231steps catalyzed by endogenous nucleoside kinases. Deoxycytidine kinase (DCK)
controls the rate-limiting step in the activation cascade of dFdC and ara-C. DCK
activity varies signifi cantly among individuals and across different tumor types and
is a critical determinant of tumor responses to these prodrugs. Current assays to
measure DCK expression and activity require biopsy samples and are prone to sam-
pling errors. Noninvasive methods that can detect DCK activity in tumor lesions
throughout the body could circumvent these limitations. An approach to detecting
DCK activity in vivo has been demonstrated by using positron emission tomogra-
phy (PET) and^18 F-labeled 1-(2′-deoxy-2′-fl uoroarabinofuranosyl) cytosine]
18 FFAC, a DCK substrate with an affi nity similar to that of dFdC as a PET probe
(Laing et al. 2009 ). In vitro, accumulation of^18 FFAC in murine and human leukemia
cell lines is critically dependent on DCK activity and correlates with dFdC sensitiv-
ity. In mice,^18 FFAC accumulates selectively in DCK-positive vs. DCK-negative
tumors, and^18 FFAC microPET scans can predict responses to dFdC. The results
suggest that^18 FFAC PET might be useful for guiding treatment decisions in certain
cancers by enabling individualized chemotherapy.
PET Imaging with Tyrosine Kinase Inhibitors
Several small molecule tyrosine kinase inhibitors (TKIs) have been developed and
approved. Treatment effi cacies with TKI therapeutics are still too low and improve-
ments require a personalized medicine approach. PET with radiolabeled TKIs
(TKI-PET) is a tracking, quantifi cation and imaging method, which provides a
unique understanding of the behavior of these drugs in vivo and of the interaction
with their target(s). An overview of tracer synthesis and development indicated that
each TKI requires a tailor made approach (Slobbe et al. 2012 ). Moreover, current
preclinical work and the fi rst proof-of-principle clinical studies on the application of
TKI-PET illustrate the potential of this approach for improving therapy effi cacy and
personalized cancer treatment.
Tissue Systems Biology Approach to Personalized
Management of Cancer
Cellular Systems Biology (CSB™) applied to tissues has been named “Tissue
Systems Biology” (TSB™) and involves the use of panels of fl uorescence-based
biomarkers that report the systems read-out of patient samples. Cellumen Inc (par-
ent company of Cernostics) has successfully applied CSB™ to drug discovery, drug
development and personalized medicine over 3 years. As of September 2008,
Cernostics Pathology was creating a complete digital imaging pathology platform
by integrating the best available components, while building advanced informatics
tools to manage, mine and classify patient tissue samples. The fi rst diagnostic/thera-
peutic test being developed by Cernostics is a breast cancer test as part of collabora-
tion with the Mayo Clinic.
Determination of Response to Therapy