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Brainstem Tumors pp 347–392Cite as

Future Therapies for Malignant Brainstem Tumors

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Abstract

Malignant brainstem tumors are a heterogenous group of tumors, where diffuse intrinsic pontine glioma (DIPG) is the most common type. Because of the infiltrative nature of the tumor and the structure of the brainstem, surgical resection is not a therapeutic option for DIPG. Radiation therapy is the current standard of care for this tumor but is only palliative. Conventional chemotherapy has not shown efficacy. Obstacles in achieving effective nonsurgical treatment in this tumor include, but are not limited to, the relatively intact blood-brain barrier, the drug efflux transporters, and the immune privilege and specialization.

Emerging therapies for DIPG include therapeutic agents targeting recently discovered genetic and epigenetic aberrations, drug delivery methods to address the relatively intact blood-brain barrier and drug efflux transporters, antibody- and cell-based immunotherapies, and oncolytic viruses. Some of these therapies are being evaluated in clinical studies, and some results were recently reported. Convection-enhanced delivery (CED) is one of the drug delivery methods; when used to deliver a radiolabeled antibody, CED showed good safety data and potential therapeutic efficacy. In some therapeutic vaccine trials in DIPG patients, immune responses were detected against glioma-associated antigens, and some patients had prolonged survival. Adoptive cell therapies and oncolytic virus therapies for DIPG are also under development. Despite the challenges in treating DIPG, these emerging therapies will likely improve the outcomes of the disease.

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Abbreviations

AA:

Anaplastic astrocytoma

ABC:

ATP-binding cassette

ABCG:

ATP-binding cassette, subfamily G

ACVR1:

Activin A receptor, type I

Ad5:

Adenovirus serotype 5

ADC:

Antibody-drug conjugate

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ALA:

5-aminolevulinic acid

AlPcS2a:

Aluminum phthalocyanine disulfonate

AML:

Acute myeloid leukemia

ATRT:

Atypical teratoid rhabdoid tumor

ATRX:

Alpha thalassemia/mental retardation syndrome X-linked

BBB:

Blood-brain barrier

BMPs:

Bone morphogenic proteins

CARs:

Chimeric antigen receptors

CAR-T:

Chimeric antigen receptor T-cell

CBTRUS:

Central Brain Tumor Registry of the United States

CDC:

Complement-dependent cytotoxicity

CED:

Convection-enhanced delivery

CMV:

Cytomegalovirus

CNS:

Central nervous system

CPT-11:

Camptothecin-11

CSF:

Cerebrospinal fluid

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

CYP450s:

Cytochromes P450

DIPG:

Diffuse intrinsic pontine glioma

DNA:

Deoxyribonucleic acid

DT:

Diphtheria toxin

EGFR:

Epidermal growth factor receptors

EGFRvIII:

EGFR variant III

ETANTR:

Embryonal tumor with abundant neuropil and true rosettes

ETX:

Epsilon toxin, active form

ETXp:

Epsilon prototoxin

EZH2:

Enhancer of zeste homolog 2

FUS:

Focused ultrasound

G34R:

Glycine-to-arginine missense at position 34

GBM:

Glioblastoma multiforme

Gd-DTPA:

Gadolinium-diethylenetriamine penta-acetic acid

HDACi:

Histone deacetylase inhibitor

HER2:

Human epidermal growth factor receptor 2

HGG:

High-grade glioma

HLA:

Human leukocyte antigen

HSV:

Herpes simplex virus

ICOS:

Inducible costimulator

IDH:

Isocitrate dehydrogenase

IDO1:

Indoleamine 2,3-dioxygensase 1

IFN:

Interferon

K27M:

Lysine-to-methionine missense at position 27

LAG-3:

Lymphocyte activation gene 3

LDLR:

Low-density lipoproteins receptor

LRPs:

LDLR-related proteins

MDR:

Multidrug resistance

MHC:

Major histocompatibility complex

MRI:

Magnetic resonance imaging

MRP:

Multidrug-resistance-associated protein

NK:

Natural killer

PCI:

Photochemical internalization

PD-1:

Programmed death-1

PDGFR:

Platelet-derived growth factor receptors

PDT:

Photodynamic therapy

PE:

Pseudomonas exotoxin

PET:

Positron emission tomography

P-gp:

P-glycoprotein

PNET:

Primitive neuroectodermal tumor

PRC2:

Polycomb repressive complex 2

PTEN:

Phosphatase and tensin homolog

RNA:

Ribonucleic acid

RTKs:

Receptor tyrosine kinases

scFv:

Single-chain variable fragment

SPECT:

Single photon emission computed tomography

TCRs:

T-cell receptors

Tf:

Transferrin

TGF-β1:

Transforming growth factor β1

TIL:

Tumor-infiltrating lymphocyte

TIM-3:

T-cell immunoglobulin and mucin domain-containing 3

TK:

Thymidine kinase

Treg:

Regulatory T cell

TTRNA-DC:

Total tumor mRNA-pulsed autologous dendritic cell

VEGF:

Vascular endothelial growth factors

WHO:

World Health Organization

α:

Alpha

β:

Beta

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Acknowledgments

The authors would like to thank David J. Pisapia, MD, for providing histology and immunohistochemistry photographs of DIPG.

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Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Zhiping Zhou

  2. Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, USA

    Mark M. Souweidane

  3. Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA

    Mark M. Souweidane

  4. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Mark M. Souweidane

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  1. Zhiping Zhou
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Editors and Affiliations

  1. Department of Neurosurgery, Institute for Brain Protection Sciences, Johns Hopkins University School of Medicine, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA

    George I. Jallo

  2. Department of Neurosurgery, Institute for Brain Protection Sciences, Johns Hopkins University School of Medicine, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA

    Mohammad Hassan A. Noureldine

  3. Institute of Neuroscience, Geisinger Medical Center, Geisinger Commonwealth School of Medicine, Danville, PA, USA

    Nir Shimony

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Zhou, Z., Souweidane, M.M. (2020). Future Therapies for Malignant Brainstem Tumors. In: Jallo, G., Noureldine, M., Shimony, N. (eds) Brainstem Tumors. Springer, Cham. https://doi.org/10.1007/978-3-030-38774-7_15

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