With a shotgun: A new genetic approach to cancer therapies

Recently The New York Times depicted the growing effort to incorporate genomics into cancer care as “an arms race within the war on cancer.”

It documents the large investments in both infrastructure and staff being made by prominent medical institutions, including Mount Sinai, Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center right in New York City. And, perhaps unintentionally, it vividly depicts the paradox facing the field right now, in that heavy investments must be made to realize benefits that are not guaranteed. Obviously these institutions are betting on significant future benefit, but the current returns for whole genome sequencing of tumors are admittedly modest at the price.

Genomic versus genetic

The NYT piece focuses largely on the full genomic profiles of tumors, whose massive amounts of data may carry inside them the clues needed for far more effective therapies. But it gets a bit confused about exactly what is being done right now, much of which doesn’t require sequencing and analyzing entire genomes. More targeted genetic assessments are already being used and are proving to be useful. The leukemia patient example cited in the article demonstrates how such work has made significant contributions to the treatment of patients with certain mutations in their cancers.

Cancer gene panels, such as the 46-gene test being introduced system-wide in the U.K., offer significant insight without full tumor genome sequencing and are stepping stones to true genomic medicine. True, they are generally reactive rather than proactive and offer improved therapeutic options for a small percentage of cancer patients. But they represent a large step forward, and, in the short term, they are making the most difference to patients. And innovative research efforts continue that seek new genetic therapy targets based on how cancers initiate, grow and adapt.

A shotgun approach

One such project is ongoing right here at The Jackson Laboratory. Kevin Mills, Ph.D., is investigating the biological process that induces genetic mutations to create the body’s immune response to a huge variety of pathogens. A key player in this process, activation-induced cytidine deaminase (AID), may turn out to be a key tool for fighting specific cancers.

In order to produce different antibodies to different pathogens and other invading material, B cells rearrange a specific part of their genetic material to achieve the vast variety needed. AID introduces the genetic “damage,” which is quickly repaired through a process called homologous recombination (HR). Given the consequences of broken DNA, you would think that the process would be highly specific. But it’s not—Mills equates AID’s action with that of a shotgun blast, creating many off-target breaks in addition to those in the areas responsible for antibody production.

Why it functions in this way is unclear, but there are obvious problems when it doesn’t function perfectly. Too much AID activity and/or too little HR repair leads to genetic damage, which is a recipe for cancer. In B cells this leads to the cancers we know as lymphomas and leukemias. And in cases of high AID activity, it can exacerbate the problem by creating new breaks and rearrangements that increases the cancer’s aggressiveness and ability to evade treatments.

Genetic chemotherapy

But what if the very mechanism that introduces the problem could be used to help fix it?

Cancer cells flourish with the assistance of AID because their chromosomes are unstable enough for quick adaptive responses but have enough integrity for rapid division and growth. Ironically, however, they still rely on HR for sufficient repair to stay viable. In an earlier experiment, Mills discovered that HR was necessary for the cancer cells to survive, and deleting a key component of the HR system in mice killed the cancer. Essentially, AID's "shot-gun" approach creates enough damage that without HR the genetic damage adds up to the point it becomes fatal. It's something Mills called genetic chemotherapy—the cancer's own genetic instability could be given a nudge in the right direction to create instability too extreme for cell survival.

Mills is not able to delete HR genes in humans, of course, so he looked instead for an antagonist, a substance that would block the HR system mechanically. During a screening process with a large number of compounds, he found what he was looking for: 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid, with the thankfully simple acronym DIDS, which short-circuited the HR pathway. In addition to mice and cancer cell lines, he tested DIDS in 74 chronic lymphocytic leukemia samples obtained directly from human patients, 40 percent of which expressed AID. Treated with DIDS, these cells self-destructed.

Mills has found another compound that also blocks HR but is far more efficient, thus removing a dosing issue that DIDS presented. The next step, of course, is to test it in human patients. The run-up to clinical trials is long, arduous and expensive, but Mills hopes to begin in about a year, through a company he founded called Cyteir Therapeutics, Inc. Given that the list of cancers associated with aberrant AID expression is growing, the treatment approach could apply to cancer types other than leukemias as well.

Should the clinical trials fulfill the promise of the pre-clinical research, the HR blocking pathway carries with it two distinct advantages over traditional chemotherapies. First, its toxicity to non-cancerous cells is very low, making the side effects mild and transient. There is a minor immunosuppression, as AID activity is blocked in B cells, making them unable to mount a strong immune response, but it is temporary.

"This treatment affects every cell in the body," Mills says. "But by its mode of action it kills only tumor cells that are expressing AID—it is almost entirely harmless to normal, healthy cells." 

Second, cancer cells depend to a large extent on AID to adapt and evade first-line therapies, and blocking HR also blocks this adaptive process. Even in the absence of complete cancer cell elimination, any remaining cells will, in theory at least, have far less ability to further mutate and metastasize.

The ultimate utility

Going back to the NYT article, the final quote, from a Dr. James Crawford from Hofstra, struck me as provocative: “What is the ultimate utility of this personalized medicine?” he said. “As a medical profession but also as a society we have not answered this question to our satisfaction.” We haven’t?

Having read about tens of thousands of tumors sequenced, outlays of hundreds of millions of dollars and recruiting competitions for the top talent within the space, I thought at least a basic answer had been reached. The ultimate utility of personalized/genomic/precision medicine is better outcomes for patients based on their individual genetics and genomics, and it’s worth huge effort and investment to achieve it. Encouraging progress has already been achieved. More targeted therapies that use genetics to improve both diagnostics and treatments for some patients are in hand, and more are on the way.

To give Dr. Crawford credit, the true power of full sequencing and tumor analysis—the ultimate utility, if you wish—is indeed an unknown. But with the huge efforts under way and the encouraging “stepping stones” we are finding, the future of cancer care is sure to be changed by it for the better.