April 2005, Vol. 12, No. 2116 Cancer Control
Appreciation is expressed to Sharon Reynolds, Department of Neuro-
logical Surgery, University of California, San Francisco, for editorial
Abbreviations used in this paper:
EGFR = epidermal growth factor receptor, PTEN = phosphatase and
tensin homolog, PI3K = phosphatidylinositol 3-kinase, PDGF = platelet-
derived growth factor,VEGF = vascular endothelial growth factor,MAPK
= mitogen-activated protein-kinase cascade,mAb = monoclonal antibody,
NABTC = North American Brain Tumor Consortium,TMZ = temozolo-
mide,EIAEDs = enzyme-inducing antiepileptic drugs.
GBM = glioblastoma multiforme,
Malignant gliomas are challenging to treat and are associ-
ated with a high degree of morbidity and mortality. Stan-
dard treatment usually consists of cytoreductive surgery
followed by radiation therapy. Based on several meta-
analyses,adjuvant chemotherapy appears to add some sur-
vival benefit, but its efficacy is limited.1-4
Small Molecule and Monoclonal Antibody
Therapies in Neurooncology
Nicholas Butowski, MD, and Susan M. Chang, MD
Background: The prognosis for most patients with primary brain tumors remains poor. Recent advances in molec-
ular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances
are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors.
Methods: We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain
tumor research and brain tumor clinical trials for the past 20 years.
Results: Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of
cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies
targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that
modulate these pathways and are in various stages of testing.
Conclusions: The use of targeted therapies against brain tumors promises to improve the prognosis for patients with
brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect
or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study
of these agents in well-designed cooperative clinical trials is needed.
New developments in
might improve the prognosis
for patients with brain tumors.
Pilgrims at the time of the lunar festival,Perfume Pagoda outside Hanoi,Vietnam.
Photograph courtesy of J.Bryan Murphy,MD,Clearwater,Florida.
From the Department of Neurological Surgery, Neuro-Oncology Ser-
vice, Department of Neurological Surgery, University of California,
San Francisco, California.
Submitted December 14, 2004; accepted February 8, 2005.
Address correspondence to Susan M. Chang, MD, Department of
Neurological Surgery University of California, San Francisco, 400
Parnassus Avenue, A808, San Francisco, CA 94143-0350. E-mail:
No significant relationship exists between the authors and the
companies/organizations whose products or services may be
referenced in this article.
April 2005, Vol. 12, No. 2Cancer Control 117
chemotherapy agents used to treat malignant glioma are
non-cell-cycle specific and aimed at inducing cell death.
Recent advances in molecular and cell biology have
expanded our understanding of the genetic and cellular
alterations that may lead to brain cancer.5For example,
the transformation into cancer may involve amplification
of oncogenes and/or loss of tumor suppressor genes. Such
advances in the knowledge of these genetic and cellular
alterations have been translated into new treatment agents
that “target” these alterations in cell-signaling pathways
and bring hope of improved prognosis for patients with
brain tumors. However,this hope comes with the caution
that new agents need to be studied in well-designed and
properly conducted clinical trials before efficacy can be
determined. This article reviews some of the molecular
abnormalities found in malignant glial tumors and the
related emerging molecularly targeted therapies.
We reviewed the literature on small molecule targeted
agents and monoclonal antibodies relevant to biologic path-
ways in gliomas that have been used in brain tumor
research and brain tumor clinical trials in the past 20 years.
The search included English-language electronic databases,
textbooks,specialty journals,proceedings,and Web sites of
the North American Brain Tumor Consortium and other
cooperative groups in Europe and the United States. We
focused on therapies that have had the largest discussion in
the literature or continue to be used in current phase I and
phase II studies. Additional reviews of targeted agents for
the treatment of brain tumors have been published.6-9
High-grade gliomas are the most common primary central
nervous system neoplasms in adults. They also continue to
be among the top 10 causes of cancer-related deaths
despite a relatively low incidence compared to other can-
Recent studies have demonstrated that glioblas-
toma multiforme (GBM;grade IV astrocytoma) commonly
expresses molecular or genetic abnormalities that influ-
ence the signal pathways that regulate cell proliferation.
For instance, a glioma cell may overexpress oncogenes
such as epidermal growth factor receptor (EGFR) or con-
tain mutations of tumor suppressor genes such as phos-
phatase and tensin homolog (PTEN).11Overexpression of
EGFR is the most common oncogenic alteration in GBM.
These gains or losses may promote cancerous behavior
but also may be targets for new treatments.
Primary GBMs develop de novo and usually occur in
older patients who do not have a prior history of lower-
grade astrocytoma. Primary GBMs generally overexpress
EGFR, a tyrosine kinase receptor with downstream effects
resulting in cell proliferation and invasion. Secondary GBMs
are thought to arise from lower-grade astrocytomas and typ-
ically occur in younger age groups.12,13These GBMs gener-
ally do not overexpress EGFR; instead,they commonly have
mutations in tumor suppressor gene p53.11,14
The role of EGFR is to mediate cell growth and pro-
liferation via activation of phosphatidylinositol 3-kinase
(PI3K).PI3K facilitates the phosphorylation of phos-
phatidylinositol-3,4-biphosphate (PIP2) to form phos-
antiapoptotic factors and promotes cell survival. PIP3 also
induces kinases to phosphorylate residues that activate
Akt,a protein that has antiapoptotic effects and is involved
in cell proliferation.15PTEN negatively regulates PIP3 by
dephosphorylating it back to PIP2. Therefore, the PTEN
gene product also indirectly regulates activation of Akt.
PTEN can be mutated in GBM and further predispose the
cells toward cancerous proliferation.16,17In fact,mutations
of PTEN are found in 45% of GBMs.16
The most common type of EGFR mutation is known
as EGFRvIII. This mutant receptor is constitutively active
and exists in a low-level state of autophosphorylation that
induces receptor signaling. It lacks an extracellular recep-
tor domain and cannot bind ligand. It is thus immune to
the down-regulation that would occur when ligand acti-
vates a normal receptor.18
Tumor suppressor gene p53 is responsible for cell-
cycle control, DNA repair after radiation damage, and
induction of apoptosis,and it is mutated in approximately
50% of cancers and in 30% of gliomas.19
tumor suppressor gene p53 results in decreased apoptosis
in response to DNA damage and predisposes the cell
toward neoplastic transformation.
Cell proliferation and
Simplified cell pathways. From left to right are the PI3-K, PLC, and RAS
pathways. EGF = epidermal growth factor, EGFR = epidermal growth fac-
tor receptor, VEGFR = vascular endothelial growth factor receptor, PDGFR
= platelet-derived growth factor receptor, PI3-K = phosphatidylinositol 3-
kinase, PLC = phospholipase C, PIP3 = phosphatidyl inositol-triphosphate,
PTEN = phosphatase and tensin homolog, PIP2 = phosphatidylinositol-3,4-
biphosphate, DAG = diacylglycerol, IP3 = inositol 1,4,5-triphosphate, PKC
= protein kinase C, MAPK = mitogen-activated protein kinase.
April 2005, Vol. 12, No. 2 124 Cancer Control
81. Marx GM, Pavlakis N, McCowatt S, et al. Phase II study of thalidomide
in the treatment of recurrent glioblastoma multiforme. J Neurooncol.
82. Chang SM, Lamborn KR, Malec M, et al. Phase II study of temozolo-
mide and thalidomide with radiation therapy for newly diagnosed glioblastoma
multiforme. Int J Radiat Oncol Biol Phys. 2004;60:353-357.
83. Fine HA, Kim L, Royce C, et al. A phase I trial of CC-5103, a potent
thalidomide analog, in patients with recurrent high-grade gliomas and other
refractory CNS malignancies. Proc Annu Meet Am Soc Clin Oncol. 2003;22:
105. Abstract 418.
84. Goldbrunner RH, Bendszus M, Wood J, et al. PTK787/ZK222584, an
inhibitor of vascular endothelial growth factor receptor tyrosine kinases,
decreases glioma growth and vascularization. Neurosurgery. 2004;55:426-432.
85. Yung WKA, Friedman H, Conrad C, et al. A phase I trial of single-agent
PTK 787/ZK 222584 (PTK/ZK), an oral VEGFR tyrosine kinase inhibitor, in
patients with recurrent glioblastoma multiforme. Proc Annu Meet Am Soc Clin
Oncol. 2003;22:99. Abstract 395.
86. Reardon D, Friedman HS, Yung WKA, et al. A phase I trial of single-
agent PTK 787/ZK 222584 (PTK/ZK), an oral VEGFR tyrosine kinase inhibitor,
in combination with either temozolomide or lomustine for patients with recurrent
glioblastoma multiforme (GBM). Proc Annu Meet Am Soc Clin Oncol. 2003;22:
103. Abstract 412.
87. Eskens FA, Dumez H, Hoekstra R, et al. Phase I and pharmacokinetic
study of continuous twice weekly intravenous administration of cilengitide (EMD
121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in
patients with advanced solid tumours. Eur J Cancer. 2003;39:917-926.
88. Smith JW. Cilengitide Merck. Curr Opin Investig Drugs. 2003;4:741-745.
89. MacDonald TJ, Taga T, Shimada H, et al. Preferential susceptibility of
brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist.
90. Phase I/II randomized study of cilengitide and radiotherapy in patients
with newly diagnosed glioblastoma multiforme. Available at: http://cancer.gov/
clinicaltrials/NABTT-0306. Accessed February 14, 2005.
91. Tonn JC, Kerkau S, Hanke A, et al. Effect of synthetic matrix-metallo-
proteinase inhibitors on invasive capacity and proliferation of human malignant
gliomas in vitro. Int J Cancer. 1999;80:764-772.
92. Groves MD, Puduvalli VK, Hess KR, et al. Phase II trial of temozolo-
mide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and
progressive glioblastoma multiforme. J Clin Oncol. 2002;20:1383-1388.
93. Larson DA, Prados M, Lamborn KR, et al. Phase II study of high cen-
tral dose Gamma Knife radiosurgery and marimastat in patients with recurrent
malignant glioma. Int J Radiat Oncol Biol Phys. 2002;54:1397-1404.
94. Tremont-Lukats IW, Gilbert MR. Advances in molecular therapies in
patients with brain tumors. Cancer Control. 2003;10:125-137.
95. Costa SL, Paillaud E, Fages C, et al. Effects of a novel synthetic
retinoid on malignant glioma in vitro: inhibition of cell proliferation, induction of
apoptosis and differentiation. Eur J Cancer. 2001;37:520-530.
96. Bouterfa H, Picht T, Kess D, et al. Retinoids inhibit human glioma cell
proliferation and migration in primary cell cultures but not in established cell
lines. Neurosurgery. 2000;46:419-430.
97. Malone C, Schiltz PM, Nayak SK, et al. Combination interferon-
alpha2a and 13-cis-retinoic acid enhances radiosensitization of human malig-
nant glioma cells in vitro. Clin Cancer Res. 1999;5:417-423.
98. Recchia F, Lalli A, Lombardo M, et al. Ifosfamide, cisplatin, and 13-cis
retinoic acid for patients with advanced or recurrent squamous cell carcinoma of
the head and neck: a phase I-II study. Cancer. 2001;92:814-821.
99. Recchia F, Sica G, Casucci D, et al. Advanced carcinoma of the pan-
creas: phase II study of combined chemotherapy, beta-interferon, and retinoids.
Am J Clin Oncol. 1998;21:275-278.
100. Phuphanich S, Scott C, Fischbach AJ, et al. All-trans-retinoic acid: a
phase II Radiation Therapy Oncology Group study (RTOG 91-13) in patients
with recurrent malignant astrocytoma. J Neurooncol. 1997;34:193-200.
101. Jaeckle KA, Hess KR, Yung WK, et al. Phase II evaluation of temo-
zolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive
malignant glioma: a North American Brain Tumor Consortium study. J Clin
102. Butowski N, Prados MD, Lamborn K, et al. A phase II study of concur-
rent temozolomide and cis-retinoic acid with radiation for adult patients with
newly diagnosed supratentorial glioblastoma. Int J Radiat Oncol Biol Phys. In
103. Puduvalli VK, Yung WK, Hess KR, et al. Phase II study of fenretinide
(NSC 374551) in adults with recurrent malignant gliomas: a North American
Brain Tumor Consortium study. J Clin Oncol. 2004;22:4282-4289.
104. Lang FF, Gilbert MR, Puduvalli VK, et al. Toward better early-phase
brain tumor clinical trials: a reappraisal of current methods and proposals for
future strategies. Neuro-oncol. 2002;4:268-277.