown to promote tumor growth and chemotherapy resistance in various solid tumors including colon, ovarian, and pancreatic cancers and glioblastoma through pro-survival (effects),” the researchers wrote.
Aiming the 9-ING-41 at the GSK-3 target in human patients has begun in phase I and II trials in January and are currently recruiting patients at multiple locations, including the Mayo Clinic. The target trial completion date is November 2022.
But the latest evidence in the laboratory shows its promise in xenografts in mouse models and in in-vitro models, as the academic team led by Mayo Clinic now reports.
These findings showed that the inhibitor depleted the GSK-3 kinases. That, in turn, degraded a protein called TopBP1 known for enabling the ATR pathway to conduct DNA damage repair.
Ultimately, the inhibitor’s domino effect limited the cancer’s repair abilities – and boosted the effect of chemotherapy. “9-ING-41 treatment significantly increased pancreatic tumor cell killing when combined with chemotherapy,” the researchers wrote.
The scientists said in statements on the work that they are still learning about the tumor cells’ defenses even as they test them.
“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,” said Billadeau.
“We saw this result in cell culture, and then in animal models, and we asked, ‘How is this happening?’” he added. “We started working down the pathways we thought would be involved, and stumbled upon that this inhibitor, or genetic depletion of, GSK-3 kinases could alter the activation of this ATR DNA damage response pathway… It hadn’t been discovered before that this kinase had anything to do with this pathway, which was surprising to us, since people have been studying GSK-3 since the early 1990s after its discovery.”
One patient advocacy group said they were watching the potential treatment implications. Lynn Matrisian, PhD, MBA, the chief science officer of the Pancreatic Cancer Action Network (PanCAN), told Cancer Network™ they await the results of the trials.
“Understanding the biology of how pancreatic cancer cells behave differently from healthy cells allows researchers to devise targeted therapy approaches that are more specific to the cancer cells and thus less toxic to the patient’s healthy cells,” said Matrisian. “(The authors) have identified an interesting signaling pathway, driven by glycogen synthase kinase 3β, which is a protein that can be therapeutically targeted. An early-phase clinical trial is underway to determine whether this compound may be effective, alone or in combination with chemotherapy, in patients with pancreatic and other cancer types.”
Ding L, Madamsetty S, Kiers S, et al. Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response. doi:10.1158/1078-0432.CCR-19-0799.