Abstract
25% of non-small cell lung cancers contain activating
mutations in EGFR. Patients with activating mutations can be treated with kinase
inhibitors such as gefitinib and erlotinib, however these
inhibitors become ineffective. The main
driver of this resistance is a second mutation in EGFR, where the ‘gatekeeper’ residue
is mutated from a threonine to a more bulky methionine (T790M). Further work
led to the design of irreversible inhibitors: afatinib and then osimertinib (1), with the latter now approved for
treated of T790M lung cancer. Currently both activating (e.g. L858R) and resistant (T790M)
mutations are identified from cfDNA, which identifies the presence of the mutation but provides
no information about heterogeneity in mutation status in either the
primary or metastatic tumours. Positron
emission tomography (PET) is an imaging technique that utilises positron
emitting radioactive tracers, normally a
11C or
18F
labelled compounds. If the radioactive tracer can be localised within the
tumour this radioactive decay can be imaged via the use of a PET scanner. Due
to its increased half-life compared to
11C,
18F is the
preferred radioactive nucleus.
Several EGFR PET probes have been created using
1st generation EGFR inhibitors with limited success, however
11C erlotinib has
previously been synthesised and shown to localised within tumour cell lines
with the activating mutation (e.g. HCC287, Figure 2). The
discovery and increased understanding of tumor targets has led to the
development and approval of 12 small molecule tyrosine kinase inhibitors
(TKIs). Despite tremendous efforts in TKI development, treatment efficacies
with these therapeutics are still too low and improvements require a
personalized medicine approach. Positron emission tomography (PET) with
radiolabeled TKIs (TKI-PET) is a tracking, quantification and imaging method,
which provides a unique understanding of the behavior of these drugs in vivo
and of the interaction with their target(s). In this article we provide an
overview of tracer synthesis and development because each TKI requires a tailor
made approach. Moreover, we describe current preclinical work and the first
proof-of-principle clinical studies on the application of TKI-PET, illustrating
the potential of this approach for improving therapy efficacy and personalized
cancer treatment. We proposed to develop at similar agent based
compound
1 in order to evaluate it’s
utility as a tracer and whether the co-administration of cold 1
stgeneration inhibitors could allow selective imaging of tumours bearing activating
or resistant mutations. This poster will show the design, synthesis, radiolabelling
and
in vivo study plans of the mutant
specific EGFR PET probe.
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