Review

. 2023 Apr 14:13:1154246.

doi: 10.3389/fonc.2023.1154246. eCollection 2023.

BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience

Sarah M Trinder¹, Campbell McKay², Phoebe Power^{3

4}, Monique Topp⁵, Bosco Chan⁶, Santosh Valvi¹, Geoffrey McCowage^{7

8}, Dinisha Govender⁷, Maria Kirby⁶, David S Ziegler^{3

9

10}, Neevika Manoharan^{3

10}, Tim Hassall¹¹, Stewart Kellie¹², John Heath¹³, Frank Alvaro¹⁴, Paul Wood¹⁵, Stephen Laughton¹⁶, Karen Tsui¹⁶, Andrew Dodgshun¹⁷, David D Eisenstat^{2

18

19}, Raelene Endersby^{20

21}, Stephen J Luen²², Eng-Siew Koh^{23

24

25}, Hao-Wen Sim^{26

27

28

29}, Benjamin Kong^{26

30}, Nicholas G Gottardo^{1

20}, James R Whittle³¹, Dong-Anh Khuong-Quang², Jordan R Hansford^{6

32

33}

Affiliations

¹ Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital, Nedlands, WA, Australia.
² Children's Cancer Centre, Royal Children's Hospital, Melbourne, VIC, Australia.
³ Sydney Children's Hospital, Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.
⁴ School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.
⁵ Department of Medical Oncology, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
⁶ Michael Rice Cancer Centre, Women's and Children's Hospital, North Adelaide, SA, Australia.
⁷ Department of Oncology, Children's Hospital at Westmead, Sydney, NSW, Australia.
⁸ Australasian Children's Cancer Trials, Clayton, VIC, Australia.
⁹ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
¹⁰ School of Clinical Medicine, University of New South Wales (UNSW) Medicine and Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
¹¹ Queensland Children's Hospital, University of Queensland, Brisbane, QLD, Australia.
¹² Westmead Children's Hospital, University of Sydney, Westmead, NSW, Australia.
¹³ Department of Pediatric Oncology, Royal Hobart Hospital, Hobart, TAS, Australia.
¹⁴ Department of Pediatric Oncology, John Hunter Children's Hospital, Newcastle, NSW, Australia.
¹⁵ Monash Medical Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁶ Starship Blood and Cancer Centre, Starship Children's Hospital, Auckland, New Zealand.
¹⁷ Children's Haematology/Oncology Centre, Christchurch Hospital, Christchurch, New Zealand.
¹⁸ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹⁹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
²⁰ Brain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Nedlands, WA, Australia.
²¹ Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
²² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
²³ Department of Radiation Oncology, Liverpool and Macarther Cancer Therapy Centres, Liverpool, NSW, Australia.
²⁴ Department of Medicine, University of New South Wales, Sydney, NSW, Australia.
²⁵ Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
²⁶ National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
²⁷ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
²⁸ Department of Medical Oncology, The Kinghorn Cancer Centre, Sydney, NSW, Australia.
²⁹ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
³⁰ Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
³¹ Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
³² South Australian Health and Medical Research Institute South Australia, Adelaide, SA, Australia.
³³ South Australia ImmunoGENomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia.

PMID: 37124503
PMCID: PMC10140567
DOI: 10.3389/fonc.2023.1154246

Review

BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience

Sarah M Trinder et al. Front Oncol. 2023.

. 2023 Apr 14:13:1154246.

doi: 10.3389/fonc.2023.1154246. eCollection 2023.

Authors

Affiliations

¹ Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital, Nedlands, WA, Australia.
² Children's Cancer Centre, Royal Children's Hospital, Melbourne, VIC, Australia.
³ Sydney Children's Hospital, Children's Cancer Institute, University of New South Wales, Randwick, NSW, Australia.
⁴ School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.
⁵ Department of Medical Oncology, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
⁶ Michael Rice Cancer Centre, Women's and Children's Hospital, North Adelaide, SA, Australia.
⁷ Department of Oncology, Children's Hospital at Westmead, Sydney, NSW, Australia.
⁸ Australasian Children's Cancer Trials, Clayton, VIC, Australia.
⁹ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
¹⁰ School of Clinical Medicine, University of New South Wales (UNSW) Medicine and Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
¹¹ Queensland Children's Hospital, University of Queensland, Brisbane, QLD, Australia.
¹² Westmead Children's Hospital, University of Sydney, Westmead, NSW, Australia.
¹³ Department of Pediatric Oncology, Royal Hobart Hospital, Hobart, TAS, Australia.
¹⁴ Department of Pediatric Oncology, John Hunter Children's Hospital, Newcastle, NSW, Australia.
¹⁵ Monash Medical Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁶ Starship Blood and Cancer Centre, Starship Children's Hospital, Auckland, New Zealand.
¹⁷ Children's Haematology/Oncology Centre, Christchurch Hospital, Christchurch, New Zealand.
¹⁸ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹⁹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
²⁰ Brain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Nedlands, WA, Australia.
²¹ Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
²² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
²³ Department of Radiation Oncology, Liverpool and Macarther Cancer Therapy Centres, Liverpool, NSW, Australia.
²⁴ Department of Medicine, University of New South Wales, Sydney, NSW, Australia.
²⁵ Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
²⁶ National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
²⁷ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
²⁸ Department of Medical Oncology, The Kinghorn Cancer Centre, Sydney, NSW, Australia.
²⁹ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
³⁰ Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
³¹ Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
³² South Australian Health and Medical Research Institute South Australia, Adelaide, SA, Australia.
³³ South Australia ImmunoGENomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia.

PMID: 37124503
PMCID: PMC10140567
DOI: 10.3389/fonc.2023.1154246

Abstract

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.

Keywords: BRAF; BRAF inhibitors; MAPK signaling; access; glioma; gliomagenesis.

Copyright © 2023 Trinder, McKay, Power, Topp, Chan, Valvi, McCowage, Govender, Kirby, Ziegler, Manoharan, Hassall, Kellie, Heath, Alvaro, Wood, Laughton, Tsui, Dodgshun, Eisenstat, Endersby, Luen, Koh, Sim, Kong, Gottardo, Whittle, Khuong-Quang and Hansford.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**Figure 1**
Schematic representation of ERK/MAPK pathway signaling showing normal dimerization of MAP3Ks and cross-signaling of the PI3K/AKT/mTOR pathway. Starred pathways indicate known alterations implicated in cancer.

**Figure 2**
Targeted agents focused on MAPK signaling including class 1 and 2 BRAF inhibitors and MEK and ERK inhibitors.

See this image and copyright information in PMC

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BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience

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BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience

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