Precision Medicine in Pediatric Neurooncology: A Review

Abstract

Central nervous system tumors are the leading cause of cancer related death in children. Despite much progress in the field of pediatric neurooncology, modern combination treatment regimens often result in significant late effects, such as neurocognitive deficits, endocrine dysfunction, secondary malignancies, and a host of other chronic health problems. Precision medicine strategies applied to pediatric neurooncology target specific characteristics of individual patients' tumors to achieve maximal killing of neoplastic cells while minimizing unwanted adverse effects. Here, we review emerging trends and the current literature that have guided the development of new molecularly based classification schemas, promising diagnostic techniques, targeted therapies, and delivery platforms for the treatment of pediatric central nervous system tumors.

Keywords: Precision medicine; neurooncology; pediatrics; review.

Figure 1.

(a) Incidence of pediatric (age 0–19) central nervous system (CNS) tumors by histological subtype. Of the three main categories, gliomas are the most common (53.1% of diagnoses), followed by embryonal tumors (13.8%) ependymal tumors (5.8%). (b) Average annual age-adjusted mortality rate of all primary brain and CNS tumors in comparison to other common cancers for children age 0–14 years. Reprinted from ref by permission of Oxford University Press, Copyright 2016.

Figure 2.

(a) In Seq-Well, cells are obtained from complex tissues or clinical biopsies, and digested to form a single-cell suspension. Barcoded mRNA capture beads are added to the surface of a microwell device, settling into wells by gravity, and then a single-cell suspension is applied. The device is sealed using a semipermeable membrane that confines cellular mRNAs within wells while allowing efficient buffer exchange. Liberated cellular transcripts hybridize to the bead-bound barcoded poly deoxythymine (dT) primers that contain a cell barcode and a unique molecular identifier (UMI) for each transcript molecule. After hybridization, the beads are removed from the array and bulk reverse transcription is performed to generate single-cell cDNAs attached to beads. Libraries are then made by a combination of polymerase chain reaction (PCR) and tagmentation, and then are sequenced. Afterward, single-cell transcriptomes are assembled in silico using the cell barcodes and UMIs. (b) Equipment and arrays used to capture and lyse cells, respectively, in Seq-Well. Scale bar = 100 µm. (c) Sequencing mix of human and mouse cells demonstrates distinct transcript mapping and single-cell resolution. (d) Number of trancsripts and (e) genes detected in single-cell libraries generated by Seq-Well or Drop-seq. (f) Representative single-cell RNA-seq of cancer and noncancer cells in six oligodendrogliomas. On the left, copy number variant profiles inferred from single-cell RNA-seq and DNA whole-exome sequencing of the six oligodendrogliomas. On the right, analysis of copy number variants identified two subclones of cells in tumors identified as MGH36 and MGH97. Panels (a)–(e) reprinted from ref by permission from Macmillan Pubishers Ltd.: Nature Methods, Copyright 2017. Panel (f) reprinted from ref by permission from Macmillan Publishers Ltd.: Nature, Copyright 2016.

Figure 3.

Tumor and serum microRNA-720 expression in individual glioblastoma multiforme (GBM) patients. PCR-based microRNA microarrays and real-time qPCR were performed in triplicate on complementary DNA amplicons created from RNA extracted from each GBM tumor specimen and intraoperative serum sample using a human serum albumin-microRNA-720 probe. Blue bars indicate mean tumor microRNA-720 fold-change expression, red bars indicate mean serum microRNA-720 fold-change expression. Asterisk (*) denotes >35-fold higher expression than the normative standard. Figure courtesy of A. C. Wang, preliminary data.

Figure 4.

(a) Illustration of helical tomotherapy as an intensity-modulated radiation therapy device where a linear accelerator continuously revolves around the patient, while slowly advancing the patient through the plane of rotation. For radiation therapy dose delivery, a collimator is used to allow only sections of the fan beam to reach the patient. The collimator pattern changes as a function of gantry position, which provides many degrees of freedom to deliver highly conformal dose distributions. (b) Representative dose volume histograms comparing conventional three-dimensional conformal radiotherapy (dashed line) versus intensity-modulated radiotherapy (solid line) plans for a patient with a left parietal lobe tumor. Note the dose reduction for uninvolved parts of the brain. (c) Comparison of dose distribution using a proton beam. Note that ionization increases as the proton beam enters the patient, reaches intended dose at the tumor, then declines as velocity decreases. (d) Comparison of a photon- and a proton-based radiation therapy plan for a pediatric patient with a supratentorial ependymoma. Representative axial, coronal, and sagittal slices are shown for each plan. Approximate percentage isodoses are shown for reference in the axial slices. PTV: planning target volume. Brain, GTV: total brain without gross tumor volume. External, PTV: total tissue volume without planning target volume. IMRT: intensity-modulated radiotherapy. Panel (b) is reprinted from ref with permission from Elsevier, Copyright 2007. Panel (c) is reprinted from ref with permission from Taylor & Francis Ltd., http://www.tandfonline.com, Copyright 2010. Panel (d) is reprinted from ref by permission from Taylor & Francis Ltd., http://www.tandfonline.com on behalf of Acta Oncologica Foundation, Copyright 2013.

Figure 5.

(a) Schematic illustrating the design of a dual-targeted gold nanoparticle (AuNP) system used to target glioblastoma (GBM) cells. The particles are functionalized with multiple receptor binding peptides to address intratumoral heterogeneity of GBM populations and the photosentizer phthalocyanine 4. (b) Transmission electron microscope image of hydrophobic gold nanoparticles used to prepare dual-targeted AuNPs. Scale bar = 100 nm. (c) Schematic illustrating nanoparticle targeting of U-251 glioblastoma cells. Localization of the gadolinium-tagged nanoparticles to glioblastoma cells implanted into mouse models is monitored via magnetic resonance imaging. Panels (a) and (b) reprinted with permission from ref . Copyright 2015 American Chemical Society. Panel (c) reprinted with permission from ref . Copyright 2015 American Chemical Society.