Illustration by Sanithna Phansavanh

Chasing Down Cancer’s Source

What scientists are discovering about what makes you you, and why that could help end cancer

By Elizabeth Mendes

It has long been known that your DNA is what makes you you. It’s often called the “blueprint” for life, responsible for your unique combination of features and traits. But what if our idea of the blueprint is incomplete?

It turns out it is. There is much more going on in your cells — complex sets of chemical reactions, all working as some sort of master program. Understanding how one cell turns into a human made up of trillions of cells that somehow work together to make you think and talk and feel — stay healthy or fall ill — is what cancer research is all about. Knowing how things go right is essential to learning how to fix what goes wrong.

Libraries of mutations

Scientists know a lot about how genetic mutations — errors in the sequence of your DNA — can cause cancer. For example, some DNA could be in the wrong order, a piece could be missing, or an extra piece could be inserted. They also know that you can either:

  • inherit, from birth, certain gene mutations that can increase your cancer risk
  • or acquire mutations, which can happen randomly or be caused by external factors such as smoking or exposure to sunlight.

Researchers have been working for years to pinpoint and document specific genetic mutations that can cause cancer. This knowledge has led to major advances in preventing and treating cancer. Two well-known mutations are those in BRCA1 and BRCA2 — both of which are linked to a higher risk of breast cancer (and some other cancers). Women can now be tested for those mutations and given options for precautions they can take should they have them.

BRCA is just one example. There are now libraries of hundreds of cancer-related genetic mutations. Despite this progress, the first — and one of the most prevalent — cancer-causing genetic mutation ever discovered in humans, many years ago, remains untouchable by modern cancer medicine.

Ras : A mighty mutation

Ras is a family of genes that, when mutated, can lead to cancer. Researchers have been studying these cancer-causing genes (oncogenes) since they were first implicated in human cancer in 1982. Scientists have struggled with ras to such a degree that many call it “undruggable.” The National Cancer Institute (NCI) launched an entire initiative in 2013 just to try to tackle ras.

Figuring out how to target ras would have a significant impact on cancer. This is because ras genes are mutated in about one third of all cancers. Ras is also frequently mutated in lung, colon, and pancreatic cancers — three of the top four cancer killers in the US.

WATCH: RAS & Cancer: A Mighty Mutation. Kevin Shannon, MD, a pediatric oncologist at University of California San Francisco Helen Diller Family Comprehensive Cancer Center and American Cancer Society Research Professor explains what ras is and why it is important to ending cancer. | Produced by: Ashley Wright and Elizabeth Mendes; Edited by: Ashley Wright; Illustrated by: Sanithna Phanasavanh
“Ras and p53 [a tumor suppressor gene] are the two most commonly mutated genes in cancer, and despite the fact that we have known this for 30+ years, there are no drugs targeted to those mutations,” says veteran ras scientist and pediatric oncologist, Kevin Shannon, MD.

He has been working on ras since the early 1990s, and the American Cancer Society has been funding his lab since 1992.

Reprinted by permission from Macmillan Publishers Ltd: [NATURE REVIEWS DRUG DISCOVERY] ( Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable Ras: mission possible? Nature reviews Drug discovery. 2014;13(11):828–851. doi:10.1038/nrd4389.), copyright 2014

“Essentially, ras is like a light switch,” says Shannon. When ras receives signals that the cell needs to divide, it turns on. When ras gets a message that the cell is in an environment where it is not appropriate to divide, it turns off.

In some cancer cells, ras gets stuck in the on position. And when ras is stuck on, it keeps telling the cell to grow. This leads to the out-of-control cell growth that causes cancer. The trouble is that getting ras unstuck is very hard to do, says Shannon. But he doesn’t plan to give up anytime soon, and he does predict that a therapy for ras-mutated cancer is on the horizon. “Sometime in the next decade, maybe in five years,” says Shannon.

On the heels of Shannon’s prediction, a one-patient study published in The New England Journal of Medicine Dec. 12 reported the first successful ras-targeted treatment. A 50-year-old woman with metastatic colon cancer was treated with a type of immunotherapy, resulting in regression of her cancer. Shannon says the finding is exciting and “could be an interesting new approach to treating cancers with ras gene mutations.” But he cautions that because it is just one patient the significance is unknown and the specific way this treatment works may prove challenging to reproduce in other cases.

It’s not just about genes

There is an entire world beyond your genes that scientists have barely begun to understand, says Brad Bernstein, MD, PhD, a Harvard University cancer researcher.

Bernstein is studying ways your DNA gets corrupted that don’t have to do with DNA sequence problems. Instead, Bernstein says the culprit is often the switches that turn your genes on and off. So your DNA sequence may be fine, all in perfect order, but if a switch goes rogue and turns off a gene that should be on, for example, that single misfire could lead to cancer. Together, these switches make up another important part of the puzzle: your epigenome.

WATCH: Epigenetics & Cancer: The Other Side of the Coin. Brad Bernstein, PhD, a Harvard University cancer researcher and American Cancer Society Research Professor explains what epigenetics is and why it is important to ending cancer. | Produced by: Ashley Wright and Elizabeth Mendes; Edited by: Ashley Wright; Illustrated by: Sanithna Phanasavanh

Epigenetic switches control which genes are active and which are inactive in a particular cell. Not every cell has the same gene program running.

Understanding your epigenetic programming will lead to a lot of new cancer drugs, predicts Bernstein.

He explains that it might prove easier to find ways to fix the activity of your genes (the epigenetic controls) than to cut out or destroy mutated genes. “There are therapies for modulating the activity of a gene that are now making their way into the clinic and some are approved. So there are a lot of conceivable possible therapeutic directions one could go in,” says Bernstein. One active area of epigenetic treatment progress: combining epigenetic drugs with immunotherapies.

It’s the repair tech’s fault

Another important new area of research is looking at your cells’ own built-in repair tools. Mistakes are a normal part of cell replication. When the DNA inside each of your cells goes through the process of replicating itself — which happens in more than 50 billion cells per day — it frequently makes mistakes. But your cells are super-smart and most times will catch the errors and use built-in systems to fix them.

Scientists are learning that in cancer, sometimes one of your cellular repair technicians falls down on the job. In a lab at Duke University, a unique research duo is digging into this issue. A young, energetic researcher named Shanen Sherrer, PhD, has worked alongside Nobel-prize-winning scientist Paul Modrich, PhD, for the past three years. Together, they are trying to figure out how to fix the DNA fix-it-tech.

The technical term here is DNA mismatch repair (MMR). “[It] is an essential pathway that all growing and replicating cells must have to prevent cancer,” explains Sherrer. “I like to say that you can imagine this process as a team with the players going around fixing mismatched socks.”

DNA MMR was first connected with cancer in 1993. Scientists are still trying to understand how it works in healthy cells. Once they know how it does what it does — and why, sometimes, it stops doing its job — they may be able to develop new ways to prevent cancer.

Sherrer has high hopes for solving DNA MMR problems. A series of experiments in cells in the lab led Sherrer to figure out that a couple of basic elements could play a role in getting your MMR mechanism to turn back on, if it gets turned off (which can lead to cancer). She and Modrich hope to publish their results soon.

There’s so much more to learn

DNA MMR is just one of the big areas researchers are tackling. Many other scientists are investigating different angles of how cancer comes about in your cells.

For example, cancer research into the role of your mitochondria — the energy centers inside each cell — is gaining traction. And what scientists are discovering might extend beyond helping to end cancer — even to slowing aging itself. Cancer and aging are inextricably linked. “Research in this area has massive potential,” says Michael Melner, PhD, director of the Molecular Genetics and Biochemistry Cancer Program for the American Cancer Society.

A lot of work is being done to better understand the roles of other genetic material in your cells, such as RNA in cancer formation and treatment. It could be as important as the roles of DNA mutations and epigenetics, with its own set of mutations linked to numerous cancers. Then there’s the explosion of research into the connections between cancer and your microbiome, the trillions of bacteria, fungi, and viruses that live in your body. And the study of immune cells (and immunotherapy) continues at a rapid pace.

Up next: See how scientists are using their growing knowledge of the cell to develop new cancer treatments>

Sabrina Singleton, ACS research historian, contributed reporting.