255Use of Radiation Sensitivity Biomarkers
to Personalized Radiotherapy
A systems-biology understanding of radiosensitivity has been used for identifying
radiation-specifi c biomarkers (Eschrich et al. 2009 ). The authors used radiosensitiv-
ity modeling, as represented by the survival fraction at 2 Gy, in 48 human cancer
cell lines. A linear regression algorithm was applied for integrating gene expression
with biological variables, including ras status (mut/wt), tissue of origin and p53
status. The biomarker discovery platform is a network representation of the by lin-
ear regression analysis. This network of top 500 genes identifi ed by this approach
was reduced to a 10-hub network that includes c-Jun, HDAC1, RELA (p65 subunit
of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1, and IRF1. Nine targets
associated with radiosensitization drugs were linked to the network, demonstrating
clinical relevance. Furthermore, the model identifi ed four signifi cant radiosensitiv-
ity clusters of terms and genes. Ras was a dominant variable in the analysis, as was
the tissue of origin, and their interaction with gene expression but not p53.
Overrepresented biological pathways differed between clusters but included DNA
repair, cell cycle, apoptosis, and metabolism. The c-Jun network hub was validated
using a knockdown approach in human cell lines representing different cancers.
This novel radiation-biomarker discovery platform, using a systems biology model-
ing approach, will play a central role in the integration of biology into clinical radia-
tion oncology for personalizing therapy. It has been clinically-validated in rectal
cancer, esophageal cancer, head and neck cancer, and breast cancer (Eschrich et al.
2012 ). Such a molecular assay of tumor radiosensitivity is a roadmap towards
biology- based personalized radiation therapy (Torres-Roca 2012 ). Cvergenx, in col-
laboration with the Moffi tt Cancer Center, is commercializing this assay.
Use of Imaging to Monitor Radioimmunotherapy
of Non- Hodgkin Lymphoma
Radiation dose to red marrow from^131 I-rituximab is inherently underestimated by
standard indirect peripheral blood counting methods. Personalized marrow dosim-
etry by quantitative gamma imaging more accurately predicts of hematopoietic
myelotoxicity by direct measurement of the bone marrow activity concentration of
131 I-rituximab. A study has measured red marrow uptake directly using serial quan-
titative whole-body imaging in conjunction with SPECT/CT in patients undergoing
routine^131 I-rituximab radioimmunotherapy of NHL (Boucek and Turner 2014 ).
Activity clearance from whole body, measured by imaging^131 I-rituximab, was sig-
nifi cantly slower than the mean effective half-life clearance calculated from the
sampling peripheral blood. Mean activity concentrations in bone marrow, measured
using SPECT/CT and by blood sampling, extrapolated to the time of administration,
were concordant. Neutrophil toxicity correlated with absorbed dose by SPECT/CT
imaging, whereas the blood sampling method demonstrated no correlation with any
parameters of hematological toxicity.
Personalized Radiation Therapy