Close

Cytostatic hypothermia and its impact on glioblastoma and survival

Syed Faaiz Enam, Cem Y. Kilic, Jianxi Huang, Brian J. Kang, Reed Chen, Connor S. Tribble, Martha I. Betancur, Ekaterina Ilich, Stephanie J. Blocker, Steven Owen, Johnathan G. Lyon, Ravi V. Bellamkonda

Posted on: 10 April 2021 , updated on: 4 January 2023

Preprint posted on 26 March 2021

Article now published in Science Advances at http://dx.doi.org/10.1126/sciadv.abq4882

Cytostatic hypothermia: a very “cool” way to stop brain tumor progression and prevent tumor recurrence

Selected by Kristina Kuhbandner

Updated 4 January 2023 with a postLight by Kristina Kuhbandner

On November 25th 2022, the peer-reviewed version of the preprint “Cytostatic hypothermia and its impact on glioblastoma and survival” by Enam and colleagues was published in Science Advances under the category “Applied Sciences and Engineering”.

Compared to the preprint version, the peer-reviewed manuscript shows no major changes. However, small modifications were made to improve (i) the readability and flow of the story – e.g., in the peer-reviewed version, all in vitro experiments were moved to the first section of the paper – and (ii) clarity, especially for some of the supplementary figures, where timeline schematics were included to better explain the experimental setup. Furthermore, the authors have added a very informative figure visualizing the conceptual model of a hypothermia device for human use. The peer-reviewed article also includes an extended histological analysis of the tumor tissue after hypothermia treatment with images included in the supplemental information. Lastly, multiple caveats and limitations of the in vivo application of hypothermia are discussed in the peer-reviewed version. The questions raised in this preLights article have not been addressed, but might be taken into account for future follow-up studies.

Overall, the changes to the preprint have further improved the quality of the manuscript and hopefully, in the future, this “cool technique” can be leveraged to successfully treat aggressive, cold-sensitive tumors.

Background

The effects of hypothermia, defined as body temperature below 35°C, and its application as a therapeutic strategy in various diseases has been studied for a long time (1). Today, mild therapeutic hypothermia is widely used in emergency medicine to improve the rates of long-term survival without neurological damage in patients with sudden cardiac arrest (2). First experiments using hypothermia in the field of neurosurgery date back to the mid-twentieth century, when the neurosurgeon Temple Fay utilized quite unconventional tools (including a beer cooler-machine pump) to locally lower the temperature in a brain tumor patient (3).

Glioblastoma is the most common type of malignant brain tumor, and affected individuals have a very poor survival rate. This might be partly due to residual cancer cells in the resection margin after surgical removal of the malignant tissue. Subsequent postoperative treatments such as radio- and chemotherapy can activate these dormant glioblastoma cells and ultimately lead to a recurrence of the tumor (4). This emphasizes the need for alternative treatment strategies able to inhibit cancer recurrence without damaging the healthy brain tissue. Recently, it has been suggested that moderate hypothermia might be a promising adjuvant glioblastoma therapy through inhibition of cancer cell proliferation (5). This preprint by Enam and colleagues investigates the effect of cytostatic hypothermia on different glioblastoma cell lines in vitro and in vivo using two different rat glioblastoma models.

“Cool” results

First, the authors aimed to define an optimal temperature range sufficient to stop tumor growth but with minimal cytotoxicity for healthy cells, which they termed “cytostatic hypothermia”. For the human glioblastoma cell lines used in this assay this ranged from 20-25°C.  Notably, cycles of hypothermia with intervals of normal temperature showed comparable cytostatic results and were even less cytotoxic. Further, they determined the effect of hypothermia on cell cycle, metabolism and cytokine synthesis. Any kind of hypothermia treatment resulted in cell cycle arrest in the G2 phase, with a concurrent decrease in metabolite consumption and production and reduced secretion of inflammatory cytokines.

Next, Elan et al. applied different simulation tools and considered parameters from previous studies to model local intracranial hypothermia in the rat brain. Based on these data, they built a hypothermia device consisting of 1) an implantable interface which attaches to the skull with a gold needle reaching into the tumor and 2) a removable cooling element. For a preliminary imaging study, rats were inoculated with tumor cells followed by implantation of the hypothermia device. MRI analysis showed that tumor size was significantly reduced in rats receiving a seven-day hypothermia treatment compared to control animals with cooler switched off.

To assess the effect of hypothermia treatment on the survival rate, two different rat models (Fisher rats inoculated with F98 and RNU rats inoculated with human U-87 MG cells, respectively) were used. In both models, cytostatic hypothermia significantly prolonged animal survival and reduced tumor burden. Finally, the authors investigated whether hypothermia can be used in combination with traditional therapeutic strategies, namely chemotherapy or CAR (chimeric antigen receptor) T immunotherapy, in vitro. While hypothermia boosted the growth-inhibiting effects of the chemotherapeutic agent temozolomide, reduced temperatures seemed to slightly impact the potency of CAR T cells to kill tumor cells.

Why I chose this preprint

Although I am not very familiar with neurosurgery, this preprint immediately caught my attention. Firstly, glioblastomas are very aggressive, and I personally knew a patient who died following tumor recurrence a few years after tumor removal. Therefore, the development of additional treatment options able to prevent this scenario is key to improve survival chances. Enam et al. show that using hypothermia might be a promising strategy to inhibit tumor cell reactivation and consequently tumor progression and recurrence. Furthermore, their results might also be useful for the treatment of other temperature-sensitive cancer types. I also like their approach going from cell culture experiments to computer-based simulations to in vivo models. Although the beneficial effect of hypothermia in vitro has been known before, this is the first study to translate these findings to the in vivo situation. Last but not least, the history and evolution of hypothermia research is absolutely astonishing and I enjoyed delving deeper into this topic reading many fascinating stories.

Questions to the authors

  • Your in vitro studies show that F98 cells are much more resistant to hypothermia. Do you have an explanation for this?
  • Developing such a hypothermia device is an enormous technical challenge and an awesome achievement. However, refinements are necessary as some of the devices failed during the trial especially when rats were more active. Furthermore, it would be very helpful if the thermistor shows compatibility with MRI. Do you already have ideas how these improvements could be realized?
  • The last experiment on possible combination therapies indicates that temperature reduction could affect the functionality of CAR T cells in vitro. Are you also planning to further investigate this and the co-therapy with chemotherapeutics or radiotherapy in vivo?
  • Considering the differences between rats and humans, what are the biggest challenges in constructing a device for application in humans?

References

  1. Bohl MA, Martirosyan NL, Killeen ZW, Belykh E, Zabramski JM, Spetzler RF, et al. The history of therapeutic hypothermia and its use in neurosurgery. J Neurosurg. 2018 May 25;130(3):1006–20.
  2. Hunter BR, Ellender TJ. Targeted temperature management in emergency medicine: current perspectives. Open Access Emerg Med OAEM. 2015 Sep 28;7:69–77.
  3. Fay T. Early Experiences with Local and Generalized Refrigeration of the Human Brain. J Neurosurg. 1959 May 1;16(3):239–60.
  4. Wion D. Therapeutic dormancy to delay postsurgical glioma recurrence: the past, present and promise of focal hypothermia. J Neurooncol. 2017 Jul 1;133(3):447–54.
  5. Fulbert C, Chabardès S, Ratel D. Adjuvant therapeutic potential of moderate hypothermia for glioblastoma. J Neurooncol [Internet]. 2021 Mar 19 [cited 2021 Mar 27]; Available from: https://doi.org/10.1007/s11060-021-03704-y

Tags: brain tumor, cancer recurrence, hypothermia

doi: https://doi.org/10.1242/prelights.28191

Read preprint (No Ratings Yet)

Author's response

Syed Faaiz Enam shared

1) Your in vitro studies show that F98 cells are much more resistant to hypothermia. Do you have an explanation for this?
We do not currently have a clear explanation for this but it is fascinating. We hypothesize that it may be due to temperature-resistant metabolic or transcriptomic pathways which need to be elucidated with further studies. Currently, our data show that cell morphology of F98 is significantly different between 25°C and 20°C. Apart from that, we still see an accumulation of cells in the G2-phase even at 25°C and a reduction in metabolite production/consumption at 25°C and 20°C. Regardless, this raises questions of whether there are cells that are even more resilient (re: cell division and temperature), what the mechanisms driving this are, and whether it is hypothetically possible to evolve around cytostatic hypothermia!
 
2) Developing such a hypothermia device is an enormous technical challenge and an awesome achievement. However, refinements are necessary as some of the devices failed during the trial especially when rats were more active. Furthermore, it would be very helpful if the thermistor shows compatibility with MRI. Do you already have ideas how these improvements could be realized?
Working with a small animal model for this application has been technically challenging but there is a lot of room for improvement. As we mentioned, MRI-compatible thermistors do exist but we experienced unreliability when using them. Currently we do not know why those thermistors failed but were unable to identify any major fault in the way they were wired to the Interface. That said, it may be worth giving them another shot because it would make longitudinal tumor volume assessment possible. The problem of active rats eventually dislodging their Interface would likely best be solved with either further miniaturization or switching to a liquid-based cooler that is hidden under the scalp. These are strategies we are considering for future studies.
 
3) The last experiment on possible combination therapies indicates that temperature reduction could affect the functionality of CAR T cells in vitro. Are you also planning to further investigate this and the co-therapy with chemotherapeutics in vivo?
Absolutely! Both findings were happy surprises. While we want to test these in vivo (with different hypothermia dosing paradigms) we also want to understand the mechanisms of why there is synergism with Temozolomide and why CAR T cells retain and lose some functionality. A mechanistic study could elucidate the scope of chemotherapy-hypothermia synergism and provide ways to overcome reduced CAR T cell functioning.
 
4) Considering the differences between rats and humans, for example much bigger tumor volume in humans, what are the biggest challenges in constructing a device for application in humans?
Currently the biggest challenge is designing a fully-implantable device that provides homogenous cytostatic hypothermia to a large region of tissue that is also practicable, potentially indefinitely, for a patient. We are working on this!

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the bioengineering category:

Engineered Nanotopographies Induce Transient Openings in the Nuclear Membrane

Einollah Sarikhani, Vrund Patel, Zhi Li, et al.

Selected by 23 September 2024

Sristilekha Nath

Bioengineering

Scalable and efficient generation of mouse primordial germ cell-like cells

Xinbao Ding, Liangdao Li, Jingyi Gao, et al.

Selected by 05 March 2024

Carly Guiltinan

Cell Biology

Generalized Biomolecular Modeling and Design with RoseTTAFold All-Atom

Rohith Krishna, Jue Wang, Woody Ahern, et al.

Selected by 24 January 2024

Saanjbati Adhikari

Bioengineering

Also in the cancer biology category:

Integrin conformation-dependent neutrophil slowing obstructs the capillaries of the pre-metastatic lung in a model of breast cancer

Frédéric Fercoq, Gemma S. Cairns, Marco De Donatis, et al.

Selected by 07 October 2024

Simon Cleary

Cancer Biology

Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects

Ritobrata Ghose, Fabio Pezzano, Savvas Kourtis, et al.

Selected by 16 May 2024

Teodora Piskova

Cell Biology

Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

Yoshiaki Yasumizu, Makoto Kinoshita, Martin Jinye Zhang, et al.

Selected by 27 March 2024

Jessica Chevallier

Immunology

Also in the neuroscience category:

The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites

Joelle Lo, Katherine F. Vaeth, Gurprit Bhardwaj, et al.

Selected by 24 September 2024

Felipe Del Valle Batalla

Neuroscience

Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster

Bhanu Shrestha, Jiun Sang, Suman Rimal, et al.

Selected by 23 September 2024

Matthew Davies

Cell Biology

Triglyceride metabolism controls inflammation and APOE4-associated disease states in microglia

Roxan A. Stephenson, Kory R. Johnson, Linling Cheng, et al.

Selected by 22 August 2024

Gustavo Stelzer, Marcus Oliveira

Biochemistry

Also in the cancer biology category:

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.

 



List by Reinier Prosee

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Anticancer agents: Discovery and clinical use

Preprints that describe the discovery of anticancer agents and their clinical use. Includes both small molecules and macromolecules like biologics.

 



List by Zhang-He Goh

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

Also in the neuroscience category:

2024 Hypothalamus GRC

This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.

 



List by Nathalie Krauth

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve
Close