Adamantinomatous Craniopharyngioma Treatment

Adamantinomatous Craniopharyngioma Treatment

Therapeutic modalities for children with Adamantinomatous Craniopharyngioma include maximally-safe surgery, radiation, and cyst-directed therapies, such as interferon and bleomycin. None of these approaches, however, are directed against unique biological characteristics of ACP. Furthermore, after many years of use, each has been shown to be associated with shortcomings regarding clinical efficacy and/or side effects 1) 2) 3) 4)5)


Aberrations in the CTNNB1 gene lead to the dysregulation of the Wnt pathway and the accumulation of nuclear β-catenin, which may play a role in tumor invasiveness. While Wnt pathway/β-catenin inhibition may be a promising treatment for ACP, potential off-target effects have limited its use in current intervention strategies. Promising evidence of the therapeutic potential of cystic proinflammatory mediators and immunosuppressants has been translated into clinical therapies, including interleukin 6 and IDO-1 inhibition. The dysregulation of the pathways of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 and its ligand (PD-1/PD-L1) has led to identification of various therapeutic targets that have shown promise as clinical strategies. The Sonic Hedgehog (SHH) pathway is upregulated in ACP and has been implicated in tumorigenesis and tumor growth; however, inhibition of SHH in murine models decreased survival, limiting its therapeutic application. While further preclinical and clinical data are needed, systemically delivered therapies could delay or replace the need for more aggressive definitive treatments. Ongoing preclinical investigations and clinical trials of these prospective pathways promise to advance treatment approaches aimed to increase patients’ quality of life 6)


Two patients with recurrent cystic ACP were offered systemically administered tocilizumab or a combination of tocilizumab and bevacizumab on a compassionate use basis. Both patients’ tumors had a significant response, with decreased cyst burden, supporting the assertion that tocilizumab with or without bevacizumab may be an option for patients suffering from cystic ACP. 7)


Zhang et al. demonstrated that CD47 plays an important role in adamantinomatous craniopharyngioma cells, suggesting that CD47 could be a new potential therapeutic target for adamantinomatous craniopharyngioma treatment, and adding to the body of literature a role for the inhibition of MAPK/ERK in ACP 8)


The evolving characterization of the biological basis of adamantinomatous craniopharyngioma (ACP) has provided insights critical for novel systemically delivered therapies. While current treatment strategies for ACP are associated with low mortality rates, patients experience severely lowered quality of life due to high recurrence rates and chronic sequelae, presenting a need for novel effective treatment regimens. The identification of various dysregulated pathways that play roles in the pathogenesis of ACP has prompted the investigation of novel treatment options. Aberrations in the CTNNB1 gene lead to the dysregulation of the Wnt signaling pathway and the accumulation of nuclear beta-catenin, which may play a role in tumor invasiveness. While Wnt pathway/beta-catenin inhibition may be a promising treatment for ACP, potential off-target effects have limited its use in current intervention strategies. Promising evidence of the therapeutic potential of cystic proinflammatory mediators and immunosuppressants has been translated into clinical therapies, including interleukin 6 and IDO-1 inhibition. The dysregulation of the pathways of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 and its ligand (PD-1/PD-L1) has led to identification of various therapeutic targets that have shown promise as clinical strategies. The Sonic Hedgehog (SHH) pathway is upregulated in ACP and has been implicated in tumorigenesis and tumor growth; however, inhibition of SHH in murine models decreased survival, limiting its therapeutic application. While further preclinical and clinical data are needed, systemically delivered therapies could delay or replace the need for more aggressive definitive treatments. Ongoing preclinical investigations and clinical trials of these prospective pathways promise to advance treatment approaches aimed to increase patients’ quality of life 9).


Early disease onset, clinical manifestation, histomorphology, and increased tendency to relapse distinguish the adamantinomatous craniopharyngioma (adaCP) from the more favorable papillary craniopharyngioma variant (papCP). A molecular hallmark of adaCP is the activated Wnt signaling pathway indicated by nuclear beta-catenin accumulation in a subset of tumor cells. A mouse model recently illustrated that these cells are the driving force in tumorigenesis of adaCP. This observation and the peculiar growth pattern points to the existence of a specific tumor stem cell (TSC) population in human CP. Tumor stem cell-like characteristics of beta-catenin accumulating cell clusters in adaCP, which may represent a tumor stem cell niche and might contribute to tumor recurrence. The potential impact of these special cell groups in regard to future CP management, including postoperative follow-up and additional treatment remains to be explored 10).

Osteogenic factor Bmp2 may play an important role in the calcification of adamantinomatous craniopharyngioma ACP via autocrine or paracrine mechanisms. Given the presence of osteogenic markers (Runx2 and Osterix), craniopharyngioma cells could differentiate into an osteoblast-like lineage, and the process of craniopharyngioma calcification resembles that which occurs in osteogenesis/odontogenesis 11).

Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms 12).


1)

Hader WJ, Steinbok P, Hukin J, Fryer C. Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children. Pediatr Neurosurg. (2000) 33:211–8. doi: 10.1159/000055955
2)

Mottolese C, Stan H, Hermier M, Berlier P, Convert J, Frappaz D, et al. Intracystic chemotherapy with bleomycin in the treatment of craniopharyngiomas. Childs Nerv Syst. (2001) 17:724–30. doi: 10.1007/s00381-001-0524-5
3)

Cavalheiro S, Dastoli PA, Silva NS, Toledo S, Lederman H, da Silva MC. Use of interferon alpha in intratumoral chemotherapy for cystic craniopharyngioma. Childs Nerv Syst. (2005) 21:719–24. doi: 10.1007/s00381-005-1226-1
4)

Sharma J, Bonfield CM, Singhal A, Hukin J, Steinbok P. Intracystic interferon-alpha treatment leads to neurotoxicity in craniopharyngioma: case report. J Neurosurg Pediatr. (2015) 16:301–4. doi: 10.3171/2015.2.PEDS14656
5)

Kilday JP, Caldarelli M, Massimi L, Chen RH, Lee YY, Liang ML, et al. Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN. Neuro Oncol. (2017) 19:1398–407. doi: 10.1093/neuonc/nox056
6)

Hengartner AC, Prince E, Vijmasi T, Hankinson TC. Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus. 2020 Jan 1;48(1):E7. doi: 10.3171/2019.10.FOCUS19705. PMID: 31896087.
7)

Grob S, Mirsky DM, Donson AM, Dahl N, Foreman NK, Hoffman LM, Hankinson TC, Mulcahy Levy JM. Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma. Front Oncol. 2019 Aug 21;9:791. doi: 10.3389/fonc.2019.00791. PMID: 31497533; PMCID: PMC6712354.
8)

Zhang H, Wang C, Fan J, Zhu Q, Feng Y, Pan J, Peng J, Shi J, Qi S, Liu Y. CD47 Promotes the Proliferation and Migration of Adamantinomatous Craniopharyngioma Cells by Activating the MAPK/ERK Pathway, and CD47 Blockade Facilitates Microglia-mediated Phagocytosis. Neuropathol Appl Neurobiol. 2022 Feb 13:e12795. doi: 10.1111/nan.12795. Epub ahead of print. PMID: 35156226.
9)

Hengartner AC, Prince E, Vijmasi T, Hankinson TC. Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus. 2020 Jan 1;48(1):E7. doi: 10.3171/2019.10.FOCUS19705. PubMed PMID: 31896087.
10)

Hölsken A, Stache C, Schlaffer SM, Flitsch J, Fahlbusch R, Buchfelder M, Buslei R. Adamantinomatous craniopharyngiomas express tumor stem cell markers in cells with activated Wnt signaling: further evidence for the existence of a tumor stem cell niche? Pituitary. 2013 Dec 20. [Epub ahead of print] PubMed PMID: 24356780.
11)

Song-Tao Q, Xiao-Rong Y, Jun P, Yong-Jian D, Jin L, Guang-Long H, Yun-Tao L, Jian R, Xiang-Zhao L, Jia-Ming X. Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis? Histopathology. 2013 Jan 31. doi: 10.1111/his.12071. [Epub ahead of print] PubMed PMID: 24387671.
12)

Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, Lawrence MS, Rodriguez FJ, Bernardo LA, Schubert L, Sunkavalli A, Shillingford N, Calicchio ML, Lidov HG, Taha H, Martinez-Lage M, Santi M, Storm PB, Lee JY, Palmer JN, Adappa ND, Scott RM, Dunn IF, Laws ER Jr, Stewart C, Ligon KL, Hoang MP, Van Hummelen P, Hahn WC, Louis DN, Resnick AC, Kieran MW, Getz G, Santagata S. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet. 2014 Jan 12. doi: 10.1038/ng.2868. [Epub ahead of print] PubMed PMID: 24413733.

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