Targeting brain metastases in ALK-rearranged non-small-cell lung cancer

Isabella Zhang, Nicholas G. Zaorsky, Joshua D. Palmer, Ranee Mehra, Bo Lu

Research output: Contribution to journalReview article

Abstract

The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

Original languageEnglish (US)
Pages (from-to)e510-e521
JournalThe Lancet Oncology
Volume16
Issue number13
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Central Nervous System Diseases
Blood-Brain Barrier
Non-Small Cell Lung Carcinoma
Neoplasm Metastasis
Tumor Microenvironment
Brain
Drug Resistance
Antineoplastic Agents
Permeability
Radiotherapy
Phosphorylation
Clinical Trials
Incidence
Research
Genes
Therapeutics
crizotinib

ASJC Scopus subject areas

  • Oncology

Cite this

Zhang, I., Zaorsky, N. G., Palmer, J. D., Mehra, R., & Lu, B. (2015). Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. The Lancet Oncology, 16(13), e510-e521. https://doi.org/10.1016/S1470-2045(15)00013-3

Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. / Zhang, Isabella; Zaorsky, Nicholas G.; Palmer, Joshua D.; Mehra, Ranee; Lu, Bo.

In: The Lancet Oncology, Vol. 16, No. 13, 2015, p. e510-e521.

Research output: Contribution to journalReview article

Zhang, I, Zaorsky, NG, Palmer, JD, Mehra, R & Lu, B 2015, 'Targeting brain metastases in ALK-rearranged non-small-cell lung cancer', The Lancet Oncology, vol. 16, no. 13, pp. e510-e521. https://doi.org/10.1016/S1470-2045(15)00013-3
Zhang, Isabella ; Zaorsky, Nicholas G. ; Palmer, Joshua D. ; Mehra, Ranee ; Lu, Bo. / Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. In: The Lancet Oncology. 2015 ; Vol. 16, No. 13. pp. e510-e521.
@article{f65f1b45d26a4e03bd5181c0ca0947f4,
title = "Targeting brain metastases in ALK-rearranged non-small-cell lung cancer",
abstract = "The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.",
author = "Isabella Zhang and Zaorsky, {Nicholas G.} and Palmer, {Joshua D.} and Ranee Mehra and Bo Lu",
year = "2015",
doi = "10.1016/S1470-2045(15)00013-3",
language = "English (US)",
volume = "16",
pages = "e510--e521",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "13",

}

TY - JOUR

T1 - Targeting brain metastases in ALK-rearranged non-small-cell lung cancer

AU - Zhang, Isabella

AU - Zaorsky, Nicholas G.

AU - Palmer, Joshua D.

AU - Mehra, Ranee

AU - Lu, Bo

PY - 2015

Y1 - 2015

N2 - The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

AB - The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

UR - http://www.scopus.com/inward/record.url?scp=84953874716&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953874716&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(15)00013-3

DO - 10.1016/S1470-2045(15)00013-3

M3 - Review article

C2 - 26433824

AN - SCOPUS:84953874716

VL - 16

SP - e510-e521

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 13

ER -