Innovative therapeutic strategies for effective treatment of brain metastases

Malcolm Lim, Simon Puttick, Zachary H. Houston, Kristofer J. Thurecht, Priyakshi Kalita-De Croft, Stephen Mahler, Stephen E. Rose, Rosalind L. Jeffree, Roberta Mazzieri, Riccardo Dolcetti, Sunil R. Lakhani, Jodi M. Saunus

Research output: Contribution to journalReview ArticleResearchpeer-review

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1280
Number of pages24
JournalInternational Journal of Molecular Sciences
Volume20
Issue number6
DOIs
Publication statusPublished - 21 Mar 2019
Externally publishedYes

Keywords

  • Brain metastases
  • Drug delivery
  • Immunotherapy
  • Nanomedicine

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