The chemotherapy drug irinotecan creates DNA damage leading to cell death and is used to treat colorectal cancer, among other cancer types. Now a University of Colorado Cancer Center study presented at the American Association for Cancer Research (AACR) Annual Meeting 2019 suggests a way to make irinotecan work even better: When researchers added the experimental drug AZD0156 to irinotecan, colorectal cancer cells and models of human colorectal cancer tumors grown in mice both showed significantly more cancer cell inhibition than with irinotecan used alone. An ongoing phase 1 clinical trial is currently testing the combination against advanced solid tumors (NCT02588105).
“It’s an exciting combination – we take a treatment that we know works in colorectal cancer and make it better,” says S. Lindsey Davis, MD, investigator at CU Cancer Center and assistant professor at the CU School of Medicine. Davis is first author of the current study and also the regional principal investigator of the phase 1 trial testing irinotecan and AZD0156 against solid tumors.
“It makes sense that these two drugs would work well together; it’s a rational combination,” Davis says.
Basically, irinotecan creates DNA damage – single strand DNA breaks that become double strand breaks when cells replicate. When the body’s machinery recognizes double-strand breaks, most of these cells are destroyed. And because cancer cells replicate more quickly than healthy cells, irinotecan preferentially targets these fast-replicating cancer cells. However, the body doesn’t destroy all cells with double-strand breaks – unfortunately, the body is also very good at repairing DNA damage and so even after irinotecan treatment, some cancer cells are repaired and survive.
Unless they are treated with AZD0156, which targets a “kinase” called ATM, which is essential for the body’s ability to repair DNA double strand breaks.
“Some cells affected by irinotecan are going to die, but the ones the body is able to repair might survive, unless this other drug keeps the body from repairing these cells, in which case they die,” Davis says.
“It’s interesting,” Davis says, “here we have DNA damage repair, which is supposed to guard against dangerous mutations, and, counterintuitively, by shutting down this system we kill cancer cells.”
In fact, in this system, neither drug is directly responsible for killing cancer cells. Irinotecan creates DNA damage and AZD0156 keeps the body from repairing this damage. But it is the body’s own mechanics that recognize double-strand breaks and kill the affected cancer cells.
The group also tested AZD0156 in combination with the widely used colorectal cancer chemotherapy 5FU, but found that while AZD0156 magnified the effect of irinotecan, it did not have the same synergism with 5FU. In fact, the pairing of irinotecan with AZD0156 worked better than all three drugs together.
In addition to the ongoing phase 1 clinical trial of irinotecan with AZD0156, Davis suggests that it may be possible to explore other agents to inhibit ATM, perhaps through a mechanism similar to AZD0156 or perhaps interfering elsewhere in the chain of events that allows the body to repair DNA double strand breaks.
“It’s exciting to be able to magnify the effect of irinotecan,” Davis says. “Inhibiting DNA damage repair is gaining interest in the field. Now we need to discover exactly the best way to do it.”