A2.3 Targeted therapy

Topic

Targeted therapy acts on a specific molecule—the molecular driver—that sustains tumor proliferation; blocking this molecular driver is what defines this treatment modality, as opposed to generally attacking any dividing cell.

Depending on the tumor, this molecular driver can take various forms: it might be a growth factor receptor overexpressed on the tumor cell surface—such as the epidermal growth factor receptor and related receptors in the same family; a kinase that remains permanently activated, as seen in chronic myeloid leukemia or a subtype of non-small cell lung cancer; a survival signaling pathway used by the tumor cell to avoid death; or a genetic repair mechanism upon which the tumor is particularly dependent because another of its repair mechanisms is already impaired. In all cases, this molecular driver is the engine of tumor proliferation and the target that targeted therapy seeks to block.

Unlike cytotoxic chemotherapy, which acts on any dividing cell, targeted therapy offers a much wider margin between the dose that damages the tumor and the dose that begins to harm normal cells. This is because the molecular driver—the treatment's molecular target—is absent or barely present in normal cells; lacking this target outside the tumor, the therapy has far less potential to damage healthy tissue.

The underlying principle of targeted therapy is enzyme inhibition: the inhibitor binds to and occupies the molecular target, and the fraction of the target occupied by the inhibitor increases as the inhibitor's concentration or its affinity for the target rises. However, that occupied fraction does not increase indefinitely; as nearly all the molecular target becomes occupied, further increasing the inhibitor concentration yields little additional occupancy because the target is becoming saturated.

The extent of molecular target occupancy, in turn, determines the biological effect on the tumor: the more the molecular driver signal is blocked, the greater the resulting biological effect. When the molecular driver is responsible for the tumor's entire proliferation and the blockade of the molecular target is virtually complete, the result is profound tumor regression—with response rates of 70% to 80% in lung tumors driven by an altered epidermal growth factor receptor or a constitutively active kinase. Thus, the entire chain of events—from the molecular driver to its blockade by the inhibitor and subsequent tumor regression—confirms the premise underlying this model: blocking the specific molecular driver that sustains the tumor is what gives targeted therapy its precision.

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