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Molecular Diagnostics Combined with Cancer Therapeutics
Basics of combination of diagnostics with therapeutics are discussed in Chap. 2.
Cancer is a good example of such a combination, which would be useful for person-
alized management of cancer. Approximately 800 oncology drugs, many of which
target specifi c mutations, are currently in development, resulting in a growing need
for new companion diagnostics. Examples of technologies that can be used to com-
bine diagnosis and therapeutics for cancer are listed below and will be discussed
further under personalized management of various cancers.
- AmpliChip P53 as companion diagnostic for the anticancer drug Nutlin
- Flow cytometry testing for minimal residual disease in CLL treated with Campath
- Abl mutations testing in CML for Gleevec-resistance
- EGFR mutations testing in NSCLC for treatment with Tarceva/Iressa
- 5q FISH testing in myelodysplastic syndrome for lenalidomide (Revlimid)
therapy
Aptamers for Combined Diagnosis and Therapeutics of Cancer
Aptamers (derived from the Latin word ‘aptus’ = fi tting) are short DNA or RNA
oligomers, which can bind to a given ligand with high affi nity and specifi city due to
their particular three-dimensional structure and thereby antagonize the biological
function of the ligand. Aptamers are beginning to emerge as a class of molecules
that rival antibodies in both therapeutic and diagnostic applications. Aptamers are
different from antibodies, yet they mimic properties of antibodies in a variety of
diagnostic formats.
High affi nity aptamers are being developed as targeted therapeutics for the diag-
nosis, imaging, staging and treatment of cancer. This method offers, apart from an
immediate application in the diagnosis, imaging and treatment of breast and other
epithelial cancers, a generic application for the treatment of neoplastic disorders and
a potential for future development. Combinatorial libraries have been used for the
selection of aptamers that bind to well-characterized and established cancer bio-
markers selectively and with high affi nity. As part of their design, the aptamers are
conjugated to ligands, molecules bearing binding sites for metal ions, to impart the
therapeutic and diagnostic properties. In particular, stable chelation of technetium,
rhenium and yttrium radioisotopes result in novel radiopharmaceutical agents for
imaging and selective cell kill as part of cancer diagnosis, imaging and therapy. The
use of paramagnetic gadolinium produces a novel, targeted MRI contrast agent that
can achieve high local concentrations around the tumor site, thus offering high defi -
nition imaging at lower gadolinium concentrations. The use of europium or terbium
confers fl uorescent properties to the aptamer complex, for use in diagnostic assays.
These molecules offer signifi cant advantages over existing antibody and peptide
based recognition procedures in that they possess higher binding affi nities to the
10 Personalized Therapy of Cancer