Season 2 Episode 1 BCL-2 Inhibitors: Driving Cells to Destruction

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

In season 2 of Unraveled, we explore the theme of momentum. The momentum that takes therapies from test bench to bedside, and then back to test bench for fine tuning. The momentum provided by researchers, who defy headwinds and even gravity to keep science moving forward. And the momentum that doctors harness, with medicines and care that can transform once lethal cancers into treatable conditions.

A beauty… that in some cases becomes tragic. It’s not the way most people would describe a virus. In the simplest of terms, a virus is a snippet of genetic code. It can’t reproduce on its own. So, in order to replicate, it needs to infect and hijack a living cell. Scientists can’t even agree on whether viruses are alive or dead. What they do know is that every so often, one of them goes, well, viral. And when it does, it can bring everything to a skidding halt. Well, almost everything. One thing the COVID pandemic didn’t stop was cancer. And that meant that everyone at Dana-Farber had to find a way to keep on working. And they had to find a way to keep themselves and their patients safe.

It’s always fun to think about the future. Flying cars. Cities in the clouds. Colonies on Venus and Mars. Ok. So we didn’t end up living like the Jetsons. But a few of those visions did come true. And Judy Wilkins knows that first hand. Wilkins is a former patient at Dana-Farber. And she’s the poster child for a bold new therapy where science fiction becomes science fact.

There are approximately 20,000 genes in the human genome. 20,000 packets that house the blueprints for every human cell. And every human cell contains a complete copy of that genome. It’s an incredible feat of bio-engineering. But here’s the question. If every human cell contains every single human gene, how does the cell know what to do? What process determines whether it becomes a pancreas or a patella? And what happens if that process falters—if the right gene is selected but cast in the wrong role.