New Drug Program Takes DNA Damage Response Treatment to Next Step

A new nuclease inhibitor drug program could lead to the commercialization of novel DNA damage response (DDR) treatments for female breast, ovarian, and other types of cancers.

by Jeff O'Heir
April 09, 2018

A pharmaceutical company is taking the next step in developing a drug program for nuclease inhibitors - one of the first of its kind - that could eventually lead to the commercialization of novel treatments for female breast, ovarian, and other types of cancers.

Artios Pharma, based in Cambridge, UK, was founded in 2016 to develop DNA damage response (DDR) treatments that prevent cancer cells from repairing damaged DNA by targeting pathways found primarily in those cells. The drugs kill cancer by either allowing mutations to build up until the cells can no longer function, or by making cells more vulnerable to radiation and chemotherapies that cause mutations.

Artios is developing several DDR inhibitors. The one that received the most attention is DNA polymerase theta (Polʟ), which is low in healthy cells but up-regulated in cancer. The nuclease inhibitor takes the company in a different direction. It plans to bring it to market as part of an ongoing licensing deal and research partnership formed with Masaryk University in Brno, Czech Republic, last June.

“We bring in their expertise and industrialize it,” Artios CEO Niall Martin says, explaining that during this new “in-licensing” phase of the partnership, they will continue to monitor the researchers’ validation processes before optioning a full licensing deal. “It’s a commitment. We’ll bring in their expertise and industrialize it."

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The research at Masaryk University is led by Lumir Krejci and Kamil Paruch, DDR experts with a particular focus on the role nucleases play in repairing damaged DNA. The two groups believe nucleases are the basis for new and innovative DDR-based cancer therapies. They could also give clinicians another tool to use against cancers that develop resistance to other DDR medicines. It could take up to seven years before the new DDR therapies enter the market. “These are long-term discovery projects,” Martin says.

The World of DDR

DNA damage occurs thousands of times daily. DNA strands break, lesions grow onto strands, or nucleic acids are out of position. When something like this occurs, the DDR process kicks in to repair the cell. The processes have evolved as being extremely effective in repairing different types of DNA damage.

DDR is essentially a series of  “repair pathways” made up of many different enzymes and proteins, each of which identifies a different type of problem and initiates a different type of repair. When DNA damage and mutations occur in the genes and enzymes that play a key role in vital cell processes, it can lead to the development of genetic diseases such as cancer.

Like all cells, cancer cells need ways to repair their DNA. Since they have already lost some DDR functionality, to survive they must use alternative DNA repair pathways. These alternates are less stable than conventional DDR pathways, and explain in part why cancers mutate and evolve into more advanced diseases.

Inhibiting or blocking those alternative pathways can kill cancer cells by allowing disabling mutations to build up, something called synthetic lethality, Martin explains.

But cancer cells are tricky. As a tumor evolves and uses those alternative pathways, it can build up resistance to treatments, including new DDR inhibitors like PARP (poly (ADP-ribose) polymerase) inhibitors. This sparked Artios to search for other targets in the DDR process. Suppressing nucleases, an essential tool in DNA repair, could lead to more effective cancer treatments.

“This whole area of synthetic lethality and selecting targets to kill tumors has taken off,” Martin says.

He should know. Before taking his current position, Martin worked as the director of drug discovery at KuDOS, a UK-based DDR biotech company that AstraZeneca bought for $210 million in 2006. At AstraZeneca, he served as project leader on the company’s PARP inhibitor program. Martin says he played a key role there in identifying Lynparza, the first a PARP inhibitor that was the first DDR medicine to hit the market.

PARP inhibitors target BReast CAncer 1 (BRCA1) or BReast CAncer 2 (BRCA2) proteins, which repair damaged DNA. If either of these two proteins are damaged, breast and ovarian cells may mutate into cancer. These cancerous cells rely on PARP enzymes to repair their damaged DNA. PARP inhibitors prevent this from happening, so mutations build up and prevent the cancers from growing. Because some cancers have built up a resistance to PARP inhibitors, Artios is seeking new targets, particularly nuclease inhibitors.

Enter the Nuclease

Nucleases are made up of enzymes that act as scissors and snip open DNA to repair it. By using nuclease inhibitors, Artios will work to develop more accurate and successful treatments that target subpopulations of breast and ovarian cancers, and possibly lung and intestinal cancers. The concept, Martin explains, is to focus treatments based more on a patient’s specific genetic background than on a general type of cancer.

“That’s what’s changing in cancer treatments,” he says.

Those changes, Martin and others say, could lead to safer, less destructive treatments than radiotherapy and chemotherapy, which damages DNA and normal tissue and causes a host of negative side effects. The new DDR inhibitor treatments can be finely tuned and tailored to take advantage of a cancer cell’s particular weakness, such as a lack in its specific DDR function. They can be safely used in those long-term treatments because, unlike chemotherapies, they are not toxic to all cells, and target only pathways in specific types of cells, he says.

Artois plans to continue developing DDR treatments that complement others in its drug program development pipeline. “We’re putting a program together to tackle unmet needs,” Martin says.