Finding Cancer’s Achilles’ Heel

For much of his research career, Ray Deshaies, Caltech professor of biology, has been interested in what he calls the cellular garbage disposal system of the body. In this self-cleansing process, proteins are eliminated either when they become damaged or in response to particular cellular signals. This system is integral to maintaining a healthy, functioning body. It's a significant operation, involving about 5 percent of the proteins encoded by the human genome, and for years Deshaies has focused on the biological nitty-gritty of how it works.

The therapeutic potential of the system took shape in the late 1990s, when clinical trials began showing promise regarding a drug for multiple myeloma: a cancer of the cells that produce antibodies. The drug, called Velcade, worked by inhibiting a protein complex known as a proteasome, which aids in the degradation process that Deshaies had been studying. Cancer cells need lots of active proteasomes to stay alive, so when you block proteasome function, the cancer cells die.

At about the same time, Deshaies, an investigator with the Howard Hughes Medical Institute, attended a conference and met a chemist from Yale named Craig Crews, who was investigating a soil bacterium that produces a chemical that is also effective against cancer cells by targeting the proteasome. At their first meeting, they agreed to collaborate, working on promising molecules that target proteasomes, including an enzyme that Deshaies had discovered, as well as other novel approaches to exploiting the degradation process. They soon realized that the projects they were working on had commercial potential for developing anti–multiple myeloma drugs, and decided to start a company.

Launching a company, Deshaies admits, did not come naturally to him, so the expertise of Caltech's Office of Technology Transfer (OTT) helped smooth the start-up process. "I worked with Scott Carter—a Caltech alum who received his PhD in chemistry in 1999 and who had become a patent agent in OTT," Deshaies says. "He had helped me file some patents and he demystified a lot of the technology transfer process for me," including lining up meetings with venture capitalists to obtain funding for the new company, called Proteolix, and helping find corporate counsel.

"We raised capital, closed financing in late 2003, and began pursuing Craig's molecule, called YU101, and new enzymes that my lab had discovered that were essential to proteasome function," Deshaies says. With typical start-up financial pressures, Proteolix had to focus its resources on one drug, and since Crews's molecule was furthest along in the pipeline, the focus turned to Carfilzomib, a drug based on YU101, which soon entered clinical trials and showed great promise. Carfilzomib worked by stopping the multiple myeloma cells from getting rid of their waste, causing the cancer cells to die.

To develop Carfilzomib further, Proteolix needed a larger corporate partner. It sent out the word in the biotech community that it would welcome a merger, and in 2009, it was acquired by Onyx Pharmaceuticals in a deal valued at up to $850 million, pending successful completion of milestones. "When Onyx took over Proteolix, it acquired all of the intellectual property [IP] that Proteolix had developed, including IP from Caltech on the targets that I had identified, which was really no longer being pursued," Deshaies says. With the help of OTT and the generous cooperation of Onyx, Deshaies was able to get the rights to his IP returned to Caltech so that he could pursue commercial development of his proteasome targets.

In 2011, with OTT's help, Deshaies started a new company, called Cleave Biosciences, which is trying to build upon new inhibitors of the degradation system that Deshaies has developed in collaboration with chemistry laboratories at UC San Diego (UCSD) and the University of Kansas. He cofounded Cleave with Seth Cohen, a professor of chemistry and biochemistry at UCSD, and Francesco Parlati, a scientist who was one of the original scientists at Proteolix and who spent a year in the Deshaies group after the company was acquired by Onyx.

One of the questions they'd like to answer is whether proteasome inhibition can be effective against other cancers besides multiple myeloma, which strikes about 15,000 people each year in the United States, less than one-tenth the rate of new breast cancer cases. One challenge is that the existing proteasome inhibitors operate in the body for only a few hours, enough time to neutralize multiple myeloma, but apparently not long enough to target other types of cancer. So they are trying to develop new types of proteasome-inhibiting drugs that last longer and other drugs that may be effective against different players in the protein degradation process besides the proteasome.

"What you have to do in cancer is, you have to find Achilles' heels," Deshaies says. "You have to find processes that the cancer cells are more highly dependent upon than a normal cell. And then you go in there and you inhibit that process and if you can thread the eye of the needle, if you will, you can get the drug at a level where you can kill a cancer cell but not a normal cell, because if the cancer cell has a higher dependency on that function, then you can have a therapeutic benefit."

For Deshaies, the hunt for a cancer cure is fulfilling as a scientist, but it's also personal. "My mother died one year before my first child was born. She died of lung cancer. There's nothing worse than seeing people close to you die and knowing you couldn't do anything even if you knew something about the disease. I do believe basic research science is fundamental to medical science. So, for a scientist like me to have an impact against a life-threatening disease like multiple myeloma, that's very satisfying."