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Small-Molecule Inhibitors in Glioblastoma: Key Pathways and Resistance Mechanisms

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Resistance to Targeted Therapies Against Adult Brain Cancers

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

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Abstract

Glioblastoma, the most common and aggressive form of primary adult brain tumor, is a devastating disease with a dismal two-year survival. Attempts to improve patient survival include a variety of treatment options, from monoclonal antibodies, vaccines, and microbubbles to exosomes and small-molecule inhibitors, all of which are in various stages of preclinical and clinical development. The most frequently tested type of novel therapeutics are the small-molecule inhibitors targeting key signaling pathways dysregulated in GBM, including TP53, retinoblastoma, and the receptor tyrosine kinase-driven EGF, PDGF, and c-MET pathways. This chapter will compare preclinical and clinical results for a subset of inhibitors targeting the receptor tyrosine kinase families EGF, VEGF, and PDGF along with the PI3K/Akt/mTor pathway and cell cycle inhibitors. In the discussion, potential resistance mechanisms which continue to pose significant barriers to effective small-molecule inhibition treatment of GBM will be discussed along with possible improvements.

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Abbreviations

AG:

Anaplastic glioma

CDK:

Cyclin-dependent kinase

DSBs:

Double-stranded breaks

EGF:

Epidermal growth factor

ErbB:

Erythroblastic leukemia viral oncogene homolog

mTor:

Mammalian target of rapamycin

mTorc1-2:

Mammalian target of rapamycin complex 1 and 2

PDGF:

Platelet-derived growth factor

PFS:

Progression-free survival

PTEN:

Phosphatase and tensin homolog

RT:

Radiation therapy

RTK:

Receptor tyrosine kinase

TSC2:

Tuberous sclerosis 2

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Authors and Affiliations

  1. Department of Neurosurgery, Stanford University, 1201 Welch Rd, MSLS Building, Stanford, CA, 94305, USA

    Jenny L. Pokorny

  2. Department of Radiation Oncology, Mayo Clinic, 1st St SW, Guggenheim Building, Rochester, MN, 55905, USA

    Gaspar J. Kitange & Daniel J. Ma

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Correspondence to Jenny L. Pokorny .

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  1. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland

    Amanda Tivnan

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Pokorny, J.L., Kitange, G.J., Ma, D.J. (2016). Small-Molecule Inhibitors in Glioblastoma: Key Pathways and Resistance Mechanisms. In: Tivnan, A. (eds) Resistance to Targeted Therapies Against Adult Brain Cancers. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-46505-0_7

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