A new breast cancer drug is turning heads in the hard-to-faze pharmaceutical industry. The compound, called palbociclib, has already shown remarkable results in breast cancer patients and is being tested for use against other forms of cancer.
Pfizer, the company behind the drug, achieved accelerated approval of palbociclib by the U.S. Food and Drug Administration (FDA) in February 2015, under its Breakthrough Therapy designation. Two other major pharmaceutical companies, Eli Lilly and Novartis, have similar drugs in advanced stages of clinical trials.
But the path to palbociclib has been neither short nor easy. Before it was on the minds of patients, doctors, and pharmaceutical executives, the compound was just an idea at the center of a complex mystery being pursued independently by two researchers who, by a stroke of luck, met on a bus after leaving a science meeting some 25 years ago.
On the Hunt
In 1991, Charles Sherr, an HHMI investigator and cancer biologist at St. Jude Children’s Research Hospital, had just discovered a cellular protein in mice with an important job. The cyclin D1 protein was crucially involved in regulating the cell division cycle, the progression of steps a cell takes to duplicate itself.
A so-called G1 cyclin, the D1 protein helps push the cell from the G1 stage of the cycle to the S phase, when the cell fully commits to dividing into two daughter cells. The discovery was potentially relevant to understanding cancer, which causes the cell cycle to lose control of this transition, leading to unregulated cell replication. However, Sherr knew he wouldn’t have a robust finding until he could show D1 doing its job in an organism, as a cyclin.
One of Sherr’s colleagues suggested that yeast might be a good model organism for his purposes. So Sherr started hunting for a yeast geneticist willing to work with him on an experiment looking at D1’s activity in the rapidly reproducing fungi.
Meanwhile, David Beach was working as an HHMI investigator at Cold Spring Harbor Laboratory in New York. Beach had been studying yeast cells for years and more recently had extended his studies to cell cycle control in human cells. Having established that cyclins A and B physically associate with and act through cell cycle protein kinases, his team was working with mutant yeast with a cyclin deficiency that blocked the cells’ ability to move from the G1 to the S stage. As a result, the yeast cells couldn’t divide. Interestingly, Beach’s team had found a new protein that corrected the mutant cell cycle defect.
This human protein, if taken out of the cell, would lead to a halt in cell division. Reintroducing the protein would cause the cell to start multiplying again. But, says Beach, “Our problem at the time was that we knew almost nothing about this [blasted] thing except that it rescued the yeast.” And that it looked like a whole new class of cyclin that presumably acted through a protein kinase. The mystery behind the protein would soon be cleared up, however.
Late one night, on the way back to his hotel from an HHMI science meeting, Sherr happened to get on the same bus as Beach. “I sit down next to David Beach, look at his nametag and say, ‘You don’t know me, but I’m familiar with your work,’” recounts Sherr, trying his best to describe an interaction with Beach that happened over two decades ago. “I said, ‘We have G1 cyclins; we want to test them in yeast. Would you be willing to do that?’” Beach explained to Sherr that the very experiment he was describing had already been carried out in his lab, on a protein that Beach’s team had found. By the end of the short bus ride, the two scientists had decided to compare their proteins.
The next day, they sent each other the amino acid sequences, and to their astonishment, they were the same. “When I saw the results, I sent him a fax – you know, there was little email use then,” recounts Sherr. “I said, ‘These proteins are identical!’” Beach remembers his team’s excitement, and also being slightly taken aback. “I just wrote back saying, ‘Yes, we noticed,’” he says. “In truth, I was a tiny bit [ticked] off – who is this guy?”
This finding resulted in the two scientists publishing back-to-back papers (one by Beach and one by Sherr) in Cell in 1991. It was the start of a story that eventually would lead to an unfolding of the molecular processes behind the cell cycle and how the cycle could be regulated. The question that remained to be answered was how this D1 protein actually worked.
Pathway to a Drug
Sherr’s team plunged headlong into the problem. The next year he discovered that D1, when expressed, attached itself to a second protein that his group named CDK4. But that raised yet another question: what was this complex doing to save the cell cycle?
Sherr expected CDK4 to be a kinase – a protein that adds a phosphate to another molecule, altering its activity as a result. But he couldn’t find CDK4’s target. “I had worked with kinases for quite some time, and I was struck by the fact that we couldn’t phosphorylate anything with this complex.” But then he heard from another scientist, David Livingston, whom he had worked together with at the National Cancer Institute many years before.
Livingston’s team had discovered that the retinoblastoma protein, RB, was a target for phosphorylation during the G1 stage of the cell cycle, when cell division is initiated. RB was widely known to be a tumor suppressor, meaning its activity prevented a cell from dividing uncontrollably.
I lament the time that it took to get from Chuck and David's original work to patients.
Robert Abraham, Pfizer
For Sherr, this was an exciting possible connection. “I had no hesitance just calling [Livingston] up and explaining what I wanted to do.” Would CDK4 phosphorylate recombinant RB? Livingston sent him some of the protein. To Sherr’s delight, his team found that CDK4 directly phosphorylated RB, rescuing the cell cycle and allowing the cells to divide. In October, 1992, the scientists published a paper in Cell showing evidence that D1 activates CDK4, which in turn phosphorylates RB, allowing cell division.
With the story starting to come together, the final chapter would be written by Beach’s lab team. They were looking for a protein that could bind to CDK4 and stop its activity – something that would let RB do its job. That search ended when they found yet another protein, p16, in the pathway. In December 1993, the team reported in Nature that p16 inhibits the activity of CDK4 – meaning CDK4 would not be able to phosphorylate RB, so RB could continue its role as a tumor suppressor.
With this new piece of the puzzle, Beach and Sherr both realized that an artificial CDK4 inhibitor had immense potential as a therapeutic for cancer. During tumor growth, proteins like RB that hold cell division in check stop functioning properly, leading to continuous and usually uncontrollable proliferation. Knowing that CDK4 prevented RB from doing its job, Beach decided to start a company with the objective of developing a CDK4 inhibitor.
“It was obvious at the very beginning that this could be a target,” says Beach about starting his company, Mitotix. “But what happened was that, as the data came out, the logic just got better and better.” He was able to recruit several partners to help him with the start-up, which soon was getting a lot of attention. But finding a CDK4 inhibitor turned out to be harder than they had expected.
Final Steps
Though Mitotix was successful in creating many CDK4 inhibitors, the company failed to develop a drug selective enough to be useful in clinical applications. Sherr acknowledges that tools for studying chemistry were just not good enough at the time. Looking back, Beach says, “I would say we were defeated by time.” The board sold the company in 2000.
Fortunately, chemists at Parke-Davis, a pharmaceutical company that had been approached by Mitotix and was eventually bought by Pfizer, had been working on the same problem. In the early 2000s, Parke-Davis announced that its researchers had isolated a CDK4 inhibitor specific enough to be clinically useful. Now, over a decade later, palbociclib is finally being used by patients.
“I lament the time that it took to get from Chuck and David’s original work to patients,” says Robert Abraham, who is senior vice president of oncology at Pfizer and has been involved in the development of palbociclib from the beginning. “I was very familiar with David and Chuck’s company, Mitotix, and they really had the idea that blocking D1 progression could be effective in terms of cancer therapy.”
Abraham says there is an explosion of interest in the compound. In the U.S. alone, there are between 150,000 and 250,000 patients living with breast cancer. And with further approvals from the FDA, palbociclib and similar compounds will be used for various other forms of cancer as well.
“All that work stands on the shoulders of giants in the field like David Beach and Chuck Sherr, who laid the groundwork for us and told us where to go,” says Abraham.
Often in science, it is hard to see the direct impact of fundamental research. Sherr says, “I’ve always been interested in whether a discovery might lead to something useful for patients.” For him and for Beach, a chance encounter on a bus 25 years ago has led to just that.
