Dataset Information

RARE-10. ADAMANTINOMATOUS CRANIOPHARYNGIOMA RESIDES OUTSIDE THE BLOOD BRAIN BARRIER

ABSTRACT: Abstract

BACKGROUND

Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. Genetically engineered mouse models of ACP demonstrate that perturbation of the fetal anterior pituitary can generate tumors analogous to ACP. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control, with the most common agent being the humanized monoclonal antibody, tocilizumab. This agent demonstrated poor blood-brain barrier (BBB) penetration in primates. We present findings from two children enrolled on a phase 0 clinical trial (NCT03970226) of a single dose of preoperative intravenous tocilizumab prior to resection of newly diagnosed ACP.

METHODS

Blood samples were obtained at multiple timepoints. Serum was isolated via ficoll separation. Tumor tissue and cyst fluid were obtained 4–6 hours following the single IV dose of tocilizumab. Tissue was snap-frozen. Tumor was homogenized in RIPA buffer. Free tocilizumab in serum, cyst fluid, and tumor tissue was measured using enzyme-linked immunosorbent assay (ELISA) against a standard curve.

RESULTS

Both patients in this trial demonstrated clinically relevant levels of tocilizumab (? 4µg/mL) in serum, cyst fluid, and tumor tissue, compared to undetectable levels in control samples.

CONCLUSION

ACP resides outside BBB protection. In addition to demonstrating the feasibility of systemic delivery of tocilizumab, these findings indicate that other large molecules, including those known to have poor BBB penetration, may be systemically delivered as part of an antitumor regimen in the treatment of ACP.

SUBMITTER: Prince E

PROVIDER: S-EPMC7715731 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Project description:Purpose:Several recent studies have documented CTNNB1 and BRAF mutations which are mutually exclusive for adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) tumors. This discovery is helpful in the development of novel targeted therapies in successful clinical trials with BRAF mutations in PCP cases. However, no such targeted therapy is available yet for ACP. Here, we report novel mutations, which are not previously reported, in a case of an adult ACP using NGS analysis. Results:Patient DNA was sequenced using Ion PI v3 chip on Ion Proton. A total of 16 variants were identified in this tumor by NGS analysis, out of which four were missense mutations, seven were synonymous mutations, and five were intronic variants. In CTNNB1 gene a known missense mutation in c.101G>T; in TP53 a known missense mutation in c.215C>G; and two known missense variants in PIK3CA, viz., in c.1173A>G; in exon 7, and in c.3128T>C; in exon 21, were found, respectively. Seven synonymous mutations were detected in this tumor, viz., in IDH1 (rs11554137), in FGFR3 (rs7688609), in PDGFRA (rs1873778), in APC (COSM3760869), in EGFR (rs1050171), in MET (rs35775721), and in RET (rs1800861), respectively. Three known, intronic variants were found in genes, such as PIK3CA, KDR, and JAK3, respectively. Also, a 3'-UTR and a splice site acceptor site variant in CSF1R and FLT3 genes were found in this tumor. We have shown allele coverage, allele ratio, and p-value, for all these mutations. The p-values and Phred quality score were significantly high for these variants. Conclusion:As reported in previous studies, in ACP tumors we found a CTNNB1 mutation by NGS analysis. The PIK3CA variants we detected were not known previously in ACP tumors. Finding the PIK3CA mutations in the ACP tumors may help develop targeted therapy for a subset of craniopharyngiomas with PIK3CA activating mutations. Clinical trials are in progress with specific PIK3CA inhibitors in advanced stages of many cancers.

Project description:Although histologically benign, adamantinomatous craniopharyngioma (AC) pediatric brain tumor is a locally aggressive disease that frequently determines symptoms and hormonal dysfunctions related to the mass effect on the surrounding structures. Another typical feature of this benign neoplasm is the presence of voluminous liquid cysts frequently associated with the solid component. Even if studies have been devoted to the proteomic characterization of the tumor intracystic fluid, poor explorations have been performed on its solid part, principally investigated by transcriptomics technologies. In the present study, seven specimens of AC whole tumor tissue have been analyzed by LC-MS for a preliminary assessment of the proteomic profile by a top-down/bottom-up integrated approach. Thymosin beta 4, ubiquitin, calmodulin, S100 proteins, prothymosin α isoform 2, alpha-defensins 1-4, and fragments largely belonging to vimentin, hemoglobin, and glial fibrillary acidic protein characterized the intact proteome. The identification of alpha-defensins, formerly characterized in AC intracystic fluid, reinforces the hypothesis of a role for inflammation in tumor pathogenesis. A total number of 1798 unique elements were identified by a bottom-up approach with a special focus on the 433 proteins commonly characterized in the 85.7% of the samples analyzed. Their gene ontology classification evidenced the involvement of the adherence system, intermediate filaments, and actin cytoskeleton in tumor pathogenesis and of elements part of the Wnt, FGF, and EGFR signaling pathways. In addition, proteins involved in calcium modulation, innate immunity, inflammation, CCKR and integrin signaling, and gonadotropin-releasing hormone receptor pathways were also outlined. Further than confirming proteomic data previously obtained on AC intracystic fluid, these results offer a preliminary overview of the AC whole tissue protein phenotype, adding new hints towards the comprehension of this still obscure pediatric brain tumor.