Kinases have turned out to be one of the richest target mines of all for oncology drug discovery and development, and companies are now exploiting them in batches through drugs that hit many at once. It is slightly ironic because it turns out that most marketed kinase inhibitors already have multiple effects. But the art form is now to select for particular effects and avoid others: Something drug developers could earlier only dream of with this class of compounds. Several multi-target kinase inhibitors are now in development, two are already approved in the United States, and more will likely be approved soon. (See Table 1 at the end of this article.)

Screen Dream
Researchers have long known that you could hit multiple kinases with a single drug. What has changed, however, is that we know more about many different kinases and how they are structurally and functionally similar or different. As a result, companies can now screen drugs for multiple effects. As the understanding of tumor biology has expanded, the number of good mechanisms to target has also grown. Angiogenesis, or blood vessel formation, is a favorite, as is apoptosis – the cell death process. But scientists have uncovered many new cogs and wheels in the cancer growth and development process, and many of these are now being specifically targeted. By hitting many of these targets at once, they hope to overcome the fact that tumors have many, and often overlapping, biological paths they can use to grow, resist death, and spread.

For example, Onyx's Nexavar (sorafenib), developed with Bayer Pharmaceuticals, is the first drug targeting both the RAF/MEK/ERK pathway (involved in cell proliferation) and the VEGFR-2/PDGFR-ß signaling cascade (involved in angiogenesis). Onyx originally chose this drug because it hit RAF – a key kinase in the RAS pathway. About 20% of all human cancers have RAS mutations. Some tumors, such as melanomas or cancers of the pancreas, colon, or lung (small cell type), have a much higher proportion of these mutations and will be some of the first indications sought for Nexavar. The drug's first approval came in December 2005 for advanced kidney cancer, a disease that is believed to be highly dependent on angiogenesis.

Sutent was fast on Nexavar's heels, however, and in January 2006, Pfizer received approval in two indications – advanced kidney cancer and gastrointestinal stromal tumors (GIST). It was the first time the FDA has ever approved a drug for two cancers at once, and the drug was approved in a remarkable six months.

Right behind those two compounds is Bristol-Myers Squibb's (BMS's) dasatinib (formerly BMS-354825) a SRC/ABL kinase inhibitor currently in clinical trials for both chronic myelogenous leukemia (CML) and solid tumors. In late December 2005, BMS submitted a new drug application (NDA) seeking FDA approval of dasatinib for treatment of CML in chronic, accelerated or blast phases and also for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. The company followed up with a European application in January.

Close behind these agents are AstraZeneca's Zactima (ZD6474) for advanced non-small-cell lung cancer, GlaxoSmithKline's Tykerb (lapatinib) for breast cancer, and Novartis's STI571 for multiple cancers.

A New Paradigm

The favorite metaphor for cancer drug developers has long been the "smart bomb." Everyone hoped to design a drug that could hone in on cancer's weak spot, knocking out tumor cells while leaving normal cells undamaged. Cancer cells, however, have been smarter than most of the bombs we can throw at them. To grow and spread throughout the body, they use multiple biological triggers and pathways. Hit them in one spot, and they regroup to redeploy along new growth paths. Instead of one smart bomb, you need to throw a lot.

That realization has led to development of combination targeted therapies, which are becoming the new paradigm for cancer treatment. With the arrival of multi-kinase inhibitors, the question is whether it will be best to use combinations of single agents, or drugs like these, with multiple effects.

Clearly, a lot of companies are betting on multi-kinase inhibitors. Part of their enthusiasm stems from the effects seen with these drugs. Both Nexavar and Sutent reached the market along the fast track review process because they addressed urgent needs and had noticeable effects in desperate patients. They are also nicely filling in holes left behind by Novartis's Gleevec (imatinib), the "miracle" drug that led to disappointment when tumors developed resistance to it. GIST and CML patients, for example, were formerly dependent on Gleevec. Once the drug stopped working, their miracle came to an end. Now, the former can also use Sutent, while the latter should soon have the option of dasatinib. Given that Gleevec (Glivec in Europe) now earns $2.17 billion for Novartis, sales of similar drugs are also expected to be healthy. Analysts have pegged first-year sales of Nexavar at about the $600 million mark.

Not everyone is jumping on the multi-kinase inhibitor bandwagon. Other companies, including Genentech and Cyclacel, are focusing on designing a series of highly targeted drugs instead. After all, one of the obvious possible problems with drugs that have multiple actions is that we do not often know which particular actions are going to be most important in any particular cancer. In addition, some experts are concerned that more activity also could mean more side effects. A "cleaner" drug should be more predictable and give physicians greater flexibility.

Right now, experts are carefully watching the data. If any of these drugs work in cancers where there has been a desperate need for new drugs for a long time, such as advanced kidney cancer or melanoma, they will be warmly welcomed no matter how many targets they hit or don't hit. But the blueprint for targeted therapy calls for matching drugs directly to tumor characteristics. Hordes of companies are starting to look for biomarkers – biological signs of any kind – that will tell them which targets are most important for particular tumor types. As that work advances, the winners will be companies that have picked the targets that are most common across cancers and arise at critical junctures, knocking out multiple tumor defense systems at once.