Biology Reference
In-Depth Information
target six different genes in several tyrosine kinase signaling pathways. Successful imple-
mentation of personalized healthcare in oncology will require different strategies to develop
complex multi-analyte biomarkers for drugs with more diverse mechanisms of action.
2.2 BIOMARKERS
The term biomarker has been used in multiple contexts, but one definition put forth by the
FDA is: 'a measurable characteristic that is an indicator of normal biologic processes, patho-
genic processes, and / or response to a therapeutic or other intervention'. Multiple types of
biomarkers that meet this definition are currently used, with many more being developed, to
identify groups of patients who have a better prognosis, are more likely to respond to a partic-
ular treatment, are successfully responding to their treatment, or may go on to develop resist-
ance. As such, pharmacodynamic, predictive, prognostic, resistance, and surrogate biomarkers
will be discussed, along with current examples relevant to the oncology field.
2.2.1 Pharmacodynamic Biomarkers
Pharmacodynamic biomarkers measure the effects of a drug on the tumor itself and / or
the disease in general. They can be used to guide dose selection in the early stages of clini-
cal development. A general example is the use of the extent of proliferation or apoptosis in
a tumor following administration of a particular drug, or the change in a downstream fac-
tor that is regulated by the drug target, such as changes in protein phosphorylation after
inhibition of a protein kinase. A specific example of using a pharmacodynamic biomarker
in a clinical setting relates to the use of imatinib in chronic myelogenous leukemia (CML).
Imatinib blocks the oncogenic fusion protein break point cluster-Abelson tyrosine kinase
(BCR-ABL) from initiating a signaling cascade important for the development of CML [2] .
The reduction in protein kinase activity of BCR-ABL is used to indicate response to imatinib
in patients with CML, such that the magnitude of inhibition correlates with clinical out-
come. This pharmacodynamic relationship has been used successfully to benefit patients
with CML by identifying the most effective clinical doses, which are considerably lower
than the doses associated with imatinib toxicity [2,3] .
2.2.2 Predictive Biomarkers
Predictive biomarkers assess the likelihood that tumors will respond to a particular treat-
ment. They can be used to guide the choice of therapy for a particular group of patients and
may also play a role in identifying optimal drug dose and / or predicting toxicity. Multiple
examples of the practical use of predictive biomarkers exist in clinical oncology. There are
many types of predictive markers, which can be grouped into the following categories: tar-
get / pathway expression; target / pathway mutation or genetic alteration; and drug metabo-
lism. The type of predictive marker identified not only speaks to its MOA, but also relates to
the timing of when the particular marker is most likely to be incorporated into clinical devel-
opment. For example, if the expression of the drug target itself predicts response to treat-
ment, there is great potential that this hypothesis was studied early in the drug development
 
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