One of the biggest stories in 2019 was Pfizer’s (New York, NY) acquisition of Array Biopharma (Boulder, CO) for the tidy sum of $11 billion. Array Biopharma brings an impressive portfolio to Pfizer, including the approved combined use of BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) for the treatment of BRAFV600E or BRAFV600K mutant unresectable or metastatic melanoma. Because of its specific expertise, Pfizer plans to keep Array’s Boulder facilities open as a research site for Pfizer.

This article takes a closer look at targeted therapeutics and their discovery platforms.

TARGETED THERAPY

Targeted therapy has improved the lives of countless cancer patients and their loved ones. These specialized treatments identify and attack specific kinds of cancer cells while causing less harm to healthy cells than chemotherapies and other more traditional approaches. To the average person, targeted therapies can almost sound like magic..

Behind the magic, science is working hard. Targeted therapies block the action of certain enzymes, proteins, or other molecules that fuel the growth and spread of cancer cells.

How do we even get to targeted therapy in the first place? Typically, there are two strategies: target-based and phenotype-based.

In target-based drug discovery, researchers home in on one molecule integral to a disease process. For instance, some cancers involve a cellular enzyme that mutates to promote the wrong kind of cell division. Researchers screen the enzyme against enormous chemical libraries to see what comes up. They’re searching for a molecule that interacts with the drug target in a possibly therapeutic way. Companies then further screen any “hits” to find potential drugs.

Researchers test a chemical compound in cell, tissue, or animal models for the phenotype approach to see whether it exerts the desired effect, such as putting the brakes on cancer cell division. Compounds that seem beneficial move forward in the drug discovery process. The mechanism of action—the drug target—sometimes remains undefined until much later.

Using its discovery platforms, Array Biopharma gained FDA approval for two kinase inhibitors, Braftovi and Mektovi, in June 2018. The drugs were approved to use together to treat melanoma caused by specific mutations in the BRAF gene. These mutations show up in about half of all melanomas.

What are kinase enzymes? Further, how does inhibiting them help people with cancer? Kinases are enzymes that add a phosphate molecule to proteins. Phosphate molecules are small, negatively-charged chemical groups. The addition changes the shape of the recipient protein. Mostly, this shape-shifting turns the protein “on” from an “off” state. This process, phosphorylation, is vital in sending growth signals within a cell.

Typically, kinase enzymes transmit growth signals only when activated by a growth factor. However, mutations cause some of them, like BRAF, to stay active all the time. This heightened state triggers excessive cellular growth and division: cancer. Inhibiting the mutant kinases can shut cancer down.

Braftovi halts the mutated, overactive version of the kinase BRAF. Mektovi inhibits the kinase enzyme MEK, which is overactive in many cancers, including melanoma.

Although hailed as safer and more effective in treating cancer, targeted therapies have a critical limitation: resistance. People may develop resistance to their treatments in two ways:

• The target protein mutates, preventing the therapy from interacting with it further.
• The tumor finds a different way to grow, no longer depending on the target molecule.

To reduce the likelihood of resistance, doctors often prescribe targeted therapeutics with other drugs. This is why the FDA approved Braftovi to be prescribed in combination with Mektovi, which inhibits a different cell-signaling pathway. Clinical studies demonstrate that the combination is more effective than Braftovi alone.

Ongoing clinical studies are examining combinations of targeted therapies and immune checkpoint inhibitors.

Targeted therapies continue to be an essential weapon in the fight against cancer. As researchers continue to collect and characterize more and more tumor genome sequence data, which aids in identifying new targets, we expect to see additional targeted therapies.