Cancer biologists and drugmakers have tried, and failed, to find ways to protect a gene known as p53 for more than two decades, and for good reason: the famous tumor suppressor gets shut down in some form by every single known type of cancer. Yet an eight-year-old startup out of Cambridge, MA, named Aileron Therapeutics thinks it’s found a way to fight cancer by turning the tumor suppressor back on.
Aileron is attempting to develop a drug that is supposed to simultaneously hit proteins made by two genes, known as MDM2, and MDMX, that deactivate p53. This is more concept than reality so far: Aileron has only tested forms of a molecule, a “stapled” peptide, or fused combination of protein fragments, in preclinical studies. It won’t actually begin dosing an optimized version of the drug candidate in human patients until next year, and has many hills yet to climb. But by homing in on the proteins that affect p53, it is attempting a strike at one of the most well-known, yet largely untouchable pathways in cancer biology.
“At some point, everyone has taken a run at this target,” says Aileron CEO Joe Yanchik.
P53 is bound to the DNA in the nucleus, and has been named as the “Guardian of the Genome,” because it is the cell’s first line of defense. Its job is keep cell division in check, sense whether anything is wrong, and order the cell to commit suicide if it is. That’s the job of a “tumor suppressor.” When it’s deactivated—either by being mutated, or repressed by another gene—cells begin rapidly replicating. This process causes both liquid and solid tumors to form in every type of cancer. It’s no surprise, then, that pharmaceutical companies have burned through millions of dollars trying to develop drugs that can stop this from happening.
“If you could somehow re-harness that capability, you now have something that could be impactful across all cancers, and across all tissue types,” Yanchik says.
Both antibodies, and small-molecule drugs, however, haven’t been able to do it. Antibodies attach to disease targets on cell surfaces, so they can’t make it to the proper site. And while pharmaceutical companies have turned to small molecules, they aren’t big enough to rip apart the protein-protein interaction that causes p53 to shut down.
Here’s why. When a small molecule makes its way into a cell, it burrows into what Yanchik calls a “deep pocket,” or cavity, on the targeted protein. To reactivate p53, the pharmaceutical industry, he says, has exclusively used small molecules to attack MDM2, which is known to become overactive and switch off p53 to allow tumors to form. That target also has the deep cavity that makes it easy for a small molecule to slide into, and bind to it.
This is only getting half the job done, however. Another gene known as MDMX also goes haywire and helps deactivate p53, and has been ignored by the industry because its grooves are too shallow for a small molecule to latch on to, according to Yong Chang, Aileron’s vice president of biology and translational research. As a result, though the biology of p53 is well understood, no one, as of yet, has been able to find a way to completely switch it back on.
This is where Aileron is betting one of its stapled peptides can do the trick. These compounds are two protein fragments that are chemically “stapled” to one another, holding them in an alpha-helical shape—the common structure of proteins. This is supposed to make them not only travel through the system to the disease site without getting chewed up by enzymes, but also bind to more protein targets inside a cell than small molecules can—and more significantly in this instance, attach to two at a time. So Aileron thinks it can engineer a stapled peptide that is specially configured to bind to the deep grooves on MDM2 and the flatter ones on MDMX, which, it believes, would fully reactivate p53. In addition, by targeting the overactive proteins, and not p53 itself—which is found in all of the cells of the body—Aileron hopes such a drug would bypass healthy cells and only hit the ones with the malfunctioning genes. Aileron wants to tailor a drug towards the 50 percent of cancers in which P53 is functional, but deactivated by these proteins—so-called “wild type” p53—rather than the other 50 percent in which it’s mutated and defective, to increase its odds of success, according to Yanchik.
Aileron plans to test the drug in people with solid and liquid tumors, and a variety of different cancers, in an early-stage clinical trial that will get underway during the first half of 2014, he says.
While this means we won’t know for some time just how effective Aileron’s approach will be, a lot of pharmaceutical companies will be paying close attention. The program is part of the $1.1 billion partnership Aileron struck with Roche in 2010, and Aileron’s venture backers include a Big Pharma quartet of Roche, Eli Lilly, GlaxoSmithKline, and Novartis.
“People understand, starting with our existing investors, how important this could be,” Yanchik says.