Journal Article

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma

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

2015

Overview

Introduction 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. Results 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. Conclusions 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.

• Publisher: BioMed Central,BioMed Central Ltd
• Subject: Adolescent / Amphiregulin / Analysis / Biomedical and Life Sciences / Biomedicine / Brain tumors / Care and treatment / Child / Child, Preschool / Craniopharyngioma - drug therapy / Craniopharyngioma - genetics / Craniopharyngioma - metabolism / Drug Delivery Systems - methods / EGF Family of Proteins - genetics / EGF Family of Proteins - metabolism / Female / Gene Expression / Genes / Genetic aspects / Health aspects / Humans / Infant / Infant, Newborn / Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics / Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism / Male / Medical research / Medicine, Experimental / Microarray Analysis - methods / Neurology / Neurosciences / Pathology / Pituitary gland tumors / Quality of Life - psychology / Radiotherapy / Receptor, EphA2 - genetics / Receptor, EphA2 - metabolism / Receptor, Epidermal Growth Factor - genetics / Receptor, Epidermal Growth Factor - metabolism / Receptor, ErbB-3 - genetics / Receptor, ErbB-3 - metabolism / RNA / RNA, Messenger - metabolism / src-Family Kinases - genetics / src-Family Kinases - metabolism / Up-Regulation