The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on radiation inducible molecular targets that is, exploring the use of multi-fractionated (MF) radiation as well as higher single doses (SD) to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy. In essence, radiation would set up the tumor for enhanced drug killing. This project has now demonstrated that different dose sizes of radiation- MF and SD - (10 Gy x1, 2 Gy x5, 1 Gy x10 and down to 0.5 Gy x 10) produce different phenotypes. We have demonstrated and published that the cells post-radiation are more drug sensitive for at least 1 drug in the short term and 1 drug 60 days later, indicating cellular adaptation. This is now published. The novel observation of an inducible target has broad implications for cancer adaptation to treatment for both molecular-targeted therapy and immunotherapy. We are now studying combination therapy of targets and synthetic lethality We have made significant progress in studying the inducible mRNA, miRNA, proteins and metabolomics changes. Projects now in progress include studying metabolomic changes, in vivo SD and MF for PC3 cells, and epigenetic changes. We are now working with experts in complex systems analysis to identify pathways to target and working on timing of radiation and drug(s). With the major interest in immune modulation, our work has significant bearing on the dose and fractionation of radiation that can be exploited for immune enhancement for tumor control, including direct and abscopal effects. With a recently successful laboratory review we are expanding collaborations by which we can possibly detect the adaptive changes working with Jim Mitchell of RBB and Deb Citrin or ROB and Murali Cherukuri of RBB who has hyperpolarized MRI techniques to study metabolic adaptation Closely related to this work are efforts being done on identifying biomarkers of radiation injury. This relates to cancer and also to work I do in the Office of the Assistant Secretary for Preparedness and Response in Health and Human Services (HHS). I am heading a group developing civilian medical response planning for radiological and nuclear terrorism and other events. This involves planning, policy, and normal tissue injury-related science. Medical countermeasures are being developed through NIAID support in the Centers for Medical Countermeasures Against Radiation (CMCR). This overall program has major impact to U.S. preparedness and also has a spin-off for normal tissue injury from radiation and the potential for post-exposure mitigators and treatments. We are working with other agencies (NIAID and Dept of Defense) on the potential of bringing these mitigators into cancer care. The critical importance of the NCI- HHS linkage is bringing up-to-date scientfic thinking to medical countermeasure development and diagnosis - A more direct linkage between the NIH and DHHS programs is our work on biomarkers for biodosimetry supported by NIAID. This is looking at RNA expression at various times after a range of whole body doses, currently using a mouse model. The importance of having an accurate point-of-care diagnostic with which to triage potential radiation casualties cannot be over estimated given the potential size of a nuclear/radiological disaster. The biomarker work is supported by NIAID and BARDA (of ASPR).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010670-14
Application #
9779681
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Eke, Iris; Makinde, Adeola Y; Aryankalayil, Molykutty J et al. (2018) Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer. Mol Cancer Res 16:1855-1864
Aryankalayil, Molykutty J; Chopra, Sunita; Levin, Joel et al. (2018) Radiation-Induced Long Noncoding RNAs in a Mouse Model after Whole-Body Irradiation. Radiat Res 189:251-263
Eke, Iris; Makinde, Adeola Y; Aryankalayil, Molykutty J et al. (2018) Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example. Mol Cancer Ther 17:355-367
Aryankalayil, Molykutty J; Chopra, Sunita; Makinde, Adeola et al. (2018) Microarray analysis of miRNA expression profiles following whole body irradiation in a mouse model. Biomarkers :1-15
Ahmed, Mansoor M; Coleman, C Norman; Mendonca, Marc et al. (2018) Workshop Report for Cancer Research: Defining the Shades of Gy: Utilizing the Biological Consequences of Radiotherapy in the Development of New Treatment Approaches-Meeting Viewpoint. Cancer Res 78:2166-2170
Vanpouille-Box, Claire; Alard, Amandine; Aryankalayil, Molykutty J et al. (2017) DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8:15618
Coleman, C Norman (2017) The Radiation Stress Response: Of the People, By the People and For the People. Radiat Res 187:129-146
FitzGerald, Thomas J; Bishop-Jodoin, Maryann; Followill, David S et al. (2016) Imaging and Data Acquisition in Clinical Trials for Radiation Therapy. Int J Radiat Oncol Biol Phys 94:404-11
Makinde, Adeola Y; Eke, Iris; Aryankalayil, Molykutty J et al. (2016) Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy. Semin Radiat Oncol 26:254-60
Coleman, C Norman; Higgins, Geoff S; Brown, J Martin et al. (2016) Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials. Clin Cancer Res 22:3138-47

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