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Review
. 2023 Dec;12(23):21075-21096.
doi: 10.1002/cam4.6647. Epub 2023 Nov 23.

Chemotherapy in pediatric brain tumor and the challenge of the blood-brain barrier

Johid Reza Malik  1 , Anthony T Podany  1   2 , Parvez Khan  3 , Christopher L Shaffer  2 , Jawed A Siddiqui  3 , Janina Baranowska-Kortylewicz  4 , Jennifer Le  5 , Courtney V Fletcher  1 , Sadia Afruz Ether  1 , Sean N Avedissian  1   2
Affiliations
Review

Chemotherapy in pediatric brain tumor and the challenge of the blood-brain barrier

Johid Reza Malik et al. Cancer Med. 2023 Dec.

Abstract

Background: Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti-cancer drugs in PBT.

Methods: We conducted our search for chemotherapeutic agents associated with the blood-brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software.

Focus: We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non-randomized studies, preclinical research, review articles, and research papers.

Finding: Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors.

Keywords: blood-brain barrier; central nervous system; chemotherapy; oncology; pediatric brain tumor.

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Conflict of interest statement

All authors, no relevant conflicts.

Figures

FIGURE 1
FIGURE 1
Presentation of BBB interplay with PBT, (A) Constituent cells of BBB and the in vivo environment, (B) enlarged part of CNS depicting BBB in healthy brain and brain tumor with the associated BBB inhibition of drug entry, and (C) molecular‐level comparison of the normal brain with a brain tumor. BBB, blood–brain‐barrier; PBT, pediatric brain tumor; CNS, central nervous system; MMPs, metrix metalloproteases. *Figure was generated utilizing Biorender.com.
FIGURE 2
FIGURE 2
Major pathways or targets of (A) epigenetic drugs panobinostat (upper panel) and temozolomide (lower panel), and (B) polyamine synthesis targeting drug difluoromethylornithine. HATs, histone acetyltransferase; HDACs, histone deacetylase; MGMT, O6‐methylguanine‐DNA methyltransferase; DFMO, difluoromethylornithine. *Figure was generated utilizing Biorender.com.
FIGURE 3
FIGURE 3
Bevacizumab is a humanized monoclonal antibody that inhibits angiogenesis by neutralizing vascular endothelial growth factor (VEGF), which is upregulated in tumor growth and metastasis of multiple types of CNS tumors. CNS, central nervous system; VEGFR, vascular endothelial growth factor receptor. *Figure was generated utilizing Biorender.com.
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