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Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

1
Faculty of Medicine, the University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
2
Probing Biosystems Future Science Platform, CSIRO Health & Biosecurity, Herston, Queensland 4029, Australia
3
Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, St Lucia, Queensland 4072, Australia
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Centre for Advanced Imaging, the University of Queensland, St Lucia, Queensland 4072, Australia
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ARC Centre of Excellence in Convergent BioNano Science and Technology, the University of Queensland, St Lucia, Queensland 4072, Australia
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ARC Training Centre for Biopharmaceutical Innovation, the University of Queensland, St Lucia, Queensland 4072, Australia
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Kenneth G. Jamieson Department of Neurosurgery, the Royal Brisbane and Women’s Hospital, Herston, Queensland 4029, Australia
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Diamantina Institute, Translational Research Institute, the University of Queensland, Brisbane, Queensland 4102, Australia
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Pathology Queensland, the Royal Brisbane and Women’s Hospital, Herston, Queensland 4029, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1280; https://doi.org/10.3390/ijms20061280
Received: 14 February 2019 / Revised: 8 March 2019 / Accepted: 9 March 2019 / Published: 14 March 2019
Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery. View Full-Text
Keywords: brain metastases; nanomedicine; immunotherapy; drug delivery brain metastases; nanomedicine; immunotherapy; drug delivery
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MDPI and ACS Style

Lim, M.; Puttick, S.; Houston, Z.H.; Thurecht, K.J.; Kalita-de Croft, P.; Mahler, S.; Rose, S.E.; Jeffree, R.L.; Mazzieri, R.; Dolcetti, R.; Lakhani, S.R.; Saunus, J.M. Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases. Int. J. Mol. Sci. 2019, 20, 1280. https://doi.org/10.3390/ijms20061280

AMA Style

Lim M, Puttick S, Houston ZH, Thurecht KJ, Kalita-de Croft P, Mahler S, Rose SE, Jeffree RL, Mazzieri R, Dolcetti R, Lakhani SR, Saunus JM. Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases. International Journal of Molecular Sciences. 2019; 20(6):1280. https://doi.org/10.3390/ijms20061280

Chicago/Turabian Style

Lim, Malcolm; Puttick, Simon; Houston, Zachary H.; Thurecht, Kristofer J.; Kalita-de Croft, Priyakshi; Mahler, Stephen; Rose, Stephen E.; Jeffree, Rosalind L.; Mazzieri, Roberta; Dolcetti, Riccardo; Lakhani, Sunil R.; Saunus, Jodi M. 2019. "Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases" Int. J. Mol. Sci. 20, no. 6: 1280. https://doi.org/10.3390/ijms20061280

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