The dynamic genome

Groundbreaking cancer research at JAX could eventually mean more effective treatment for cancer patients.

If you're impressed with how your local repair shop keeps your car running smoothly, you'll marvel at what keeps your cells working well. Inside the nucleus of every cell, one of nature's great repair and maintenance operations is in constant action. And that operation may hold the key to improving cancer care.

Each nucleus houses a copy of our genome, which includes all of our DNA. We usually represent DNA as a static sequence of letters—GATTACA perhaps?—but it’s actually part of a very active and complex system of change, damage and repair.

For Jackson Laboratory Associate Professor Kevin Mills, Ph.D., all the moving parts raise intriguing questions: How do we keep our own genomes operating smoothly, and what happens when things break down?

"The genome is a fantastically dynamic entity," says Mills. "There’s lots of second-by-second activity, and some of that activity poses a risk for instability—for rearrangements, for losses or gains of genetic information, for abnormalities of many different kinds. So cells have very intricate systems for ensuring the integrity of the genome that are critical for normal function."

Investigating the inner workings of the genome is a new scientific frontier, and each discovery uncovers new layers of fascinating complexity. But while the scientists might be intrigued, what use does the new understanding have in day-to-day life? As it turns out, basic genomic research, looking at the fundamental biology at work, holds huge promise for significant medical progress. Mills' work is a prime example.

"The primary goal of my research is to uncover the processes that maintain a stable genome and to understand how those processes are important for human health or disease," says Mills. "There are a number of high hurdles in taking basic discoveries and translating those into cures, but this is an exciting time to be doing science. I think we're in a time where science and technology are accelerating discovery, and the barriers between research and clinic are tumbling faster than we can imagine."

Blast and stitch

To investigate genome damage and repair, Mills and his lab turned to a kind of cell in which those two processes happen all the time, by design. In fact, for these cells, the B cells of the immune system, damage and repair are vital to their function.

Our immune systems respond to the millions of different substances and microorganisms we encounter by producing antibodies. But we only have about 20,000 genes, so how do can we keep producing unique antibodies? The answer is a system that uses the same stretch of DNA but patches different segments together in different ways. To illustrate, think of the word "Saskatchewan." By extracting sets of letters and combining them in different ways, you can make a number of different words: skate, chew, sat, hen and so on. Reshuffling segments of DNA in the same way allows our bodies to fine-tune the immune response to individual antigens.

Two key players in the process are activation-induced cytidine deaminase (AID), a DNA-breaking enzyme, and XRCC2, a repair protein. So AID breaks the DNA and XRCC2 helps put it back together. But about three years ago Mills and his colleagues showed that there’s a surprising twist.

"You'd expect AID to have high target specificity, with its activity precisely confined to certain regions in the genes responsible for antibody production," said Mills at the time. "But the DNA damage is really more like a shotgun blast. AID creates a lot of DNA breaks at many locations in the genome, and the high fidelity repair function of XRCC2 is then essential for repairing off-target breaks."

Why does the system function with such low-specificity and seemingly high-risk? No one knows. But for Mills, it offered an opportunity. Many cancers are first initiated by genome disruption, but then paradoxically depend on the repair systems to keep the damage from getting out of hand. Initial research in the Mills lab indicated that the dysfunctional balance between DNA damage and repair could be given a push in cancer cells. If pushed the right way, the DNA damage becomes too great to overcome, leading to cell death.

Genetic chemotherapy

AID is supposed to be produced only in activated B cells, but around the time Mills was looking at AID and XRCC2 function in detail, researchers were finding it present in a range of different cancers, including leukemias. Just because it’s there doesn't mean it's actually doing anything, of course, but other findings have implicated it in tumor initiation, progression and the development of therapy resistance.

It makes sense in theory. Cancer cells are known for their high mutation rates and adaptability. What if, in some human cancers, AID is out of control, blasting the genome on a regular basis? And what if the repair process allows some changes but is still good enough to keep the cell alive? If so, perhaps the malignant damage/repair balance in cancer patients could be disrupted like in Mills' lab, providing a new clinical therapy. A genetic chemotherapy.

The Mills lab team, including postdoctoral associate Kristin Lamont, Ph.D., and associate research scientist Muneer Hasham, Ph.D., turned to a repair mechanism called RAD51, in which XRCC2 plays a role. What if they could block its function? They screened a large number of different compounds and found a molecule with the mercifully easy acronym DIDS (short for 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid) that did just that. Adding DIDS to chronic lymphocytic leukemia cells short-circuited the repair mechanism, and the DNA damage added up until it killed the cells.

They tested the concept in a range of cells—normal and cancerous cells from mice, human cancer cell lines, and cells from human cancers sourced directly from patients—and the data added up. "We collected 74 different primary patient CLL samples," Lamont says, "and measured AID expression in those samples. We found that about 40 percent of them express AID, and if we treated those with DIDS in vitro, the AID-expressing ones had significantly higher levels of DNA damage and died."

Also promising is the fact that blocking the repair mechanism doesn’t affect cells without active AID function. Therefore, while this kind of therapy might impair B cell function somewhat, it might have no effect on other tissues. "By its selectivity for cancer cells expressing AID, it reduces the issue of the really nasty side effects associated with chemotherapy treatments," Mills explains.

In addition to killing the cancer cells, preventing repair can also block the adaptability provided by small changes in the genome. So the treatment concept could be used in concert with other therapies, blocking cancer's ability to adapt and grow resistant. In essence, it would give them no way out, ensuring their death and elimination.

Finally, while not all cancer involves AID, the list of cancers associated with aberrant AID expression is growing. Therefore the treatment approach could apply not only to leukemia but also a range of other AID-positive cancer types. 

An exciting time to do science

The work is so promising that Mills founded a biotechnology company, Cyteir Therapeutics Inc., in 2012. While he keeps working to better understand the cellular mechanisms in the lab, Cyteir is pursuing the development of cancer therapies. Mills and his team have already identified a new molecule that has the same action as DIDS but with significantly higher potency, bringing the treatment even closer to the clinic. In fact, Cyteir hopes to begin clinical trials by the end of 2014.

If it succeeds in trials, Mills' genetic chemotherapy would provide many cancer patients with a safer, more effective therapy. And that would show how understanding a basic process, in this case how our immune cells damage and repair their own DNA to protect us from outside pathogens, leads to better medicine.

"The kinds of things that we can do in the laboratory today were inconceivable even five years ago," says Mills. "I can't even imagine the kinds of things we’ll be doing five years from now. So, it's a terribly exciting time to be a scientist, and it's a great time to be at The Jackson Laboratory, because there's so much at our disposal, so many things that we can do, so many unanswered biological questions. I'm in just the right place to do it. We're in just the right place to do it."

Using genetic chemotherapy to stop cancer

Using genetic chemotherapy to stop cancer Kevin Mills wants to bring genetic chemotherapy to the clinic.

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