Biomedical Engineering Reference
In-Depth Information
standard laboratory techniques such as FISH and PCR (Kaeda et al. 2002).
This also makes CML an ideal disease in which to identify novel agents which
target cancer stem cells.
5.1 BCR-ABL Tyrosine Kinase Inhibitors in CML
There have been major advances in the treatment of CML in recent years
with the development of IM (Druker et al. 1996; O'Brien et al. 2003) and,
more recently, the oral, multi-targeted kinase inhibitor dasatinib (Talpaz
et al. 2006) and the second-generation BCR-ABL kinase inhibitor, nilotinib
(Kantarjian et al. 2006). IM is a tyrosine kinase inhibitor (TKI) which
competitively inhibits ATP binding to BCR-ABL, resulting in inhibition of
downstream signal transduction pathways. Despite inducing a complete
cytogenetic response in the majority of CML patients in chronic phase
(O'Brien et al. 2003; Druker et al. 2006), nearly all patients treated with
IM have detectable disease at the molecular level by quantitative RT-PCR
(Hughes et al. 2003; Branford et al. 2004) and, therefore, are unlikely to be
cured. It has been demonstrated that this molecular persistence results from
a population of quiescent CML stem cells which are not effectively targeted
by IM (Graham et al. 2002). In addition, a minority of CML patients harbor
BCR-ABL kinase domain mutations, rendering them IM-resistant (Gorre
et al. 2001; Shah et al. 2002). Dasatinib and nilotinib target IM-resistant
mutations (Shah et al. 2004; O'Hare et al. 2005) and, in the case of dasatinib,
reach further into the stem cell compartment (Copland et al. 2006). However,
despite inhibition of BCR-ABL, quiescent CML stem cells remain insensitive
to these compounds (Copland et al. 2006; Jorgensen et al. 2007). Therefore,
strategies are required to target both quiescent and proliferating BCR-ABL +
cells.
5.2 CML Stem Cell Modeling
Recently, two different dynamic models of CML have been proposed (Michor
et al. 2005; Roeder et al. 2006) which arrive at different conclusions. The first
model suggests that although IM is a potent inhibitor of differentiated CML
cells, it does not reduce the CML stem cell population (Michor et al. 2005). In
CML, BCR-ABL transcripts exhibit a biphasic decline in patients responding
to IM, but even after years of therapy, the majority of patients have persistent
disease at the molecular level (Hughes et al. 2003; Branford et al. 2004). The
biphasic decline in BCR-ABL transcripts consists of an initial rapid decline,
followed by a slower decrease representing the death of more primitive CML
progenitors in response to IM. In support of this first hypothesis, in a propor-
tion of patients that discontinued IM after prolonged treatment and had
Search WWH ::




Custom Search