Page 14 - Read Online

multi-target kinase inhibitors and combinations of CONCLUSION
single-targeted kinase inhibitors that simultaneously
affect multiple pathways such as signaling, repair, and Based on the information provided above, we propose
angiogenesis have been tested in clinical trials for their an experimental study that will apply a strategy for
ability to effectively prolong the median survival time peptide-mediated delivery of compounds deep into
of patients and to establish future directions in GBM tumor parenchyma using tumor-homing peptides.
therapy. Overall, the identification of new targeted Selected tyrosine kinase inhibitors such as imatinib
strategies for GBMs remains a very challenging area in will be coupled to tumor-specific homing peptides and
the field, since it has the potential to positively affect will be used for the treatment of various GBM cell lines.
patient outcome, survival rate, and quality of life. Such targeted delivery of the antitumor agent can result
in higher drug concentrations in tumors, increasing
Preclinical, as well as clinical studies with various drug efficacy and reducing peripheral toxicity, thus
integrin antagonists, have demonstrated their overcoming the chemo-resistance of cancer cells, which
effectiveness in blocking tumor progression. Phase is usually mediated by membrane transporters. This
II clinical trials with cilengitide (Merck KGaA, initiative is expected to result in new drug candidates by
Darmstadt, Germany), an α β and α β integrin obtaining reliable data on the molecular pathogenesis
v
5
3
v
antagonists, have shown clinical activity and few side of GBMs and molecular-targeted treatment options for
effects in patients with glioblastoma. [17] Cilengitide GBMs. The development of drug candidates involving
is a synthetic Arg-Gly-Asp (RGD) pentapeptide a delivery system based on previous knowledge and
recognizing the RGD ligand binding motif on the targeting intracellular pathways would facilitate the
integrin receptors α β and α β [18] and competitively identification of more effective treatment options,
ν 3
ν 5
blocks integrin ligand binding. It has been shown to thereby positively affecting the outcome, survival rate,
diminish angiogenesis in vitro. [19] In an important early and quality of life in patients with GBM.
preclinical study, cilengitide markedly suppressed
tumor growth in amedulloblastoma and orthotopic REFERENCES
glioblastoma models (i.e., when tumors were grown
in the brain), whereas no growth inhibition was 1. Sathornsumetee S, Reardon DA. Targeting multiple kinases
demonstrated in a heterotopic model (i.e., when in glioblastoma multiforme. Expert Opin Investig Drugs
tumors were grown in the flank of nude mice) or 2. 2009;18:277‑92.
Argyriou AA, Antonacopoulou A, Iconomou G, Kalofonos HP.
when an inactive peptide was used. [20] This suggests Treatment options for malignant gliomas, emphasizing towards
that the brain environment is particularly susceptible new molecularly targeted therapies. Crit Rev Oncol Hematol
to the integrin inhibition and has led to subsequent 2009;69:199‑210.
clinical investigation. [21] 3. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN,
Cavenee WK, DePinho RA. Malignant glioma: genetics and biology
of a grave matter. Genes Dev 2001;15:1311‑33.
In addition, a new variant of RGD (internalizing RGD, 4. Noda SE, El‑Jawahri A, Patel D, Lautenschlaeger T, Siedow M,
iRGD) that combines the RGD motif with a tissue Chakravarti A. Molecular advances of brain tumors in radiation
penetration element called C-end rule (CendR) has been oncology. Semin Radiat Oncol 2009;19:171‑8.
recently presented. [22] Like the earlier RGD peptides, 5. Argyriou AA, Kalofonos HP. Molecularly targeted therapies for
malignant gliomas. Mol Med 2009;15:115‑22.
iRGD homes to tumors, but exposure of the CendR 6. Behin A, Hoang‑Xuan K, Carpentier AF, Delattre JY. Primary brain
motif activates a transport system through tumor tumours in adults. Lancet 2003;361:323‑31.
blood vessel walls into the tumor core. Interestingly, 7. Yeung YT, McDonald KL, Grewal T, Munoz L. Interleukins in
it was shown that coupling of iRGD to anti-cancer glioblastoma pathophysiology: implications for therapy. Br J
Pharmacol 2013;168:591‑606.
drugs allowed them to penetrate deeply into tumors, 8. Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic
effectively increasing the activity of the drugs. [22] indicator for patients with astroglial brain tumors. Cancer
More specifically, intravenously injected compounds 1996;77:362‑72.
coupled to iRGD bound to tumor vessels and spread 9. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch.
Nat Rev Cancer 2003;3:401‑10.
into the extravascular tumor parenchyma, whereas 10. Semenza GL. Vasculogenesis, angiogenesis, and arteriogenesis:
conventional RGD peptides only delivered the cargo mechanisms of blood vessel formation and remodeling. J Cell
to the blood vessels. iRGD homes to tumors through a Biochem 2007;102:840‑7.
three-step process: the RGD motif mediates binding to 11. D’Abaco GM, Kaye AH. Integrins: molecular determinants of glioma
invasion. J Clin Neurosci 2007;14:1041‑8.
α integrins on tumor endothelium, and a proteolytic 12. Cox BD, Natarajan M, Stettner MR, Gladson CL. New concepts
v
cleavage then exposes a binding motif for neuropilin-1, regarding focal adhesion kinase promotion of cell migration and
which mediates penetration into tissue and cells. proliferation. J Cell Biochem 2006;99:35‑52.
Conjugation to iRGD significantly improved the 13. Hauck CR, Hsia DA, Schlaepfer DD. The focal adhesion kinase‑a
regulator of cell migration and invasion. IUBMB Life 2002;53:115‑9.
sensitivity of tumor-imaging agents and enhanced the 14. Walsh EM, Kim R, Del Valle L, Weaver M, Sheffield J, Lazarovici P,
activity of an antitumor drug. Marcinkiewicz C. Importance of interaction between nerve growth

6 Neuroimmunol Neuroinflammation | Volume 2 | Issue 1 | January 15, 2015