Dataset Information

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB).

ABSTRACT: Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.

SUBMITTER: Bailey AW

PROVIDER: S-EPMC6315664 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB).

Bailey Anders W AW Suri Amreena A Chou Pauline M PM Pundy Tatiana T Gadd Samantha S Raimondi Stacey L SL Tomita Tadanori T Sredni Simone Treiger ST

Bioengineering (Basel, Switzerland) 20181104 4

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated <i>PLK4</i> expression in NBs of the CNS (CNS-NB) and validated our findings by performing ...[more]

PMID: 30400339

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Project description:The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å(2) (25-60 Å(2)), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740-970 Å(3), (vi) solvent accessible surface area of 460-580 Å(2), and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The chemoinformatics approaches for graphically analyzing multiple properties efficiently are presented.

Project description:Abstract BACKGROUND: While immunotherapy has revolutionized the treatment for several solid tumors, pseudoprogression, radiographically defined as the initial increase in tumor volume followed by tumor shrinkage, is less clearly defined. This is particularly noteworthy for patients with central nervous system metastases, commonly seen in patients with advanced melanoma or non-small cell lung cancer treated with PD-1 or CTLA-4 inhibitors. B7-H3 (CD276) is a transmembrane protein belonging to the B7 family of costimulatory molecules. 1 Several solid tumors overexpress B7-H3, and expression appears to be closely associated with immune escape, tumor cell invasion and metastases. The incidence of pseudoprogression after B7-H3 therapy is unknown. METHOD: A 4 year old girl with central nervous system metastases of neuroblastoma underwent resection of 2 left parietal lobe lesions, the largest 1.4 cm with edema, enhancement and restricted diffusion, followed by craniospinal radiation therapy, irinotecan, temozolomide, inducing a second remission with expected MR appearance in the operative cavity. She was then registered to clinicaltrials.gov (NCT00089245) with intraventricular 131-I-anti B7-H3. One month after therapy, routine MR revealed increased nodular enhancement around both operative cavities with adjacent leptomeningeal enhancement, concerning for progressive neuroblastoma. The patient remained asymptomatic. RESULTS: A repeat brain performed 2 weeks later showed interval resolution of both the operative cavity and leptomeningeal enhancement and edema. Repeat brain and spine MR performed 6 months later shows continued remission with complete resolution of all enhancement and edema. RESULTS: Anti- B7-H3 therapy caused an immediate inflammatory reaction with spontaneous radiographic resolution and return to baseline 2 weeks later, all in the absence of concurrent steroid administration. CONCLUSION: Though the precise frequency and timeline is unclear, B7-H3 directed therapy may be added to the list of immunotherapeutic agents recognized to cause pseudoprogression. Key efforts are now being made to correlate the appearance of CNS neuroblastoma pseudoprogression with overall survival.

Dataset Information

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB).

Publications

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB).

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