Some challenges in Targeted Therapy

February 25, 2013

By Sheldon Z. Goldberg

What makes a target? Our understanding of disease is a model, an imagined defect in a fanciful machine. The workings of the intact organism are understood on the basis of the tools at hand and conform to the models of other world events and inventions. In the 19th century, the microscope became a useful tool and the cell was the agent of health and disease. DNA, the agents of heredity, became the basis of the most advanced therapy in the late 20th century. DNA was the target for chemotherapy, as soon as its importance in heredity was realized .

DNA as a target has fallen out of fashion. Now, we imagine the cell as a network of messages, an internet, with signals, noise and switches. These are the modern targets: growth factor receptors (and their mutations), kinases (and their mutations); the cellular equivalents of antennae and amplifiers.

This is the model that is generating today’s medicines (often at a price greater than $10,000 per month). The model should also limit the use of these drugs to patients who have appropriate targets. But sometimes the targets are not well identified; sometimes the model of the target is based upon observations that are not tightly connected to the mechanism of action. The amplification of Her2/neu may be an example of this error of assumption. . Recent work suggests that amplification is not the only pathway to sensitivity to agents that act on this receptor. Activating mutations also exist which confer sensitivity to Trastuzumab and, presumably related agents.  Given the continued interest in this important target, including the approval of new agents directed at this target a rethinking of the nature of the cancer that might respond the these ( expensive) drugs seems in order.

Recent controversies about off label prescribing are also relevant to this issue. When an established, responsive target is found in a cancer other than the one in which the (very expensive) randomized trial demonstrated activity, that constitutes an off-label ( not paid for) use of the drug – regardless of how poor and toxic and expensive “standard” treatment is.

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