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A novel pyrido[2,3-d]pyrimidine derivative, PD180970, has been shown to
potently inhibit Bcr-Abl and induce apoptosis in Bcr-Abl-expressing leukemic cells
in patients who develop a resistance to Gleevec. Developing additional Abl kinase
inhibitors would be useful as a treatment strategy for chronic myelogenous leuke-
mia. The key to curing more CML patients is to provide customized treatment for
each individual, based on the particular molecular mutation that causes their resis-
tance to Gleevec. Leukemia cells from patients with advanced CML should be pro-
fi led and the appropriate inhibitor or combination of inhibitors selected for treatment.
This approach is similar to the method that has been used to treat HIV drug resis-
tance. Treatment would be individualized for each patient, by combining specifi c
inhibitors in an ‘inhibitor cocktail’ that would be able to combat various Bcr-Abl
isoforms. ‘The paradigm is to understand the genetic abnormality that drives the
growth and survival of cancer, and tailor a treatment to reverse this genetic defect.
Development of B cell receptor antagonists has been a therapeutic advance in
chronic lymphocytic leukemia (CLL). Although B cell receptor ligation in normal
cells induces proliferation, apoptosis, or anergy, pathway dysregulation in CLL
results in the propagation of proliferative and prosurvival signals. Several agents
targeting the B cell receptor pathway are in development, including the Bruton’s
tyrosine kinase (BTK) inhibitor ibrutinib. A sequencing study showed that acquired
resistance to ibrutinib is due at least in part to recurrent mutations in BTK and
PLCγ2 (Woyach et al. 2014 ). C481S mutation in BTK confers resistance to ibruti-
nib by preventing irreversible drug binding. The S707Y, R665W, and L845F muta-
tions in PLCγ2 are all potentially gain-of-function mutations that allow B cell
receptor-mediated activation that is independent of BTK. In October 2014, the
European Commission approved ibrutinib (Imbruvica™) once daily capsules for
the treatment of adult patients with relapsed or refractory MCL or CLL who have
received at least one prior therapy, or as fi rst line therapy in the presence of 17p
deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. In
patients without B cell receptor pathway mutations, resistance may be mediated
through mutations in other coding genes providing alternative survival signals that
are not inhibited by ibrutinib or through noncoding RNA, epigenetic activation or
silencing, or selective gene amplifi cation. Other mutations may act in combination
with BTK or PLCγ2 mutations to drive resistance. Knowledge of downstream medi-
ators of resistance may lead to the development of rational combinations to prevent
or treat resistant disease.
Resistance to Vaccines in Cancer Recurrence After Surgery
Of the >700,000 patients who undergo cancer surgery in the US each year, >40 %
develop recurrences that have a poor outcome. Recurrent tumor cells have few phe-
notypical differences from those in tumors prior to surgery. An alternative explana-
tion proposed for the resistance of recurrent tumors is that surgery promotes
inhibitory factors that allow lingering immunosuppressive cells to repopulate small
10 Personalized Therapy of Cancer