This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Traxler, P. Articles by Caravatti, G. Search for Related Content PubMed PubMed Citation Articles by Traxler, P. Articles by Caravatti, G.

AEE788

A Dual Family Epidermal Growth Factor Receptor/ErbB2 and Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor with Antitumor and Antiangiogenic Activity

¹ Novartis Institutes for Biomedical Research, Oncology Research, Basel, Switzerland; ² Vivo Pharm Pty, Ltd., Thebarton, Australia; and ³ Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC

Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7H-pyrrolo[2,3-d]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nM range (IC₅₀s: EGFR 2 nM, ErbB2 6 nM, KDR 77 nM, and Flt-1 59 nM). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC₅₀s: 11 and 220 nM, respectively). AEE788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a murine implant model. Antiangiogenic activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.

This article has been cited by other articles:

				L. Horn and A. Sandler Epidermal Growth Factor Receptor Inhibitors and Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer Clin. Cancer Res., August 15, 2009; 15(16): 5040 - 5048. [Abstract] [Full Text] [PDF]

				N. A. Pennell and T. J. Lynch Jr. Combined Inhibition of the VEGFR and EGFR Signaling Pathways in the Treatment of NSCLC Oncologist, April 1, 2009; 14(4): 399 - 411. [Abstract] [Full Text] [PDF]

				A. Rappl, G. Piontek, and J. Schlegel EGFR-dependent migration of glial cells is mediated by reorganisation of N-cadherin J. Cell Sci., December 15, 2008; 121(24): 4089 - 4097. [Abstract] [Full Text] [PDF]

				M. R. Schneider, S. Werner, R. Paus, and E. Wolf Beyond Wavy Hairs: The Epidermal Growth Factor Receptor and Its Ligands in Skin Biology and Pathology Am. J. Pathol., July 1, 2008; 173(1): 14 - 24. [Abstract] [Full Text] [PDF]

				C. Halin, H. Fahrngruber, J. G. Meingassner, G. Bold, A. Littlewood-Evans, A. Stuetz, and M. Detmar Inhibition of Chronic and Acute Skin Inflammation by Treatment with a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Am. J. Pathol., July 1, 2008; 173(1): 265 - 277. [Abstract] [Full Text] [PDF]

				A. L. Boehm, M. Sen, R. Seethala, W. E. Gooding, M. Freilino, S. M. Y. Wong, S. Wang, D. E. Johnson, and J. R. Grandis Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-XL Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck Mol. Pharmacol., June 1, 2008; 73(6): 1632 - 1642. [Abstract] [Full Text] [PDF]

				J. N. Contessa, M. S. Bhojani, H. H. Freeze, A. Rehemtulla, and T. S. Lawrence Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells Cancer Res., May 15, 2008; 68(10): 3803 - 3809. [Abstract] [Full Text] [PDF]

				M M Muresan, P Olivier, J Leclere, F Sirveaux, L Brunaud, M Klein, R Zarnegar, and G Weryha Bone metastases from differentiated thyroid carcinoma Endocr. Relat. Cancer, March 1, 2008; 15(1): 37 - 49. [Abstract] [Full Text] [PDF]

				W. Wu, M. S. O'Reilly, R. R. Langley, R. Z. Tsan, C. H. Baker, N. Bekele, X. M. Tang, A. Onn, I. J. Fidler, and R. S. Herbst Expression of epidermal growth factor (EGF)/transforming growth factor-{alpha} by human lung cancer cells determines their response to EGF receptor tyrosine kinase inhibition in the lungs of mice Mol. Cancer Ther., October 1, 2007; 6(10): 2652 - 2663. [Abstract] [Full Text] [PDF]

				C. Oehler-Janne, W. Jochum, O. Riesterer, A. Broggini-Tenzer, G. Caravatti, V. Vuong, and M. Pruschy Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models Mol. Cancer Ther., September 1, 2007; 6(9): 2496 - 2504. [Abstract] [Full Text] [PDF]

				A. M.P. Omuro, S. Faivre, and E. Raymond Lessons learned in the development of targeted therapy for malignant gliomas Mol. Cancer Ther., July 1, 2007; 6(7): 1909 - 1919. [Abstract] [Full Text] [PDF]

				J. Tabernero The Role of VEGF and EGFR Inhibition: Implications for Combining Anti-VEGF and Anti-EGFR Agents Mol. Cancer Res., March 1, 2007; 5(3): 203 - 220. [Abstract] [Full Text] [PDF]

				C. Yu, B. B. Friday, J.-P. Lai, A. McCollum, P. Atadja, L. R. Roberts, and A. A. Adjei Abrogation of MAPK and Akt Signaling by AEE788 Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis through Reactive Oxygen Species Generation Clin. Cancer Res., February 15, 2007; 13(4): 1140 - 1148. [Abstract] [Full Text] [PDF]

				M. Failly, S. Korur, V. Egler, J.-L. Boulay, M. M. Lino, R. Imber, and A. Merlo Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells Mol. Cancer Ther., February 1, 2007; 6(2): 773 - 781. [Abstract] [Full Text] [PDF]

				B. Fu, J. Xue, Z. Li, X. Shi, B.-H. Jiang, and J. Fang Chrysin inhibits expression of hypoxia-inducible factor-1{alpha} through reducing hypoxia-inducible factor-1{alpha} stability and inhibiting its protein synthesis Mol. Cancer Ther., January 1, 2007; 6(1): 220 - 226. [Abstract] [Full Text] [PDF]

				M. N. Younes, Y. W. Park, Y. D. Yazici, M. Gu, A. A. Santillan, X. Nong, S. Kim, S. A. Jasser, A. K. El-Naggar, and J. N. Myers Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model. Mol. Cancer Ther., November 1, 2006; 5(11): 2696 - 2705. [Abstract] [Full Text] [PDF]

				T. W. Wong, F. Y. Lee, C. Yu, F. R. Luo, S. Oppenheimer, H. Zhang, R. A. Smykla, H. Mastalerz, B. E. Fink, J. T. Hunt, et al. Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling. Clin. Cancer Res., October 15, 2006; 12(20): 6186 - 6193. [Abstract] [Full Text] [PDF]

				E. I. Fomchenko and E. C. Holland Mouse models of brain tumors and their applications in preclinical trials. Clin. Cancer Res., September 15, 2006; 12(18): 5288 - 5297. [Abstract] [Full Text] [PDF]

				C. S. Mitsiades, V. Kotoula, V. Poulaki, E. Sozopoulos, J. Negri, E. Charalambous, G. Fanourakis, G. Voutsinas, S. Tseleni-Balafouta, and N. Mitsiades Epidermal Growth Factor Receptor as a Therapeutic Target in Human Thyroid Carcinoma: Mutational and Functional Analysis J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3662 - 3666. [Abstract] [Full Text] [PDF]

				J. W. B. de Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors Endocr. Rev., August 1, 2006; 27(5): 535 - 560. [Abstract] [Full Text] [PDF]

				A. Morabito, E. De Maio, M. Di Maio, N. Normanno, and F. Perrone Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions Oncologist, July 1, 2006; 11(7): 753 - 764. [Abstract] [Full Text] [PDF]

				M. N. Younes, Y. D. Yazici, S. Kim, S. A. Jasser, A. K. El-Naggar, and J. N. Myers Dual Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Inhibition with NVP-AEE788 for the Treatment of Aggressive Follicular Thyroid Cancer. Clin. Cancer Res., June 1, 2006; 12(11): 3425 - 3434. [Abstract] [Full Text] [PDF]

				N. F. Voelkel, R. W. Vandivier, and R. M. Tuder Vascular endothelial growth factor in the lung Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L209 - L221. [Abstract] [Full Text] [PDF]

				D. A. Reardon and P. Y. Wen Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. Oncologist, February 1, 2006; 11(2): 152 - 164. [Abstract] [Full Text] [PDF]

				R. Saez, M. A. Molina, E. E. Ramsey, F. Rojo, E. J. Keenan, J. Albanell, A. Lluch, J. Garcia-Conde, J. Baselga, and G. M. Clinton p95HER-2 Predicts Worse Outcome in Patients with HER-2-Positive Breast Cancer Clin. Cancer Res., January 15, 2006; 12(2): 424 - 431. [Abstract] [Full Text] [PDF]

				Z. Weihua, R. Tsan, A. J. Schroit, and I. J. Fidler Apoptotic Cells Initiate Endothelial Cell Sprouting via Electrostatic Signaling Cancer Res., December 15, 2005; 65(24): 11529 - 11535. [Abstract] [Full Text] [PDF]

				A. Arora and E. M. Scholar Role of Tyrosine Kinase Inhibitors in Cancer Therapy J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 971 - 979. [Abstract] [Full Text] [PDF]

				K. Yokoi, T. Sasaki, C. D. Bucana, D. Fan, C. H. Baker, Y. Kitadai, T. Kuwai, J. L. Abbruzzese, and I. J. Fidler Simultaneous Inhibition of EGFR, VEGFR, and Platelet-Derived Growth Factor Receptor Signaling Combined with Gemcitabine Produces Therapy of Human Pancreatic Carcinoma and Prolongs Survival in an Orthotopic Nude Mouse Model Cancer Res., November 15, 2005; 65(22): 10371 - 10380. [Abstract] [Full Text] [PDF]

				M. B. Thomas and J. L. Abbruzzese Opportunities for Targeted Therapies in Hepatocellular Carcinoma J. Clin. Oncol., November 1, 2005; 23(31): 8093 - 8108. [Abstract] [Full Text] [PDF]

				M. E. Digan, C. Pou, H. Niu, and J.-H. Zhang Evaluation of Division-Arrested Cells for Cell-Based High-Throughput Screening and Profiling J Biomol Screen, September 1, 2005; 10(6): 615 - 623. [Abstract] [PDF]

				L.-Z. Liu, J. Fang, Q. Zhou, X. Hu, X. Shi, and B.-H. Jiang Apigenin Inhibits Expression of Vascular Endothelial Growth Factor and Angiogenesis in Human Lung Cancer Cells: Implication of Chemoprevention of Lung Cancer Mol. Pharmacol., September 1, 2005; 68(3): 635 - 643. [Abstract] [Full Text] [PDF]

				P. H. Thaker, S. Yazici, M. B. Nilsson, K. Yokoi, R. Z. Tsan, J. He, S.-J. Kim, I. J. Fidler, and A. K. Sood Antivascular Therapy for Orthotopic Human Ovarian Carcinoma through Blockade of the Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptors Clin. Cancer Res., July 1, 2005; 11(13): 4923 - 4933. [Abstract] [Full Text] [PDF]

				P. Sini, L. Wyder, C. Schnell, T. O'Reilly, A. Littlewood, R. Brandt, N. E. Hynes, and J. Wood The Antitumor and Antiangiogenic Activity of Vascular Endothelial Growth Factor Receptor Inhibition Is Potentiated by ErbB1 Blockade Clin. Cancer Res., June 15, 2005; 11(12): 4521 - 4532. [Abstract] [Full Text] [PDF]

				M. N. Younes, O. G. Yigitbasi, Y. W. Park, S.-J. Kim, S. A. Jasser, V. S. Hawthorne, Y. D. Yazici, M. Mandal, B. N. Bekele, C. D. Bucana, et al. Antivascular Therapy of Human Follicular Thyroid Cancer Experimental Bone Metastasis by Blockade of Epidermal Growth Factor Receptor and Vascular Growth Factor Receptor Phosphorylation Cancer Res., June 1, 2005; 65(11): 4716 - 4727. [Abstract] [Full Text] [PDF]

				G. Giaccone Epidermal Growth Factor Receptor Inhibitors in the Treatment of Non-Small-Cell Lung Cancer J. Clin. Oncol., May 10, 2005; 23(14): 3235 - 3242. [Abstract] [Full Text] [PDF]

				K. Yokoi, P. H. Thaker, S. Yazici, R. R. Rebhun, D.-H. Nam, J. He, S.-J. Kim, J. L. Abbruzzese, S. R. Hamilton, and I. J. Fidler Dual Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation by AEE788 Reduces Growth and Metastasis of Human Colon Carcinoma in an Orthotopic Nude Mouse Model Cancer Res., May 1, 2005; 65(9): 3716 - 3725. [Abstract] [Full Text] [PDF]

				J. Baselga and C. L. Arteaga Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer J. Clin. Oncol., April 10, 2005; 23(11): 2445 - 2459. [Abstract] [Full Text] [PDF]

				S. Kim, B. A. Schiff, O. G. Yigitbasi, D. Doan, S. A. Jasser, B. N. Bekele, M. Mandal, and J. N. Myers Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788 Mol. Cancer Ther., April 1, 2005; 4(4): 632 - 640. [Abstract] [Full Text] [PDF]

				Y. W. Park, M. N. Younes, S. A. Jasser, O. G. Yigitbasi, G. Zhou, C. D. Bucana, B. N. Bekele, and J. N. Myers AEE788, a Dual Tyrosine Kinase Receptor Inhibitor, Induces Endothelial Cell Apoptosis in Human Cutaneous Squamous Cell Carcinoma Xenografts in Nude Mice Clin. Cancer Res., March 1, 2005; 11(5): 1963 - 1973. [Abstract] [Full Text] [PDF]

				C. Tuccillo, M. Romano, T. Troiani, E. Martinelli, F. Morgillo, F. De Vita, R. Bianco, G. Fontanini, R. A. Bianco, G. Tortora, et al. Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor Clin. Cancer Res., February 1, 2005; 11(3): 1268 - 1276. [Abstract] [Full Text] [PDF]

				C. Waldherr, I. K. Mellinghoff, C. Tran, B. S. Halpern, N. Rozengurt, A. Safaei, W. A. Weber, D. Stout, N. Satyamurthy, J. Barrio, et al. Monitoring Antiproliferative Responses to Kinase Inhibitor Therapy in Mice with 3'-Deoxy-3'-18F-Fluorothymidine PET J. Nucl. Med., January 1, 2005; 46(1): 114 - 120. [Abstract] [Full Text] [PDF]

				R. K. Goudar, Q. Shi, M. D. Hjelmeland, S. T. Keir, R. E. McLendon, C. J. Wikstrand, E. D. Reese, C. A. Conrad, P. Traxler, H. A. Lane, et al. Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition Mol. Cancer Ther., January 1, 2005; 4(1): 101 - 112. [Abstract] [Full Text] [PDF]