Neovascularization in
Glioblastoma: Current Pitfall in Anti-angiogenic therapy
Sanath Kumar, Ali S
Arbab
Sanath Kumar, Radiation Oncology, Henry Ford
Hospital, Detroit, MI-48202, the United
States
Ali
S Arbab, Cellular and Molecular Imaging
Laboratory, Radiology, Henry Ford Hospital, the
United States
Ali S Arbab, Radiology, Wayne State University School of
Medicine, Detroit, MI, the United States
Correspondence
to: Ali S. Arbab, MD, PhD, Senior Scientist and Director, Cellular
and Molecular Imaging Laboratory, Henry Ford Health System, 1 Ford Place, 2F,
Box ¨C 82, Detroit, MI 48202, the United States. saali@rad.hfh.edu
Tel: +01-313-874-4435
Fax: +01-313-874-4494
Received: May
2, 2013
Revised: May 12, 2013
Accepted: May 12, 2013
Published
online: August 18, 2013
ABSTRACT
Glioblastoma (GBM) is the most
common malignant primary brain tumor in adults. However, the survival of
patients with GBM has been dismal after multi-disciplinary treatment with
surgery, radiotherapy, and chemotherapy. In the efforts to improve clinical
outcome, anti-angiogenic therapy with bevacizumab (Avastin) was introduced to
inhibit vascular endothelial growth factor (VEGF) mediated tumor
neovascularization. Unfortunately, the results from clinical trials have not
lived up to the initial expectations. Patients either fail to respond to
anti-angiogenic therapy or develop resistance following an initial response.
The failure of anti-angiogenic therapy has led to a frustration among
physicians and research community. Recent evidence indicates that the dogma of
tumor neovascularization solely dependent on VEGF pathways to be overly
simplistic. A realistic model of tumor neovascularization should include
alternative pathways that are independent of VEGF signaling. A better
understanding of the underlying processes in tumor neovascularization would
help in designing successful anti-angiogenic treatment strategies.
©
2013 ACT. All rights reserved.
Key words: GBM;
VEGF; Neovascularization; Angiogenesis; Vasculogenesis; Vascular mimicry
Kumar S, Arbab AS. Neovascularization in
Glioblastoma: Current Pitfall in Anti-angiogenic therapy. Journal of tumor 2013; 1(3): 16-19
Available from: URL: http://www.ghrnet.org/index.php/jt
INTRODUCTION
Since the concept of angiogenesis-dependent tumor growth was first
proposed, improving tumor control with the use of anti-angiogenic (AA) therapy
was considered a potential treatment option. Various factors known to play a
role in tumor angiogenesis, such as vascular endothelial growth factor (VEGF), have
been identified in the past two decades, and different therapeutic targets have
been selected. However, results from clinical trials and laboratory experiments
have identified the emergence of resistance to AA therapy. Here we briefly
discuss the current state of AA therapies targeting VEGF, emerging alternative
pathways for neovascularization, and future directions for designing novel
therapeutic strategies.
VEGF DEPENDENT
NEOVASCULARIZATION
It has been more than four decades since the concept
of angiogenesis-dependent tumor growth was first proposed[1]. This
idea led to a belief that the use of AA therapy would improve tumor control.
Various factors known to play a role in tumor angiogenesis have been identified
in the past two decades[2]. VEGF has been the single most important
factor described in tumor angiogenesis to date[3]. The discovery of VEGF led to the
development of drugs that target VEGF dependent angiogenesis. One of the first
agents shown to block tumor growth in vivo against VEGF was a monoclonal
antibody, bevacizumab[4]. Currently, bevacizumab is being widely
used in patients with various types of cancers, including recurrent
glioblastoma (GBM)[5,6]. Unfortunately, no significant improvement
in overall survival (OS) has been noted with the use of bevacizumab monotherapy[7].
In addition to bevacizumab, multi-targeted VEGF receptor tyrosine kinase
inhibitors, such as cediranib, sorafenib, sunitinib, and vandetanib have been
tested in clinical trials, but without improvement in progression free survival
(PFS) or OS[7]. Many clinical trials have tested the efficacy of
sunitinib in patients with recurrent high-grade glioma with no objective
evidence of tumor control[8-10]. Similarly, vatalanib was shown to
have limited efficacy in the treatment of newly diagnosed GBM[11]. A
phase III clinical trial in patients with recurrent GBM showed no improvement
in PFS with the addition of cediranib alone, or in combination with
chemotherapy[12]. The failure of the drugs targeting the VEGF
pathway in the clinical setting has raised questions on the classical view of
tumor neovascularization solely based on angiogenesis.
RESISTANCE TO VEGF DEPENDENT
ANTI-ANGIOGENIC THERAPY AND ALTERNATIVE PATHWAYS OF NEOVASCULARIZATION
Although many patients experience an initial response to AA therapy, no
significant improvement in OS or PFS has been achieved clinically. In some
instance, patients do not show any response at all. The initial or acquired
resistance to VEGF based AA treatment, has been a frustrating clinical problem
in the management of GBM patients. One possible mechanism of resistance to VEGF
dependent AA therapy might be the activation of alternative angiogenesis signaling
pathways, such as the basic fibroblast growth factor (bFGF), Tie-2,
stromal-cell derived factor-1¦Á (SDF-1¦Á), and an increase in the invasiveness of
the tumor cells due to increased VEGF production[13-15]. Another
distinct mechanism of resistance might be due to vasculogenesis, where
endothelial progenitor cells (EPCs) and pro-angiogenic monocytes are recruited
to the tumor site from the bone marrow. AA therapy disturbs tumor vasculature,
which leads to tumor hypoxia. Hypoxia leads to up-regulation of
hypoxia-inducible factor 1-alpha (HIF-1¦Á), which in turn leads to the
up-regulation of SDF-1¦Á. SDF-1¦Á is a potent chemo-attractant for bone
marrow-derived EPCs, due to the presence of CXCR4 receptors in these cells[16,17].
Any treatment that recruits EPCs to the tumor site might promote
neovascularization and tumor growth. Thus, the use of VEGF inhibitory therapy
could paradoxically enhance an unwanted angiogenic and pro-growth response.
Activation of the SDF-1¦Á-CXCR4 pathway provides a mechanistic explanation for
the role of hypoxia in promoting resistance to anti-VEGF therapy. Our recent
work with rat orthotopic human glioma model showed a paradoxical increase in
the production of VEGF at the peripheral part of the tumors, as well as an
elevated expression of HIF-1¦Á and SDF-1 ¦Á, and a significant increase in the
number of dilated blood vessels in animals that underwent two weeks of PTK787
(small molecule tyrosine kinase inhibitor; vatalanib) treatment[18].
We also observed increased production of granulocyte colony stimulating factor
(G-CSF) in glioma treated with vatalanib. G-CSF is known to mobilize bone
marrow cells. We have also shown the involvement of bone marrow progenitor
cells in promoting GBM growth[19]. Other VEGF-independent mechanisms
of tumor neovascularization include vascular co-option, vascular mimicry, and
GBM endothelial cell trans-differentiation[20]. Vascular co-option
precedes tumor angiogenesis and involves infiltration of tumor cells around
pre-existing micro vessels[21]. Vascular mimicry is a process by
which GBM cells form functional vascular networks in the tumor[22].
Trans-differentiation of glioma stem cells into endothelial cells is another
mechanism of tumor neovascularization unaffected by VEGF signaling[23].
These processes may be responsible to a varied extent in reducing tumor
sensitivity to anti-VEGF drugs. Figure 1 shows a schematic of VEGF dependent
and VEGF-independent pathways in tumor neovascularization. Apart from treatment
resistance, the use of bevacizumab has been noted to enhance tumor invasiveness
and metastatic potential in patients with relapsed GBM[24]. Also,
VEGF inhibition has been shown to paradoxically increase co-option and
vasculogenesis[25,26].
THERAPEUTIC APPROACH BASED ON
ALTERNATIVE PATHWAYS OF NEOVASCULARIZATION
There has been a considerable effort in recent years to develop drugs
that target VEGF-independent angiogenesis. These include agents that target the
angiopoietin/Tie2 pathway, which is involved in vessel stability[27].
One such drug, AMG 386 (Trebanabnib), is currently being tested in a phase II
clinical trial for recurrent GBM[7]. Other agents such as
ramucirumab (monoclonal antibody targeting PDGF¦Á), XL184 (pan-tyrosine kinase
inhibitor), Tandutinib (inhibitor of type III receptor tyrosine kinases
including PDGFR-¦Â, FLT-3, and c-Kit), Aflibercept (VEGF-Trap), and many other
agents have been tested or are undergoing investigation in clinical trials[7,27].
Many of the clinical trials were stopped prematurely due to significant drug
related toxicity related to the drugs. To date, none of these agents have
demonstrated a survival benefit or gained FDA approval for clinical use.
CONCLUSION AND FUTURE
DIRECTIONS
In addition to VEGF based therapy, future improvements in AA therapy
for GBM should include modulating the various processes involved in tumor
neovascularization. This would entail a broad approach of using combination
agents to block multiple pathways.
One strategy would be to use drugs that block tumor invasion in
combination with AA agents to overcome treatment induced invasive phenotypes.
In addition, future efforts should be directed towards developing agents that
block VEGF-independent processes in tumor neovascularization. One such
mechanism could be to block SDF-1¦Á-CXCR4 signaling to prevent vasculogenesis.
AMD3100, a CXCR4 receptor antagonist, was initially developed as an anti-HIV
drug and later used to mobilize CD34+ hematopoietic stem cells to the
peripheral circulation[28]. Although AMD3100 increases the number of
peripheral CD34+ cells, recent investigations point towards inhibition of tumor
vasculogenesis following continuous treatment with AMD3100 or similar CXCR4
receptor antagonists[28,29]. On a physiological level, as hypoxia is
known to induce treatment resistance, efforts should be made to improve oxygen
saturation in the tumor microenvironment. The latest results from clinical
trials employing agents that target VEGF-independent pathways
(angiopoietin/Tie2 pathway) are eagerly awaited and could lead to a paradigm
shift in AA therapy of GBM.
ACKNOWLEDGMENT
This work is supported by NIH grants R01CA160216 and R01CA172048
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Peer reviewers: Jian-Yi Li,
MD, PhD, Assistant Professor and Co-Director of Neuropathology, Department of
Pathology and Lab Medicine, Director of Neuropathology at the Brain Tumor
Institute, North Shore-Long Island Jewish Health System, Hofstra North
Shore-LIJ School of Medicine, 6 Ohio Drive, Suite 202, Lake Success, NY 11042,
the United States; Kamalakannan Palanichamy, Assistant Professor, Department of
Radiation Oncology, Ohio State University James Cancer Center, 400 W, 12th
Avenue, Rm#385E, Wiseman Hall, Columbus, OH 43210, the United States.
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