Episode 5: Turning Science Fiction into Fact

Cigall Kadoch had a hunch that the research in her lab might be relevant to endometrial cancer research. She had spent more than a decade studying the molecular machinery that unwinds DNA in the nucleus of a cell to make the right DNA instructions readable by the cell at the right time. This machinery – the SWI/SNF or BAF complex – is altered by gene mutations in about 20 percent of cancers, including an aggressive form of endometrial cancer. The discovery of that connection, and the collaborative translational research done with gynecologic oncologist Jessica St. Laurent, MD, at Dana-Farber to determine if an inhibitor targeting these complexes could benefit patients with endometrial cancer — it’s the story we’re sharing in this episode of Unraveled Presents: Conversations About Cancer.

As our universe of knowledge expands, sometimes incrementally and more often, exponentially, its new dimensions create new challenges. The more we know, the better our tools are, the more choices we have. And that's great, but it's hard to distill mountains of patient data, clinical trials, therapies, discoveries, and a boatload of externalities. Hard to distill all of these into the best possible research and care. Oh, and don't forget the human genome in its almost infinite complexity. It can be overwhelming when you try to think about it absent, sort of having some help. But what kind of human mind could provide that help? Could it be that the help we need, the intelligence we need isn't human at all.

If there is such a thing as a holy grail in cancer research, a secret spell or golden ring that can ward off any and all forms of the disease, it probably lives somewhere in the realm of immunotherapy. A new category of immunotherapy drugs, called checkpoint inhibitors, take the brakes off the immune system and let the T cells do their job: attack cancer. They've been approved for more than 25 different types of cancer. However, the average response rate for checkpoint inhibitors is 20 to 30%, which means that it's not working for 70% of the people who take it. So that's the project now: to extend the benefits of immunotherapy to all cancer patients, instead of to just a few. And the best way to do that, it seems, is by doubling down, by pairing immunotherapy with other therapies so patients can benefit from both. Sound logical? Sure. Sound easy? Not on your life. It's called combination immunotherapy, and it's what this episode of Unraveled is about.

By the early 2000s, researchers at Dana-Farber and elsewhere knew that a certain protein appeared in many tumors taken from lung cancer patients. Based on that data, doctors started treating those patients with a drug that inhibited that protein. Unfortunately, for reasons that weren’t clear at the time, most of the patients didn’t respond — but there was a small percentage of patients, about one out of ten, who did. People called it a "Lazarus-like effect." So how can doctors know which of their patients is Lazarus? How can they know which ones will respond to a drug and which ones won’t? In other words, how can they interpret data so it makes sense? That's the subject of this episode of Unraveled about precision medicine and the EGFR discovery. It's an episode that begins with a riddle and ends with a roadmap.

Cancer is often a problem of cell division; cancer cells keep doubling and doubling, faster and faster. Eventually, they crowd out the healthy cells we need to survive. So researchers proposed a question: Why not stop that land grab? Why not find a way to jam the gears of the cell cycle to stop cancer cells from dividing? Today, we have drugs that do just that: They're called CDK-4/6 inhibitors. The story of those drugs, the momentum that brought them from bench to bedside, was written largely at Dana-Farber Cancer Institute — and keeps being written today. It's the story we're telling in episode three of Unraveled.