Pathway inhibition: emerging molecular targets for treating glioblastoma

Wolfgang Wick

Michael Weller

Markus Weiler

Tracy Batchelor

Alfred Yung

Michael Platten

Department Neurooncology, National Center for Tumor Disease Heidelberg, University Clinic Heidelberg, Heidelberg, Germany (W.W., Ma.W., M.P.); Department of Neurology, University Hospital Zürich, Zürich, Switzerland (Mi.W.); Stephen E. and Catherine Pappas Center for Neuro-Oncology,, Boston, Massachusetts (T.B.); Department of Neuro-Oncology, Margaret and Ben Love Chair in Clinical Cancer Care, The University of Texas MD Anderson Cancer Center,, Houston,, Texas (A.W.K.Y.)

Corresponding Author: Wolfgang Wick, MD, Department of Neurooncology, National Center of Tumor Disease, University Clinic Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany (ed.grebledieh-inu.dem@kciw.gnagflow).

Received 2010 Nov 18; Accepted 2011 Feb 28.

Abstract

Insights into the molecular pathogenesis of glioblastoma have not yet resulted in relevant clinical improvement. With standard therapy, which consists of surgical resection with concomitant temozolomide in addition to radiotherapy followed by adjuvant temozolomide, the median duration of survival is 12–14 months. Therefore, the identification of novel molecular targets and inhibitory agents has become a focus of research for glioblastoma treatment. Recent results of bevacizumab may represent a proof of principle that treatment with targeted agents can result in clinical benefits for patients with glioblastoma. This review discusses limitations in the existing therapy for glioblastoma and provides an overview of current efforts to identify molecular targets using large-scale screening of glioblastoma cell lines and tumor samples. We discuss preclinical and clinical data for several novel molecular targets, including growth factor receptors, phosphatidylinositol-3 kinase, SRC-family kinases, integrins, and CD95 ligand and agents that inhibit these targets, including erlotinib, enzastaurin, dasatinib, sorafenib, cilengitide, AMG102, and APG101. By combining advances in tumor screening with novel targeted therapies, it is hoped that new treatment options will emerge for this challenging tumor type.

Keywords: integrins, PI3 kinase, receptor tyrosine kinase, SRC-family kinases, VEGF signaling

Abstract

Glioblastoma is the most common primary central nervous system tumor, accounting for ∼60% of the 17, 000 primary brain tumors diagnosed annually in the United States.¹ Patients who receive a diagnosis of glioblastoma have a dismal prognosis, typically dying within 3 months if untreated. Standard treatment increases median survival to 12 months, although disease tends to progress within 6–9 months and the 2-year survival rate is <25%.² In this review, we discuss the limitations of existing therapies for glioblastoma before summarizing ongoing efforts to identify novel molecular targets and develop novel targeted agents for this disease.

CCNU indicates lomustine; CML indicates chronic myeloid leukemia; CRC indicates colorectal carcinoma; EGFR indicates epidermal growth factor receptor; GBM indicates glioblastoma multiforme; HCC indicates hepatocellular carcinoma; HDAC indicates histone deacetylase; HER2 indicates human epidermal growth factor receptor 2; HNSCC indicates head and neck squamous cell carcinoma; MAPK indicates mitogen-activated protein kinase signaling; MBC indicates metastatic breast cancer; NSCLC indicates nonsmall cell lung carcinoma; PDGFR indicates platelet-derived growth factor receptor; Ph+ ALL indicates Philadelphia chromosome-positive acute lymphoblastic leukemia; PI3K indicates phosphatidylinositol 3-kinase; PKC indicates protein kinase C; RCC indicates renal cell carcinoma; RT indicates radiotherapy; TMZ indicates temozolomide; and VEGFR indicates vascular endothelial growth factor receptor.

AG indicates anaplastic glioma; BID indicates twice daily; CCNU indicates lomustine; CI indicates confidence interval; cPR indicates confirmed partial response; CR indicates complete response; GI indicates gastrointestinal; DLT indicates dose-limiting toxicities; EGFR indicates epidermal growth factor receptor; GBM indicates glioblastoma multiforme; MG indicates malignant glioma; MGMT indicates methyl guanine methyltransferase; MTD indicates maximum tolerated dose; NA indicates not available; NR indicates not recorded; OR indicates objective response; OS indicates overall survival; ph indicates phase; PD indicates progressive disease; PFS indicates progression-free survival; PR indicates partial response; PTEN indicates phosphatase and tensin homolog; RT indicates radiotherapy; SD indicates stable disease; and TMZ indicates temozolomide.

CCNU indicates lomustine; DLT indicates dose-limiting toxicities; MTD indicates maximum tolerated dose; NA indicates not available; OS indicates overall survival; PFS indicates progression-free survival; PK indicates pharmacokinetics; RT indicates radiotherapy; and TMZ indicates temozolomide.

Acknowledgments

We take full responsibility for the content of this publication and confirm that it reflects our viewpoints and medical expertise.

Conflict of interest statement. W.W. has received research grants from Apogenix and Eli Lily for projects unrelated to the current manuscript; has acted as an advisor for Roche/Genentech, Eli Lilly, Schering-Plough/MSD, BMS, Antisense Pharma, and Noxxon Pharmaceutics; and has received honoraria from the speakers' bureaus of Roche/Genentech, Schering-Plough/MSD and Wyeth/Pfizer. M. Weller has served on advisory boards for Astra Zeneca, Bayer Schering, BMS, MSD, Merck Serono, Miltenyi Biotech, Roche/Genentech, and Schering-Plough; has received speakers honoraria from Merck Serono and Schering-Plough; and has received unrestricted research funding from Merck Serono and MSD for projects unrelated to the current manuscript. T.B. has served as a paid consultant for Schering-Plough/MSD and Genentech/Roche and has received grant or research support from Millenium, Astra Zeneca, and Schering-Plough. A.W.K.Y. has served as a paid consultant for Eden; has received honoraria from the speakers' bureaus of Schering-Plough/MSD, Merck, and Genentech; has played an advisory role for Genentech, Merck, Novartis, Eli Lilly, and Antisense Pharma; and has received research support from Novartis for projects unrelated to the topic of the manuscript. M.P.: has served on the advisory board for Miltenyi Biotech; has received speakers honoraria from Merck Serono, Sigma Tau Pharmaceuticals, and Miltenyi Biotech; and has received unrestricted research funding from Merck Serono and Nuon Therapeutics for projects unrelated to the current manuscript. M. Weiler has no conflict of interest.

Acknowledgments

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