Charles L. Limoli, Ph.D.

Charles L. Limoli, Ph.D.

Professor

Biography

Dr. Limoli is a Professor of Radiation Oncology at the University of California Irvine (UCI). He holds a BS degree in chemistry from MIT and a PhD in biomedical sciences from UCSD. Over the years he has served on and chaired numerous peer-review committees and has been the recipient of multiple extramural grants from agencies such as the NINDS, NCI, NASA, ACS and DTRA. He served as the 65th president of the Radiation Research Society and is an internationally recognized expert in radiation biology with over 175 publications in peer reviewed journals and book chapters.

Research Focus

The global focus of my research program involves space radiobiology, stem cell/exosome biology, cancer biology and FLASH radiotherapy, as it applies to radiation-induced mechanisms impacting functional outcomes in the CNS. We have been funded by NASA for over 20 years and have uncovered a wealth of findings elucidating the adverse effects of the space radiation environment on CNS functionality. My group has also pioneered stem cell and extracellular vesicle transplantation strategies to overcome radiation-induced normal tissue injury in the brain, heart and lung. More recently, we have focused our research on evaluating the translational potential of ultra-high dose rate “FLASH” radiotherapy in the brain, which has the potential to revolutionize radiotherapy worldwide.

Research Details

Research in FLASH radiotherapy:
FLASH-radiotherapy (FLASH-RT) refers to ultrahigh dose rate (≥ 100 Gy/s) radiation delivery which results in remarkable normal tissue sparing while maintaining isoefficient tumor control. The idea that dose-rate modulation can be used for improving the therapeutic index of cancer treatments has generated considerable excitement worldwide and opens previously unforeseen opportunities for delivering higher curative doses without elevating normal tissue complications. Further, FLASH-RT has proven beneficial in every normal tissue bed analyzed (brain, lung, gut, muscle, skin) in multiple pre-clinical models (zebrafish, mouse, mini-pig, cat, dog) and has been equally efficacious in forestalling the growth of over 20 types of murine and human cancers – pointing to the global utility of this radiation modality. Dr. Limoli has established the benefits of FLASH-RT using pre-clinical models of two deadly forms of brain cancer, one that afflicts adults (Glioblastoma multiforme, GBM) and the other that afflicts pediatric patients (Medulloblastoma, MB). The capability of FLASH-RT to improve the therapeutic index has motivated nearly every radiation oncology department nationally and worldwide to invest in this promising technology where it’s poised to revolutionize radiation oncology. Dr. Limoli serves as PI and director of P01 grant CA244091 and R01 CA254892 from the NCI, each implementing FLASH-RT as the primary platform for his investigations. Dr. Limoli collaborates with an international team on FLASH-RT including Drs.’ Vozenin and Bailat (CHUV, Lausanne Switzerland), Dr. Loo (Stanford), Dr. Spitz (UIowa) and Dr. Maxim (UCI).

Stem cells and extracellular vesicles related research:
My group was the first to demonstrate that intracranial transplantation of human embryonic stem cells (hESC) could resolve cognitive dysfunction resulting from whole brain irradiation of rodents. We have since used multiple sources of human neural stem cells to show that such a strategy could resolve radiation- and chemotherapy-induced cognitive decrements involving the attenuation of neuroinflammation and the preservation of host neuronal morphology. This work has since been translated to the use of stem cell-derived extracellular vesicles (EV), where they provide functionally equivalent benefits when compared to stem cell transplantation in the irradiated brain. Ongoing work has now demonstrated that EV can deliver similar benefits when administered systemically in immune competent hosts, obviating the need for surgery and immune suppression. Further, systemic administration of various EV can eradicate a range of normal tissue toxicities in the brain, heart, and lung, following irradiation, and acts through a mechanism involving in part, specific microRNA bioactive cargo contained within. Additional data has demonstrated the capability of certain EV to metabolically reprogram cells, and to rebalance excitatory/inhibitory neurotransmission. Newer findings have pointed to the capability to precondition the brain though systemic EV injections prior to irradiation, thereby preventing the undesirable normal tissue toxicities associated with cranial irradiation. Safety studies have also been completed and now show that hESC- derived EV do not elevate the incidence of spontaneous cancers in p53 deficient mouse models. Implementing such strategies may soon provide new opportunities in personalized medicine, affording benefits to those afflicted with a variety of age, degenerative and cancer treatment associated complications.

NASA related research:
My group has been the first to describe many of the adverse effects of space relevant low doses (≤ 50 cGy) and dose rates (1 mGy/day) on the brain, uncovering some unexpected if not surprising neurocognitive and electrophysiological decrements that persist for months to years following exposure. We have detailed, that space radiation exposure results in elevated neuroinflammation and reductions in the dendritic complexity of mature neuronal subtypes, factors that are contributory (if not causal) to space radiation-induced cognitive dysfunction. We have used complex Galactic Cosmic Ray simulations on Earth, implementing a sequence of 33 mixed ions and energies, and defined potentially beneficial countermeasures targeting histone acetylation, microglia and neuroinflammation. In more recent work we have uncovered an unexpected effect of subatomic particles (pions) in their capability to significantly disrupt learning and memory. Pions are generated upon the interaction of charged particles with the spacecraft and interior components, and because they are more prevalent in areas of increased shielding, pose additional concerns for deep space travel. Our data point to the capability of space radiation exposure to elevate the risk for manifesting mission critical performance decrements and longer-term neurodegeneration upon return to the terrestrial environment.

PubMed Link (selected publications)

Complete List of Published Work from My Bibliography (from a total of 160): H-index 57

https://www.ncbi.nlm.nih.gov/myncbi/charles.limoli.1/bibliography/public/

1. Montay-Gruel, P., Acharya, M.M., Petersson, K., Alikhani, L., Yakkala, C., Allen, B.D., Ollivier, J., Petit, B., Goncalves, P.J., Syage, A.R., Nguyen, T.H., Baddour, A.A.D., Lu, C., Singh, P., Moeckli, R., Bochud, F., Germond, J-F., Froidevaux, P., Bailat, C., Bourhis, J., Vozenin, M-C. and Limoli, C.L. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. Proc. Natl. Acad. Sci. USA. 116(22):10943-10951 (2019), PMID: 31097580, doi: 10.1073/pnas.1901777116.

2. Alaghband, Y., Cheeks, S.N., Allen, B.D., Montay-Gruel, P., Doan, N-L., Petit, B., Jorge, P.G., Giedzinski, E., Acharya, M.M., Vozenin, M-C. and Limoli, C.L. Neuroprotection of radiosensitive juvenile mice by ultra-high dose rate FLASH irradiation. Cancers 12(6):1671 (2020). PMID: 32599789, doi: 10.3390/cancers12061671.

3. Montay-Gruel, P., Acharya, M.M., Jorge, P.G., Petit, B., Petridis, I., Fuchs, P., Petersson, K., Gondre, M., Ollivier, J., Moeckli, R., Bochud, F., Bailat, C., Bourhis, J., Germond, J-F., Limoli, C.L. and Vozenin, M-C. Hypo-fractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side-effects in mice. Clin. Cancer Res. 27(3):775-784 (2021). PMID: 33060122, doi:10.1158/1078-0432.CCR-20-0894.

4. Acharya, M., Christie, L.-A., Lan, M., Donovan, P.J., Cotman, C.W., Fike, J.R. and Limoli, C.L. Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc. Natl. Acad. Sci. USA 106:19150-19155 (2009).

5. Parihar, V.K. and Limoli, C.L. Cranial irradiation compromises neuronal architecture in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 110:12822-7 (2013).

6. Acharya, M.M., Martirosian, V., Chmielewski, N.N., Hanna, N., Tran, K.K., Liao, A.C., Christie, L-A., Parihar, V.K. and Limoli, C.L. Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. Cancer Res. 75(4):676-86 (2015).

7. Baulch, J.E., Acharya , M.M., Allen , B.D., Ru N., Chmielewski, N.N., Martirosian, V., Giedzinski, E., Syage, A., Park, A.L., Benke, S.N., Parihar, V.K. and Limoli, C.L. Cranial grafting of stem cell derived microvesicles improves cognition and reduces neuropathology in the irradiated brain. Proc. Natl. Acad. Sci USA, 113(17): 4836-41 (2016).

8. Leavitt, R., Acharya, M.M., Baulch, J.E. and Limoli, C.L. Extracellular vesicle-derived miR-124 resolves radiation-induced brain injury. Cancer Res. 80(19):4266-4277 (2020). doi: 10.1158/0008-5472.CAN-20-1599.

9. Montay-Gruel, P., Zhu, Y., Benoit, P., Leavitt, R., Warn, M., Giedzinski, E., Ollivier, J., Sinclair, D., Vozenin , M-C. and Limoli, C.L. Extracellular vesicles for the treatment of radiation-induced normal tissue toxicity in the lung. Frontiers Oncol. 10 (2021), doi:10.3389/fonc.2020.602763.

10. Parihar, V.K., Allen, B., Tran, K.K., Macaraeg, T., Chu, E., Kwok, S., Chmielewski, N.N., Craver, B.M., Baulch, J.E., Acharya, M.M., Cucinotta, F.A. and Limoli, C.L. What happens to your brain on the way to Mars. Science Advances, May 1;1(4): e1400256. PMID: 26180843, (2015).

11. Limoli, C.L. Deep-Space Deal Breaker. Scientific American, 316(2):54-59 (2017)

12. Acharya, M.M., Baulch, J.E., Klein, P.M., Baddour, A.A.D., Apodaca, L.A., Kramár, E.A., Alikhani, L., Garcia Jr. C., Angulo, M.C., Batra, R.S., Fallgren, C.M., Borak, T.B., Stark, C.E.L., Wood, M.A., Britten, R.A., Soltesz, I. and Limoli, C.L. New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation. eNeuro, 22;6(4) (2019).  pii: ENEURO.0094-19, doi:10.1523/ENEURO.0094-19

13. Desai, R.I., Limoli, C.L., Stark, C.E. and Stark S.M. Can biomarker signatures from combined spaceflight stressors be used to inform risks to overall CNS health. In Press, Neurosci. Biobehav. Rev. (2022).