Unraveled Dana-Farber Cancer Institute

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.

Momentum isn't always one way. And it's not always constant. Sometimes it shoves you sideways, sometimes it stops you in your tracks. And sometimes only sometimes, it drives you to write one of the most astonishing second acts in all of medicine. That's the story we're telling today about thalidomide, its second act in multiple myeloma, and the promise of protein degradation.

The story begins decades ago with a man named Stanley Korsmeyer, who led the molecular oncology program at Dana-Farber from 1998 until his death in 2005. He discovered that B-cell cancers like CLL over-produced a protein called BCL-2, and interfered with apoptosis, or programmed cell death. But how that went from an interesting discovery to a game-changing cancer drug is a story of persistence and momentum, and it’s the first episode of season two of Unraveled