The Nanomedicine Lab at UCL’s School of Pharmacy in London houses a tray of cancer cells on one of its optical microscopes. These cells are a part of a study that originated in a hotel bar over a drink of beer.
This study began the road to a revolutionary cancer treatment possibility. Millions of dollars from investors subsequently came in, and rival companies started on the path to developing the process. All of this revolves around one microscopic garbage truck. This “garbage truck” is a metaphor for something called the proteasome. Its job will be to destroy and dispose of obsolete and broken proteins hanging out in your body.
Craig Crews and Raymond Deshaies are biochemists that were casually discussing the theory over drinks at an annual conference in 1998. This proteasome had a clear description, but no current domestication. It is known to destroy proteins in the cell that are not needed anymore. The tricky part is to get this proteasome to work for cancer destroying purposes by doctors.
This particular research question has fueled Crews’ entire career. At 51 years of age, Crews is going on 20 years of trying to work with these “garbage trucks” for cells. His work involves complex ideas and theories aimed at convincing the proteasome to work in his favor.
His success includes a molecule that a major pharma giant gave up on. Crews were able to use this molecule to make a cancer drug that has been incorporated into successful cancer treatment. He is using this proteasome and his previous success story to fuel new research designed to make other stopped or failed drug projects victories, as well. His company is called Arvinas, and its purpose is to bring treatment options to diseases that are now stated as “undruggable.” He thinks this proteasome can help many diseases, not just cancer.
Crews are not the only research specialists focusing on this topic. Andrew Phillips, chief scientific officer of C4 Therapeutics, states that “Every big pharmaceutical company in the world is thinking about this area.” Phillips’ company is working on the same question.
Crews were new to his professorship at Yale and needed some new projects to add to his repertoire. He somewhat “stumbled” on to the idea of this proteasome. He read some research about an unusual molecule that is formed in specific bacteria residing in soil. The knowledge that was being kept secret by Bristol-Myers eventually came out in a full report in 1992. This published report included their discovery that the bacteria in question successfully killed melanoma cells. The question still residing was that of why this was the case.
“This had a particular appeal to me, because it had such potency, but here was this mystery about it,” stated Crews. “They didn’t know how it worked. All they knew was that it would kill tumor cells. And that, to me, is this wonderful invitation. I was curious.
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Crews spend his childhood mesmerized by problems that seemed to have no answer. His father worked as a NASA engineer and participated in research aimed at creating lightweight aircraft wings. He was gifted with the leftovers of his father’s research, such as old levers and valves. Crews started a collection in the family garage with these, and other miscellaneous parts from cars, etc. He used them for robot building. His personal notebook was full of possible inventions. One of which was a perpetual motion machine design.
Crews had the privilege of seeing his father’s lab. He had wanted to be a scientist for as long as he could remember. He compares today’s biotech research efforts to the exciting years of the 1960’s and 1970’s at NASA.
Crews, however, did not have access to the mystery molecule written about in the work by Bristol-Myers Squib. Crews had to improvise by requesting that is team come up with their own version of the molecule. They started with a tiny strand of plastic beads. These beads were about the size of a grain of sand. This strand of beads was then coated with the target molecule. The next action can only be described as a fishing expedition to see what they could find. The filling of a cell was poured over these molecule coated beads. Everything passed by the beads except a specific cylinder of proteins. This was the proteasome.
This mysterious molecule kept the proteasome from completing its purpose of getting rid of unnecessary proteins in the cell. Crews explain, “By gumming it, by blocking the action of the proteasome, you get a buildup of toxic proteins that should have been removed.”
This action affected all kinds of cells but seemed to have a larger effect on cancer cells. Cancer cells multiply at uncontrollable rates, making proteins and getting rid of them very quickly. When the proteasome is blocked, toxic amounts of old proteins happen more quickly in the targeted cancer cells. The cancer cell dies at this point. Crews took this information to be more important than even a scientific discovery. He believed this information could be used to invent a drug.
Crews collaborated with Deshaies to start a company called Proteolix. This resulting drug was worked on for a while to iron out the complications and then produced for use in multiple myeloma patients. The FDA in approved the drug in 2012.
The drug is called Kyprolis and has been successful. Onyx Pharmaceuticals purchased Proteolix in 2009 at the price of $850 million. Onyx was then sold to Amgen in 2013 for near $10 million.
The goal to cease the “garbage truck” from doing its job turned out to be a worthwhile mission. Crews, however, had started to think about a different tactic using the proteasome. He began to consider what would happen if researchers could get the proteasome to work for the opposite cause. He wanted to try and get it to eat up the proteins guilty for initiating the disease in the first place.
Genomic analysis has helped researchers to gain significant amounts of knowledge related to the complications of diseases. Certain proteins involved in these ailments produce damage by taking up residence in different cell structures. The resulting chemical reactions are the diseases and symptoms. A majority of drugs work by blocking the places in which these proteins like to set up camp.
This method has been attributed to saving many lives along the way. As with many drugs, however, there have been some issues. The blocking molecules are not permanently adhered and will fall off at some point. This makes the need for constant medication a reality. These drugs are often toxic to the body in a different way than cancer. The side effects, however, are damaging. Toxins then remain throughout the body of the patient.
Crews and Deshaies wanted to find a way to tag these disease-causing proteins. The idea was that the disease would take notice of the specified tags and proceed with its normal action of “taking the protein that’s been tagged, unwinding it threading it in, and chewing it up,” states Chews.
The most amazing part of the theory is that the chain of molecules aimed at tagging the damaging proteins will remain free to tag more proteins after it “feeds” some to the “garbage disposal”. The chain of molecules should, in theory, remain undamaged and should not be chewed up by the “garbage truck”.
“You can imagine a small molecule, a drug, that works under this new paradigm, will truly be one that can seek and destroy rogue, disease-causing proteins, rather than simply binding and falling off, binding and falling off,” explains Crews. “So you don’t need as much drug. It gets the job done, first time around.”
This new knowledge could also lead to the treatment of diseases like Alzheimer’s that, until now, have been untreatable with drugs. Diseases like Alzheimer’s do not have the necessary docking areas to be receptive to traditional drug types.
Of course, challenges came about during the research phase. The cell membrane presents as a greasy, slippery surface. It proved difficult to the sizeable molecule chains to pass this surface. One of the postdoctoral scientists in the lab at the California Institute of Technology, working with Deshaies, was having to inject them manually.
The year 2009, however, brought a new tactic. One link in the chain was replaced with a smaller molecule. This smaller link is used instead of the larger series if amino acids called peptides. The lab has kept up the practice of working on these molecules to improve their ability to tag the proteins and alert the “garbage truck.”
“As far as tagging the protein itself and dragging it off to the shredder, no one has ever tried to treat the disease like that,” says Derek Lowe, one of the long-term pharmaceutical researchers. “It’s coming in from an entirely different direction that no one else has come in from before.” There is still the uncertainty of the success in human subjects, but “it has a lot of promise.”
In 2010 a Japanese research paper brought the table information on a drug from the year 1957 that lacked a clear understanding of the way it worked. The drug in the question tagged proteins to encourage destruction by the proteasome. The name of this drug was Thalidomide. Until its propensity for birth defects was made apparent, it was used to treat pregnant women experiencing nausea.
Crews were excited to hear this news. The information reinforced his theories and showed that the idea might be successful. Crews founded Arvinasin 2012 to better work towards his goal with the proteasome. Arvinas is working to beat its competitor C4, also working to produce new cancer treatments. C4 has named their molecular chains “degronomids”. However, the theory is comparable to that of Crews.
These two companies started in the same lab type setting and are privileged to work with well-known partners. Arvinas has coupled up with Merck and Genentech, while C4 collaborates with Roche. The hope of Crews is that in one year, his company will be in the testing phase. This sudden idea that came to him over a drink of beer in a tavern 20 years ago might finally become a reality. The next step is to find patients willing to give it a try.
