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Figure 4. Proposed approach to protect normal tissue by stimulating radioadaptive responses. Horizontal X-ray beam delivers a priming
dose to protect OAR (blue), but not the tumor (red) from subsequent, high doses delivered with a vertical beam(A); low priming dose
of charged particles (left) protect OAR (blue) from subsequent high doses (right) (B). With charged particles, priming and therapeutic
doses can be delivered along the same beamline since particles stop at predetermined depths. Charged particles also protect normal
tissue distal to the tumor (larger blue section). OAR: organs at risk

being augmented, the types of agents administered, tumor location, and the organs at risk. Therapeutic
efficacy can be increased, and side effects decreased, by employing multi-targeted approaches [236] . For
example, the Li lab combined physical (radiation) targeting with two other targeting approaches. The first
was an oncolytic adenovirus to deliver hTERT promoter-driven E1a gene for conditional replication in
hTERT-positive (tumor) cells, and the second was a replication-defective adenovirus expressing shRNA to
repress DNA-PKcs [237] . This downregulated NHEJ specifically in tumor cells within the (physically-targeted)
radiation beam. Another tumor-specific targeting approach is illustrated by recent studies targeting triple-
negative breast cancer. Here, CRISPR/Cas9 designed to knock out the Lcn2 oncogene was delivered to
breast cancer cells using a tumor-tropic, ICAM1 antibody-linked nanomaterial [238,239] . These and other
targeting strategies can be combined to enhance a wide variety of therapeutic interventions.

The adaptive response raised concerns about improved tumor cell survival when tumors are “primed” with
5-10 mGy diagnostic CT scans to localize tumors before treatment with a 2-10 Gy “challenge” (therapeutic)
dose [134] . It may be possible to invert this paradigm and exploit the adaptive response to protect normal
tissue and increase therapeutic gain. This might be done, for example, by using a transverse photon (X-ray)
beam to expose normal tissue above the tumor to low (mGy) doses. This could induce a transient adaptive
response in at-risk normal tissue [specifically, organs at risk (OAR)], protecting this tissue from high
dose radiotherapy delivered with a perpendicular beam [Figure 4A]. Such a strategy might be optimized
with particle radiation, as priming doses can be delivered to just the normal tissue region that will be
subsequently exposed to therapeutic doses in the entrance region, and particles also spare distal tissue
[Figure 4B].

In conclusion, multi-targeted strategies that combine DNA repair and DDR-modulated tumor-specific
radiosensitization, advanced photon and particle beam focusing, and radioprotection of normal tissues are
a rational path to tumor cures with minimal side effects.

DECLARATIONS
Acknowledgments
We thank Ryuichi Okayasu, Akira Fujimori, Tom Borak, Susan Bailey, Michael Weil, Claudia Wiese, and
members of the Nickoloff and Kato labs for many helpful discussions. We thank the anonymous Reviewers
for their helpful suggestions.

Authors’ contributions
conception and preparation of this manuscript: Nickoloff JA, Taylor L, Sharma N, Kato TA