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Personalized Therapy of Cancer Based on Cancer Stem Cells
Cancers may rely on “cancer stem cells” that share the self-renewal feature of nor-
mal stem cells. Cancer stem cells form new tumors and may not be eliminated by
current therapies. This has changed the perspective with regard to new approaches
for treating cancer. Cancer stem cells are slow-dividing and inherently drug-
resistant, and their eradication would be necessary for long-term success in cancer
treatment. The cancer stem cell concept could be used to better tailor treatment
strategies to individual patients. Most traditional anticancer agents affect primarily
bulk tumor cells by disrupting their proliferation and/or survival. Even the newer
‘targeted’ agents, such as receptor tyrosine kinase inhibitors and some MAbs,
though a considerable improvement over older agents, are still largely aimed at
proliferation, survival and angiogenesis pathways that may or may not affect the
stem cell population. Cancer stem cells are less likely to be killed than bulk tumor
cells by these approaches. Improved methods will be required to identify, isolate
and genetically profi le the stem cell population in cancers from individual patients.
Cancer stem cells, amplifi ed from individual clinical specimens, should be tested
for gene expression profi les and sensitivity to a battery of agents, leading to indi-
vidualized decisions on selection of the best therapeutic strategies. The antineoplas-
tic agents of the future will have to target the ancient developmental molecular
pathways on which stem cells depend on for replication and survival. Thus, an
improved understanding of these pathways and their roles in cancer stem cells could
lead to a new generation of more selective and effective antineoplastic treatments.
Role of Epigenetics in Development of Personalized
Cancer Therapies
In addition to having genetic causes, cancer is also an epigenetic disease.
Epigenetics refers to control of gene expression selectively without affecting the
genomic DNA sequence. Epigenetic regulation of gene transcription is emerged a
key biological determinant of cellular differentiation and plays a signifi cant patho-
genic role in a number of human diseases, particularly cancer. This regulation is
mediated by selective, enzyme-catalyzed, covalent modifi cation of DNA and of
proteins (especially histones) that control the conformational transition between
transcriptionally active and inactive states of chromatin. Disruption of the activity
of disease- associated epigenetic enzymes offers a mechanism-based opportunity
for pharmacologic intervention in diseases such as cancer. DNA methylation pat-
terns undergo changes in cancer cells and represent an attractive therapeutic target
because such epigenetic alterations are more readily reversible than genetic events.
When used in combination with conventional chemotherapeutic agents, epigenetic-
based therapies may provide a means to sensitize drug-resistant tumors to estab-
lished treatments.
10 Personalized Therapy of Cancer