August 2012

Right on target

Hanson now pops a 420-mg pill of ibrutinib every day. He says the daily dose “has made me feel like I have a future. I am amazed by it. I should be dead.”

But it’s not a completely rosy picture with targeted therapies, and a number of challenges dog the hunt for targets. For instance, earlier this summer, a group of researchers, which included Bert Vogelstein of Johns Hopkins University and Kelly Oliner of Amgen, demonstrated why colorectal cancer patients eventually develop resistance to a targeted therapy called panitumumab after several months of treatment (2). They showed that well before these cancer patients started on the drug treatment they had a number of tumor cells with randomly mutated genes that evolved into providing resistance to the drug.

Side effects remain a concern, despite these drugs being so-called “targeted therapies.” “We are seeing toxicities,” says Thomas Force of Temple University, citing two examples – sunitinib, sold by Pfizer as Sutent to treat gastrointestinal stromal tumors, and dasatinib, marketed as Sprycel by Bristol-Myers-Squibb to treat certain adult leukemias.

As Force explains, one organ that is inadvertently affected by drugs that target kinases is the heart. The heart is an enormous consumer of energy. Any perturbations to the energy production system, either from dialing down or up kinase activity, could cause cardiac dysfunction. Other organs may be affected, but the heart, says Force, is “the first thing to go.” With more therapies targeted against kinases in the pipeline, Force anticipates that researchers will see cardiac abnormalities crop up in some patients taking some of the drugs over the long term.

Another challenge is knowing when the therapy will work. Vemurafenib is a drug developed by Plexxicon and Hoffmann–La Roche that received FDA approval for the treatment of late-stage melanoma last summer. It is an inhibitor of B-Raf oncogene, which is mutated in about 60 percent of malignant melanomas. Patients with a particular mutation, the V600E mutation in which the valine at position number 600 in the kinase is replaced with glutamic acid, respond well to vemurafenib. But if the drug is given to patients who don’t have the mutation, they develop a secondary cancer.

“It’s the prototype right now for a drug that can be given safely to only patients with a mutation” in B-Raf, says Shokat. “If you give it to a patient who does not have the mutation and may have a Ras mutation, they are going to get another cancer induced. It’s not life-threatening like the first one, but it’s not going to benefit them.”

Other stumbling blocks are emerging. For instance, researchers are beginning to appreciate that kinases are dynamic entities that can easily change their conformations. Vemurafenib causes secondary cancers in patients missing the V600E mutation because it causes B-Raf to dimerize. The dimerized kinase stimulates more signal transduction. “Now that we know that happens, we can screen for molecules that don’t disrupt the kinase conformation and don’t allow dimerization,” says Shokat. “But just until a few years ago we didn’t think that was all that important.”

Targets can be two-faced. One kinase that drug companies are pursuing hotly is TOR. Shokat and colleagues recently demonstrated that TOR can either help or hinder therapy. They showed that inhibition of the TOR kinase could inadvertently cause acceleration of the very signaling pathway the inhibitor was supposed to stall, because TOR is involved in both positive and negative regulation of the Raf/ERK pathway. Depending on whether it’s dialing the pathway up or down, TOR can be either a target or an antitarget (3). “The difficulty is TOR is not a target in every cancer setting, but that’s because cancer is not one disease,” says Shokat.

Another challenge is that the number of feasible kinase targets is limited. “We’re running out of good kinase targets,” says Stokoe. “There are probably five to 10 really well-validated kinases that are known to drive tumorigenesis in a significant number of tumors.” The restricted number of known good kinase targets also limits the ways in which signaling pathways can be disrupted, narrowing down possibilities for therapies.

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