New perspectives in glioblastoma antiangiogenic therapy

Wspolczesna Onkologia

Volumn 20, Issue 2, 2016, Pages 109-118

  Popescu, Alisa Madalina ^a   Purcaru, Stefana Oana ^a   Alexandru, Oana ^a   Dricu, Anica ^a  

^a UNIVERSITY OF MEDICINE AND PHARMACY OF CRAIOVA   (Romania)

Author keywords

Angiogenesis; Glioblastoma; Signalling pathways

Indexed keywords

AFLIBERCEPT; BEVACIZUMAB; BUPARLISIB; CARBOPLATIN; CISPLATIN; DASATINIB; EVEROLIMUS; IMATINIB; LOMUSTINE; PEGDINETANIB; PERIFOSINE; SORAFENIB; SUNITINIB; TEMOZOLOMIDE; TEMSIROLIMUS; TYROSINE KINASE RECEPTOR;

ANTIANGIOGENIC THERAPY; CANCER CHEMOTHERAPY; CANCER RESEARCH; CARCINOGENESIS; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; DRUG EFFICACY; DRUG SAFETY; GENE EXPRESSION REGULATION; GENE MUTATION; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; GLIOBLASTOMA; HUMAN; MOLECULARLY TARGETED THERAPY; NEUROPATHOLOGY; NONHUMAN; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION;

EID: 85002169939     PISSN: 14282526     EISSN: None     Source Type: Journal    
DOI: 10.5114/wo.2015.56122     Document Type: Review

References (115)

1. Dunn GP, Rinne ML, Wykosky J, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 2012; 26: 756-84.
2. Ahmed R, Oborski MJ, Hwang M, Lieberman FS, Mountz JM. Malignant gliomas: current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods. Cancer Manag Res 2014; 6: 149-70.
3. Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary Brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 2013; 15 (Suppl 2): ii1-56.
4. Baker GJ, Yadav VN, Motsch S, Koschmann C, Calinescu A-A, Mineharu Y, et al. Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy. Neoplasia 2014; 16: 543-61.
5. Hardee ME, Zagzag D. Mechanisms of glioma-associated neovascularization. Am J Pathol 2012; 181: 1126-41.
6. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011; 144: 646-74.
7. McNamara MG, Sahebjam S, Mason WP. Emerging Biomarkers in Glioblastoma. Cancers 2013; 5: 1103-19.
8. Sooman L, Freyhult E, Jaiswal A, et al. FGF2 as a potential prognostic biomarker for proneuralglioma patients. Acta Oncol Stockh Swed 2015; 54: 385-94.
9. Walker C, Baborie A, Crooks D, Wilkins S, Jenkinson MD. Biology, genetics and imaging of glial cell tumours. Br J Radiol 2011; 84 (Spec Issue 2): S090-106.
10. Raica M, Cimpean AM, Ribatti D. Angiogenesis in pre-malignant conditions. Eur J Cancer Oxf Engl 2009; 45: 1924-34.
11. Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012; 3: 98-106.
12. Poleszczuk J, Hahnfeldt P, Enderling H. Therapeutic implications from sensitivity analysis of tumor angiogenesis models. PLoS One 2015; 10: e0120007.
13. Kesari S. Understanding glioblastoma tumor biology: the potential to improve current diagnosis and treatments. Semin Oncol 2011; 38 Suppl 4: S2-10.
14. Puputti M, Tynninen O, Sihto H, et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res MCR 2006; 4: 927-34.
15. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2012; 2(7): a006502.
16. Gotink KJ, Verheul HMW. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010; 13: 1-14.
17. Lin MI, Sessa WC. Antiangiogenic therapy: Creating a unique window of opportunity. Cancer Cell 2004; 6: 529-31.
18. Onishi M, Kurozumi K, Ichikawa T, Date I. Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme. Neurol Med Chir (Tokyo) 2013; 53: 755-63.
19. Karcher S, Steiner H-H, Ahmadi R, Zoubaa S, Vasvari G, Unterberg A, Herold-Mende C. Different angiogenic phenotypes in primary and secondary glioblastomas. Int J Cancer 2006; 118: 2182-9.
20. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013; 19: 764-72.
21. Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol (Berl) 2013; 125: 621-36.
22. Verhaak RGW, Hoadley KA, Purdom E, et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell 2010; 17: 98.
23. Clarke J, Penas C, Pastori C, et al. Epigenetic pathways and glioblastoma treatment. Epigenetics 2013; 8: 785-95.
24. Li R, Li H, Yan W, et al. Genetic and clinical characteristics of primary and secondary glioblastoma is associated with differential molecular subtype distribution. Oncotarget 2015; 6: 7318-24.
25. Jiao Y, Killela PJ, Reitman ZJ, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012; 3: 709-22.
26. Weller M, Stupp R, Reifenberger G, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 2010; 6: 39-51.
27. Batista KMP, Vega IF, Eulate-Beramendi SA de, et al. Original article Prognostic significance of the markers IDH1 and YKL40 related to the subventricular zone. Folia Neuropathol 2015; 1: 52-9.
28. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a Pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 11: 83-95.
29. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for antiand pro-angiogenic therapies. Genes Cancer 2011; 2: 1097-105.
30. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE Signal Transduct Knowl Environ 2001; 2001 (112): re21.
31. Wang L, Chen L, Wang Q, et al. Circulating endothelial progenitor cells are involved in VEGFR-2-related endothelial differentiation in glioma. Oncol Rep 2014: 32: 2007-14.
32. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140-56.
33. Xu C, Wu X, Zhu J. VEGF promotes proliferation of human glioblastoma multiforme stem-like cells through VEGF receptor 2. Sci World Journal 2013; 2013: 417413.
34. Mellinghoff IK, Schultz N, Mischel PS, Cloughesy TF. Will kinase inhibitors make it as glioblastoma drugs? Curr Top Microbiol Immunol 2012; 355: 135-69.
35. McCubrey JA, Steelman LS, Chappell WH, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget 2012; 3: 1068-111.
36. Logue JS, Morrison DK. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev 2012; 26: 641-50.
37. Bai R-Y, Staedtke V, Riggins GJ. Molecular targeting of glioblastoma: drug discovery and therapies. Trends Mol Med 2011; 17: 301-12.
38. Cao Y. Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis. Trends Mol Med 2013; 19: 460-73.
39. Zhang J, Chen T, Mao Q, et al. PDGFR-activated ACK1-AKT signaling promotes glioma tumorigenesis. Int J Cancer J Int Cancer 2015; 136: 1769-80.
40. Westermark B. Platelet-derived growth factor in glioblastomadriver or biomarker? Ups J Med Sci 2014; 119: 298-305.
41. Vogt PK, Hart JR. PI3K and STAT3: a New Alliance. Cancer Discov 2011; 1: 481-6.
42. Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int 2014; 5: 64.
43. Liu K-W, Hu B, Cheng S-Y. Platelet-derived growth factor receptor alpha in glioma: a bad seed. Chin J Cancer 2011; 30: 590-602.
44. Paul I, Bhattacharya S, Chatterjee A, Ghosh MK. Current understanding on EGFR and Wnt/b-catenin signaling in glioma and their possible crosstalk. Genes Cancer 2013; 4: 427-46.
45. Ferrari G, Cook BD, Terushkin V, Pintucci G, Mignatti P. Transforming growth factor-beta 1 (TGF-1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol 2009; 219: 449-58.
46. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti A, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16: 15-31.
47. MacDonald BT, He X. Frizzled and LRP5/6 receptors for Wnt/catenin signaling. Cold Spring Harb Perspect Biol 2012; 4(12).pii: a007880.
48. Xing Z-Y, Sun L-G, Guo W-J. Elevated expression of Notch-1 and EGFR induced apoptosis in glioblastomamultiforme patients. Clin Neurol Neurosurg 2015; 131: 54-8.
49. Guo S, Liu M, Gonzalez-Perez RR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim Biophys Acta 2011; 1815: 197-213.
50. Van Meir EG, Hadjipanayis CG, Norden AD, Shu H-K, Wen PY, Olson JJ. Exciting new advances in neuro-oncology. CA Cancer J Clin 2010; 60: 166-93.
51. Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev 2014; 34: 280-300.
52. Raju R, Palapetta SM, Sandhya VK, et al. A network map of FGF-1/FGFR signaling system. J Signal Transduct 2014; 2014: 962962.
53. Chinot OL, de La Motte Rouge T, Moore N, et al. AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastomamultiforme. Adv Ther 2011; 28: 334-40.
54. Narita Y. Drug review: safety and efficacy of bevacizumab for glioblastoma and other brain tumors. Jpn J Clin Oncol 2013; 43: 587-95.
55. Hu J, Kesari S. The molecular basis for novel therapies. Cancer J Sudbury Mass 2012; 18(1): 32-9.
56. Zhou J, Atsina K-B, Himes BT, Strohbehn GW, Saltzman WM. Novel delivery strategies for glioblastoma. Cancer J 2012; 18: 89-99.
57. Serova M, de Gramont A, Tijeras-Raballand A, Dos Santos C, Riveiro ME, Slimane K, Faivre S, Raymond E. Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib. Cancer Chemother Pharmacol 2013; 71: 1297-307.
58. Joshi AD, Loilome W, Siu I-M, Tyler B, Gallia GL, Riggins GJ. Evaluation of Tyrosine kinase inhibitor combinations for glioblastoma therapy. PLoS ONE 2012; 7: e44372.
59. Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010; 28: 207-14.
60. Tolcher AW, Sweeney CJ, Papadopoulos K, et al. Phase I and pharmacokinetic study of CT-322 (BMS-844203), a targeted adnectin inhibitor of VEGFR-2 based on a domain of human fibronectin. Clin Cancer Res 2011; 17: 363-71.
61. Wen PY, Lee EQ, Reardon DA, Ligon KL, Alfred Yung WK. Current clinical development of PI3K pathway inhibitors in glioblastoma. Neuro Oncol 2012; 14: 819-29.
62. Kim KW, Myers CJ, Jung DK, Lu B. NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma. Genes Cancer 2014; 5: 293-302.
63. Brachmann SM, Hofmann I, Schnell C, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A 2009; 106: 22299-304.
64. Giampaolo Tortora RB. Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother 2007; 10: 81-100.
65. Kessler T, Sahm F, Blaes J, Osswald M, Rübmann P, Milford D, Urban S, Jestaedt L. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget 2015; 6: 31050-68.
66. Papadopoulos K, Tabernero J, Markman B, et al. Phase I safety, pharmacokinetic and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 2445-56.
67. Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012; 30: 282-90.
68. Yu P, Laird AD, Du X, et al. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol Cancer Ther 2014; 13: 1078-91.
69. Lau D, Magill ST, Aghi MK. Molecularly targeted therapies for recurrent glioblastoma: current and future targets. Neurosurg Focus 2014; 37: E15.
70. Lv S, Teugels E, Sadones J, et al. Correlation of EGFR, IDH1 and PTEN status with the outcome of patients with recurrent glioblastoma treated in a phase II clinical trial with the EGFR-blocking monoclonal antibody cetuximab. Int J Oncol 2012; 41: 1029-35.
71. Qaddoumi I, Kocak M, PaiPanandiker AS, et al. Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas. Front Oncol 2014; 4: 67.
72. Wen PY, Chang SM, Lamborn KR, et al. Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. Neuro Oncol 2014; 16: 567-78.
73. Westphal M, Heese O, Steinbach JP, et al. A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma. Eur J Cancer 2015; 51: 522-32.
74. Schiff D, Kesari S, de Groot J, et al. Phase 2 study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma. Invest New Drugs 2015; 33: 247-53.
75. Gan HK, Fichtel L, Lassman AB, et al. A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectableglioblastoma (GBM). J Clin Oncol 2014; 32: (suppl; abstr 2021): 5s.
76. Chakravarti A, Wang M, Robins HI, et al. RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys 2013; 85: 1206-11.
77. De Groot JF, Lamborn KR, Chang SM, et al. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 2011; 29: 2689-95.
78. Gerstner ER, Eichler AF, Plotkin SR, et al. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide. J Neurooncol 2011; 103: 325-32.
79. Lassman AB, Pugh SL, Gilbert MR, et al. Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Neuro Oncol 2015; 17: 992-8.
80. Hutterer M, Nowosielski M, Haybaeck J, et al. A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07). Neuro Oncol 2014; 16: 92-102.
81. Hottinger AF, Aissa AB, Espeli V, et al. Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma. Br J Cancer 2014; 110: 2655-61.
82. Karajannis MA, Legault G, Fisher MJ, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol 2014; 16: 1408-16.
83. Coxon A, Ziegler B, Kaufman S, et al. Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non-small-cell lung cancer xenograft models. Mol Cancer 2012; 11: 70.
84. Kreisl TN, McNeill KA, Sul J, Iwamoto FM, Shih J, Fine HA. A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro Oncol 2012; 14: 1519-26.
85. Lee EQ, Kaley TJ, Duda DG, et al. A multicenter, phase II, randomized, non-comparative clinical trial of radiation and temozolomide with or without vandetanib in newly-diagnosed glioblastoma patients. Clin Cancer Res 2015; 21: 3610-8.
86. Iwamoto FM, Lamborn KR, Robins HI, et al. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro Oncol 2010; 12: 855-61.
87. Taylor JW, Dietrich J, Gerstner ER, et al. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. J Neurooncol 2015; 121: 557-63.
88. Blay J-Y, Shen L, Kang Y-K, et al. Nilotinib versus imatinib as firstline therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; 16: 550-60.
89. Lu L, Saha D, Martuza RL, Rabkin SD, Wakimoto H. Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J Neurooncol 2015; 121: 91-100.
90. Gil del Alcazar CR, Hardebeck MC, Mukherjee B, et al. Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin Cancer Res 2014; 20: 1235-48
91. Chinnaiyan P, Won M, Wen PY, et al. RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 2013; 86: 880-4.
92. Lassen U, Sorensen M, Gaziel TB, Hasselbalch B, Poulsen HS. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastomamultiforme. Anticancer Res 2013; 33: 1657-60.
93. Jane EP, Premkumar DR, Morales A, Foster KA, Pollack IF. Inhibition of phosphatidylinositol 3-kinase/AKT signaling by NVPBKM120 promotes ABT-737-induced toxicity in a caspase-dependent manner through mitochondrial dysfunction and DNA damage response in established and primary cultured glioblastoma cells. J Pharmacol Exp Ther 2014; 350: 22-35.
94. Zhang Y, Guessous F, Kofman A, Schiff D, Abounader R. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastomamultiforme and NSCLC. I Drugs Investig Drugs J 2010; 13: 112-21.
95. Singh AR, Joshi S, George E, Durden DL. Anti-tumor effect of a novel PI3-kinase inhibitor, SF1126, in 12 V-Ha-Ras transgenic mouse glioma model. Cancer Cell Int 2014; 14: 105.
96. Ekshyyan O, Anandharaj A, Nathan C-AO. Dual PI3K/mTOR Inhibitors: does p53 modulate response? Clin Cancer Res 2013; 19: 3719-21.
97. Brain Tumor News: Early Results of Phase 2 Trial of Perifosine (KRX-0401) for the Treatment of Recurrent Malignant Gliomas Presented at the 12th Annual Scientific Meeting of Society for Neuro-Oncology 2015; poster presentation.
98. Kahn J, Hayman TJ, Jamal M, Rath BH, Kramp T, Camphausen K, Tofilon PJ. The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro Oncol 2014; 16: 29-37.
99. Narla RK, Peng S, Gamez J, Katz J, Apuy J, Moghaddam M. Antitumor activity of mTOR kinase inhibitor CC-223 in a mouse model of glioblastoma 2014; 12 (11-Supplement): A165-A165.
100. Lee E, TORC1/2 Inhibitor INK128 Before and After Surgery in Treating Patients With Recurrent Glioblastoma-ClinicalTrials: NCT02133183.
101. He K, Zheng X, Li M, Zhang L, Yu J. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation. Oncogene 2015; doi: 10.1038/onc.2015.79.
102. Tai S, Sun Y, Liu N, et al. Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells. Mol Cancer Ther 2012; 11: 1320-31.
103. Lu B, Li J, Pan J, Huang B, Liu J, Zheng D. Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins. Acta Biochim Biophys Sin 2013; 45: 683-91.
104. Orlowski RZ. Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials. Semin Oncol 2013; 40: 10.
105. Liu J, Lin A. Role of JNK activation in apoptosis: A double-edged sword. Cell Res 2005; 15: 36-42.
106. Fei H, Chen G, Wang J, Wang F. Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation. Cytotechnology 2010; 62: 449-60.
107. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J Clin Oncol 2011; 2: 80-93.
108. Reardon DA, Turner S, Peters KB, et al. A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma. J Natl Compr Canc Netw 2011; 9: 414-27.
109. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006; 66: 11851-8.
110. Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res 2006; 66: 5542-8.
111. Truffaux N, Philippe C, Paulsson J, et al. Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontineglioma. Neuro Oncol 2015; 17: 953-64.
112. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell 2002; 1: 31-6.
113. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003; 3: 347-61.
114. Chen Y, Fu L. Mechanisms of acquired resistance to tyrosine kinase inhibitors. Acta Pharm Sin B 2011; 1: 197-207.
115. Fenton TR, Nathanson D, Ponte de Albuquerque C, et al. Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. Proc Natl Acad Sci U S A 2012; 109: 14164-9.