Cytostatic hypothermia and its impact on glioblastoma and survival

Enam, S. F.; Kilic, C. Y.; Huang, J.; Kang, B. J.; Chen, R.; Tribble, C. S.; Betancur, M. I.; Ilich, E.; Blocker, S. J.; Owen, S.; Lyon, J. G.; Bellamkonda, R. V.

doi:10.1101/2021.03.25.436870

bioRxiv · 10.1101/2021.03.25.436870

Cytostatic hypothermia and its impact on glioblastoma and survival

Enam, S. F.·Kilic, C. Y.·Huang, J.·Kang, B. J.·Chen, R.·Tribble, C. S.·Betancur, M. I.·Ilich, E.·Blocker, S. J.·Owen, S.·Lyon, J. G.·Bellamkonda, R. V.

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Abstract

Novel therapeutic approaches are needed for patients with glioblastoma (GBM) who otherwise have limited options. Here we studied and deployed non-freezing cytostatic hypothermia to stunt GBM growth. This contrasts with ablative, cryogenic hypothermia: a double-edged sword against tumors infiltrating otherwise healthy tissue. We investigated three grades of hypothermia in vitro and identified a cytostatic window of 20-25{degrees}C. For some glioma lines, 18 h/d of cytostatic hypothermia was sufficient to halt division in vitro. Cytostatic hypothermia induced cell cycle arrest, reduced metabolite production and consumption, and reduced inflammatory cytokine synthesis. Next, we fabricated an experimental device to test local cytostatic hypothermia in vivo in two rodent models of GBM: utilizing the rat F98 and the human U-87 MG lines. Hypothermia more than doubled the median survival of F98 bearing rats from 3.9 weeks to 9.7 weeks and two rats survived through 12 weeks. All U-87 MG bearing rats that successfully received cytostatic hypothermia survived their study period. Thus, this approach lengthened survival without chemical interventions. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia affects multiple cellular processes simultaneously. This, alongside reduced cellular division, suggests that opportunities for tumor evolution are reduced and the likelihood of translation to larger species may be more likely. In addition, based on our work, designs, and the literature, engineering a patient-centric device is tangible. Taken together, cytostatic hypothermia could be a novel approach to cancer therapy and eventually serve a valuable role to patients with GBM. One Sentence SummaryHypothermia influences multiple cellular pathways, can be a safe and effective approach to halt glioblastoma growth, and holds translational promise.

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Enam, S. F., Kilic, C. Y., Huang, J., Kang, B. J., Chen, R., Tribble, C. S., Betancur, M. I., Ilich, E., Blocker, S. J., Owen, S., Lyon, J. G., Bellamkonda, R. V.. 2021-03-26. Cytostatic hypothermia and its impact on glioblastoma and survival. https://doi.org/10.1101/2021.03.25.436870

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