Research Article: Identification of targets for rational pharmacological therapy in childhood craniopharyngioma

Date Published: May 21, 2015

Publisher: BioMed Central

Author(s): Jacob M. Gump, Andrew M. Donson, Diane K. Birks, Vladimir M. Amani, Karun K. Rao, Andrea M. Griesinger, B. K. Kleinschmidt-DeMasters, James M. Johnston, Richard C. E. Anderson, Amy Rosenfeld, Michael Handler, Lia Gore, Nicholas Foreman, Todd C. Hankinson.

http://doi.org/10.1186/s40478-015-0211-5

Abstract

Pediatric 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.

Using 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.

We 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.

Partial Text

Adamantinomatous craniopharyngioma (ACP) is the most common non-neural brain tumor with an incidence of approximately 1.9 cases/million patient-years in children [1–3]. Due to its sensitive sellar/suprasellar location and propensity to form large cysts, ACP often compresses and damages vital structures of the pituitary, hypothalamus and visual apparatus. Although seemingly well-demarcated on neuroimaging studies, histology reveals finger-like protrusions extending into neighboring visual and hypothalamic structures, eliciting tissue damage and gliosis [4]. This propensity to invade adjacent structures, in addition to the difficult surgical location, often precludes total resection in order to avoid the significantly increased risk of visual and hypothalamic damage associated with attempts to completely remove the tumor [5–8]. The current standard of subtotal resection followed by radiation reduces some of the morbidity, however, it makes recurrence relatively common, even after apparently successful primary therapy. Outcomes after recurrence are poorer, with significantly higher mortality and morbidity than after primary treatment [9–11].

Identification of potential therapeutic targets in our transcriptomic analysis confirmed findings of previous studies that had identified SHH and EGFR pathway activity in ACP and provide further evidence that therapies targeting these pathways could be used successfully in treating ACP. Transcriptomic analysis of ACP generated in a mouse model demonstrated high levels of SHH gene expression, suggesting a mitogenic autocrine/paracrine loop [25]. A subsequent study identified upregulation of members of the SHH signaling pathway in human specimens [41]. In vitro and xenotransplant model studies have demonstrated that EGFR activation is responsible for driving growth and migration in ACP [23, 24]. The proven clinical utility of EGFR inhibition in the treatment of cancer makes EGFR targeted drugs an attractive approach to ACP treatment. Our identification of high levels of EGFR ligand AREG provide a potential mechanism for EGFR activation in ACP that warrants further exploration. Furthermore, AREG has been implicated as a paracrine/juxtacrine regulator of cell survival in other cancers and epidermal cell types [42]. It has also recently been suggested that ACP may be paracrine in nature (i.e. the CTNNB1 mutant cells may promote the proliferation of another cell type that actually populates the tumor) [22]. This hypothesis could explain the extensive intratumoral heterogeneity in ACP and perhaps the difficulty we and others have found in obtaining “pure” tumor samples to accurately identify CTNNB1 mutations [15].

Current standard therapy for ACP is surgery and radiation, both of which lead to high morbidity in this sensitive region of the brain, especially in children, in whom these morbidities become a lifelong and life-altering disease. Intracystic delivery of therapeutic agents (interferon-alpha, bleomycin or Ytrrium90) has shown some efficacy in treating ACP [49], but this approach is limited by the requirement of a single cyst in the presenting tumor and requires stereotactic surgery to place a catheter and Ommaya reservoir for delivery. Systemic therapy could more safely and more effectively treat children with ACP. However, progress has been hindered by the absence of in vitro or in vivo models of this tumor that would enable the unbiased screening of drug libraries. This study forms the basis for further studies with rational therapies for ACP. The recent development of ACP xenotransplants in immune deficient mice [24] will enable pre-clinical testing of these rationally selected targeted therapies, providing further rationale for small studies on efficacy in augmenting surgery and radiation or in treating recurrent ACP. These efforts, combined with further collaborations between centers and consortiums will provide the foundation for a randomized clinical trial using targeted agents to treat ACP in the near future.

 

Source:

http://doi.org/10.1186/s40478-015-0211-5