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Foreman, Nicholas; Faestel, Paul M.; Pearson, Joanne; Disabato, Jennifer A.; Poole, Marty; Wilkening, Greta N.; Arenson, Edward B.; Greffe, Brian; Thorne, R

doi:10.1023/a:1006145724500

Cited by 57 publications

(5 citation statements)

References 21 publications

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“…ACP is among a growing number of pediatric brain tumors in which tumor growth can often be controlled with 10-year survival ranging between 64 and 92% (4) however, ACP's suprasellar location and propensity for cyst formation [present in ~90% (5)] and hypothalamic infiltration predispose many children to a life of severe disability. As such, ACP has been associated with the lowest quality of life scores of any pediatric brain tumor (6).…”

Section: Introductionmentioning

confidence: 99%

Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma

et al. 2019

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Adamantinomatous craniopharyngioma (ACP) makes up between 6 and 8% of pediatric brain tumors and is the most common pediatric tumor arising in the sellar/suprasellar region of the brain. The 10-year survival for patients diagnosed with craniopharyngioma ranges between 64 and 92%, but complicating factors such as location, common cyst formation, and potential hypothalamic infiltration cause significant morbidity in this population. There are a number of therapeutic options for children with ACP, including surgery, radiation, and cyst directed therapies such as interferon and bleomycin. Research has raised concerns regarding the efficacy and side effects associated with these conventional therapies, as well as with the difficulty in treating recurrent cystic ACP. Evidence from our group and others has shown that the cystic and solid tumor components of craniopharyngioma have high levels of IL-6R and IL-6, providing a potential target for therapy. Tocilizumab, a humanized monoclonal antibody, acts against soluble and membrane bound IL-6R, and has been widely utilized in pediatric patients. 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.

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Section: Introductionmentioning

confidence: 99%

Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma

et al. 2019

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“…Variable morbidities are associated with ACP but include endocrine, neurological, vascular, psychological and visual deficits [ 12 ]. As a result, ACP has been associated with the lowest quality of life (QoL) scores of any pediatric brain tumor [ 13 ]. Lifelong care is necessary for most childhood craniopharyngioma patients and ACP and is considered by many to be a chronic disease [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma

Gump

Donson

Birks

et al. 2015

acta neuropathol commun

103

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IntroductionPediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75–95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP.ResultsUsing mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib – LCK, EPHA2 and SRC; EGFR pathway targets – AREG, EGFR and ERBB3; and other potentially actionable cancer targets – SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples.ConclusionsWe report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.

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“…Although the 10-year survival with these approaches is very good (ranging from 64 to 92%), in the case of tumor progression or recurrence, the therapeutic options are limited. Even with surgery or radiotherapy, CPs can cause high morbidity and predispose children to a life of severe disability across different organ systems [79,80].…”

Section: Craniopharyngiomasmentioning

confidence: 99%

Advances in Targeted Therapies for Pediatric Brain Tumors

Mueller

Stücklin

Postlmayr

et al. 2020

Curr Treat Options Neurol

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Purpose of Review Over the last years, our understanding of the molecular biology of pediatric brain tumors has vastly improved. This has led to more narrowly defined subgroups of these tumors and has created new potential targets for molecularly driven therapies. This review presents an overview of the latest advances and challenges of implementing targeted therapies into the clinical management of pediatric brain tumors, with a focus on gliomas, craniopharyngiomas, and medulloblastomas. Recent Findings Pediatric low-grade gliomas (pLGG) show generally a low mutational burden with the mitogen-activated protein kinase (MAPK) signaling presenting a key driver for these tumors. Direct inhibition of this pathway through BRAF and/or MEK inhibitors has proven to be a clinically relevant strategy. More recently, MEK and IL-6 receptor inhibitors have started to be evaluated in the treatment for craniopharyngiomas. Aside these low-grade tumors, pediatric high-grade gliomas (pHGG) and medulloblastomas exhibit substantially greater molecular heterogeneity with various and sometimes unknown tumor driver alterations. The clinical benefit of different targeted therapy approaches to interfere with altered signaling pathways and restore epigenetic dysregulation is undergoing active clinical testing. For these multiple pathway-driven tumors, combination strategies will most likely be required to achieve clinical benefit. Summary The field of pediatric neuro-oncology made tremendous progress with regard to improved diagnosis setting the stage for precision medicine approaches over the last decades. The potential of targeted therapies has been clearly demonstrated for a subset of pediatric brain tumors. However, despite clear response rates, questions of sufficient blood-brain barrier penetration, optimal dosing, treatment duration as well as mechanisms of resistance and how these can be overcome with potential combination strategies need to be addressed in future investigations. Along this line, it is critical for future trials to define appropriate endpoints to assess therapy responses as well as short and long-term toxicities in the growing and developing child.

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Cited by 57 publications

References 21 publications

Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma

Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma

Advances in Targeted Therapies for Pediatric Brain Tumors

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