Table 1.
Gaps and work-in-progress
| Topic | Ongoing and future work | Details and hypotheses |
|---|---|---|
| Broadening of cell lines | Expand study of cell lines with germline mutations, with initial focus on lung cancer | Lung cancer has a dual potential for immunotherapy and molecular-targeted therapies |
| Increase in spectrum of prostate cancer cell lines | Prostate cancer often treated with primary radiation, so this will enable adaptive effects to be studied | |
| Development of a platform to study the response to radiation in patient-derived xenografts, cell lines, and organoids, ideally from consecutive biopsies | Personalized medicine will enable more accurate precision medicine | |
| Target determination | Identification of biomarkers of adaptation from an array of “omics” combined with proteomics or phosphor-proteomics | Likely to help define specific targets, including non-coding RNAs, e.g. miRNA (69) as potential targets |
| Use of immunohistochemistry and profiling of subclones over different time points to study the proportion of cells that adapt, in addition to examining the cells that survive the post-exposure “drugging” | Adaptations are likely to be heterogeneous, possibly transient, and tumor adaptation to drugs need to be determined | |
| Timing and transition of adaptation | Study additional tumor types and additional time points between the end of radiation and 2 months, as well as beyond 2 months | There are at least 2 general adaptation points: 1) starts during therapy, within days, whereby MF produces more changes than SD; and 2) starts by 2 months or later and SD predominates. This time course needs to be better defined |
| Mechanism of adaptation | Epigenetic adaptations | Preliminary data suggest that there are epigenetic changes and, if so, when does this occur and for how long does it persist? |
| Ongoing in vivo studies to examine growth delay and related biological changes for radiation, drugs, and the combination | Potential collaborations with laboratories studying charged particle therapy | |
| Normal tissue changes | Expansion of the whole-body and organ-specific radiation biomarkers | Provide biomarkers for radiation biodosimetry and normal tissue adaptations from therapy |
| Pursuant to our study of endothelial changes (19) further study of radiation inducible endothelial changes from in vitro cultures, organ-on-a-chip and in vivo experiments | Understand the role of endothelial damage in radiation injury. (This is supported in a number of laboratories by NIAIDa and BARDAb programs). | |
| Clinical applicability | Through collaboration, obtain clinical samples for normal tissue biomarkers with groups studying radiation biodosimetry | Clinical samples are limited by underlying medical conditions, dose delivered, and volume of tissue irradiated |
| Investigate the use of “radiation as a drug,” as part of an overall approach from the “Shades of Gy” workshop (13) toward “accurate, precision radiation medicine” (14) | Prospective intervention trials will depend on preclinical data. Some pre- and post-RT sampling may be done including pre- operative radiotherapy, intraoperative radiotherapy and brachytherapy |
a
NIAID Radiation and Nuclear Countermeasures Program. Available at: https://www.niaid.nih.gov/research/radiation-nuclear-countermeasures-program. Accessed April 24, 2020
b
BARDA Radiological/nuclear medical countermeasures. Availalble at: https://www.medicalcountermeasures.gov/barda/cbrn/radiological-and-nuclear-countermeasures/ Accessed April 24, 2020