Thursday, February 25, 2010

Targeting Cancer

Amy Harmon of The New York Times had an excellent three-part series this week called "Target Cancer." She follows one clinician/researcher as he pursues a "targeted" treatment for melanoma, which aims at the protein produced by a gene called B-Raf that is mutated more than half of the time in this skin cancer.

The series does a great job in following the emotional roller-coaster ride of the doctor, and of course his patients. One early targeted drug doesn't work at all, perhaps because it also attacks normal cells and the side effects become intolerable before the dose is high enough to affect the cancer. A new drug seems not to do anything, but then the team decides to wait for the drug company to reformulate it to deliver higher effective doses.

The results are spectacular: the new formulation causes a virtually unheard of remission in the cancer, and raises hopes in formerly hopeless patients and in the doctors. The excitement and the potential are palpable as some patients dare to hope and others can't bear to. But within a few months, the patients are dying again.

The new drug is an example of personalized medicine, since it is effective only for patients with a particular mutation. There are a few other examples of therapy tuned to patients with a particular genetic profile, such as the breast-cancer drug erbitux and the anticoagulant warfarin (Coumadin).

But this treatment is actually for cancers with a particular mutation--a mutation the normal cells of the patient don't have. Cancers cells generally have more and more of mutations as the disease progresses, because it disrupts the normal quality-control mechanisms in the cell. A study announced last week (registration required) showed that the specific pattern of mutations could be used to monitor the ebb and flow during treatment, although it doesn't look practical yet for tailoring treatment.

Unfortunately, as described in this series, even when a drug targets a mutation in a particular patient's cancer, cancers often develop alternate routes to proliferation. Harmon alludes to one approach to this problem: a multi-pronged "cocktail" that attacks many possible mutations at once. Such cocktails are standard, for example, in treating HIV/AIDS.

Without vilifying the drug companies, she explains some challenges for these profit-oriented companies in pursuing this approach. In particular, even if the cocktail may ultimately be more effective, getting approval might delay or threaten their profits from the drug they have in hand, even if it only extends life for a few months. This is especially true if other drugs in the cocktail are owned by competing companies. In any case, the difficulties in testing multiple drugs make it much harder to know what is effective and what side effects may appear.

The idea of analyzing molecular networks and attacking them at many points simultaneously is a recurring theme in systems biology. But sometimes it seems very far in the future.

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