Biomedical Engineering Reference
In-Depth Information
This chapter reviews the bioanalytical developments by mass spectrometry in
the field of targeted anticancer therapy, across the growing family of recent
FDA-approved oral TKIs as well as tamoxifen and its active metabolites. The text
also provides an introduction to existing pharmacokinetics-pharmacodynamics
knowledge in the field of targeted anticancer therapy.
2
New Targets, New Drugs, and New Strategies for Improved
Tolerability and Enhanced Clinical Response of the
Anticancer Therapy
2.1
New Targets, News Drugs
The first prominent example of TKIs, imatinib, has revolutionized the treatment and
prognosis of chronic myelogenous leukemia (CML) and gastrointestinal stromal
tumors (GIST) [
13,
14
]. However, imatinib treatment is not devoid of toxicity, and
resistance occurs. It is becoming increasingly recognized that the response is
influenced not only by the genetic heterogeneity of drug target determining the
tumor's sensitivity (BCR-ABL for CML, and c-KIT for GIST) but also by patient's
genetic background and environmental factors that influence drug disposition and
overall exposure in the body. Indeed, imatinib drug exposure was found to be a
predictor of clinical response in CML [
15,
16
] and in GIST [
17-
20
] .
Following imatinib, other TKIs, including sunitinib, nilotinib, dasatinib,
sorafenib, and lapatinib have been developed and are now used for treating various
hematological malignancies, solid tumors including GIST [
21
] , advanced renal cell
carcinoma (RCC), hepatocellular carcinoma (HCC), and breast cancer [
22
] , and
have shown promising activity in other tumors as well [
23
]. In addition, there was a
renewed interest for the EGRF inhibitors gefitinib and erlotinib for the treatment of
non-small cell lung cancer (NSCLC), when it was discovered that a patient sub-
group, with tumors harboring specific activating mutations of the EGFR genes, was
likely to respond better [
24,
25
]. In 2011, three additional TKIs have been approved
by the FDA: vandetanib for the treatment of thyroid cancer [
26
] , vemurafenib
against melanoma with B-RAF V600E mutation [
27
], and crizotinib for anaplastic
lymphoma kinase (ALK)-positive NSCLC [
28
] (Table
1
).
Despite their important specificity, toxicity and side effects similar to those of
the standard cytotoxic chemotherapeutic approaches can also occur with signal
transduction inhibitors.
Whereas toxicities encountered with TKIs treatment are generally less severe
than those encountered with conventional cytotoxic approaches, they can, however,
significantly impact the safety and quality of life in the long term, jeopardizing
treatment adherence. The clinical responses for TKIs may also not always be opti-
mal, calling for a renewed effort for exploring novel avenues and strategies to
improve tolerability and therapeutic response.
