Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature

Cancer Research

Volumn 72, Issue 1, 2012, Pages 239-248

  Fokas, Emmanouil ^a   Im, Jae Hong ^a   Hill, Sally ^a   Yameen, Sabira ^a   Stratford, Michael ^a   Beech, John ^a   Hackl, Wolfgang ^b   Maira, Sauveur Michel ^b   Bernhard, Eric J ^a   McKenna, W Gillies ^a   Muschel, Ruth J ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; MAMMALIAN TARGET OF RAPAMYCIN; NVP BKM120; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER CELL CULTURE; CANCER RADIOTHERAPY; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFICACY; DRUG MECHANISM; DRUG RESPONSE; ENZYME INHIBITION; HUMAN; HUMAN CELL; IN VIVO STUDY; MOUSE; NONHUMAN; OXYGENATION; PRIORITY JOURNAL; RADIATION DOSE; RADIATION RESPONSE; RADIOSENSITIVITY; SOLID TUMOR; TUMOR CELL; TUMOR GROWTH; TUMOR VASCULARIZATION; TUMOR XENOGRAFT;

ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MICE; NEOPLASMS, EXPERIMENTAL; NEOVASCULARIZATION, PATHOLOGIC; PHOSPHATIDYLINOSITOL 3-KINASES; RADIATION TOLERANCE; TOR SERINE-THREONINE KINASES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84855371890     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-11-2263     Document Type: Article

References (44)

1. Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 2011;11:239-53.
2. Budach W, Taghian A, Freeman J, Gioioso D, Suit HD. Impact of stromal sensitivity on radiation response of tumors. J Natl Cancer Inst 1993;85:988-93. (Pubitemid 23177585)
3. Cengel KA, McKenna WG. Molecular targets for altering radiosensitivity: lessons from Ras as a pre-clinical and clinical model. Crit Rev Oncol Hematol 2005;55:103-16. (Pubitemid 40981914)
4. Kim IA, Bae SS, Fernandes A, Wu J, Muschel RJ, McKenna WG, et al. Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res 2005;65:7902-10. (Pubitemid 41297268)
5. Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J, et al. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res 2008;68:5915-23.
6. Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 2004;14:198-206. (Pubitemid 38903223)
7. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62. (Pubitemid 40093472)
8. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438:932-6. (Pubitemid 43093958)
9. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
10. Kerbel RS. Tumor angiogenesis. N Engl J Med 2008;358:2039-49. (Pubitemid 351656458)
11. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004;64:3731-6. (Pubitemid 38697278)
12. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6:553-63. (Pubitemid 40017699)
13. Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 2011; 8:210-21.
14. Qayum N, Muschel RJ, Im JH, Balathasan L, Koch CJ, Patel S, et al. Tumor vascular changes mediated by inhibition of oncogenic signaling. Cancer Res 2009;69:6347-54.
15. Cerniglia GJ, Pore N, Tsai JH, Schultz S, Mick R, Choe R, et al. Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy. PLoS One 2009;4:e6539.
16. Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, et al. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res 2002;8:885-92. (Pubitemid 34742122)
17. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 2011 Jun. [Epub ahead of print].
18. Maity A, Bernhard EJ. Modulating tumor vasculature through signaling inhibition to improve cytotoxic therapy. Cancer Res 2010;70:2141-5.
19. Pore N, Gupta AK, Cerniglia GJ, Jiang Z, Bernhard EJ, Evans SM, et al. Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res 2006;66:9252-9. (Pubitemid 44521147)
20. Konstantinidou G, Bey EA, Rabellino A, Schuster K, Maira MS, Gazdar AF, et al. Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res 2009;69:7644-52.
21. Baumann M, Krause M, Zips D, Eicheler W, Dorfler A, Ahrens J, et al. Selective inhibition of the epidermal growth factor receptor tyrosine kinase by BIBX1382BS and the improvement of growth delay, but not local control, after fractionated irradiation in human FaDu squamous cell carcinoma in the nude mouse. Int J Radiat Biol 2003;79:547-59. (Pubitemid 37311060)
22. Gurtner K, Deuse Y, Butof R, Schaal K, Eicheler W, Oertel R, et al. Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression. Radiother Oncol 2011;99:323-30.
23. Krause M, Prager J, Zhou X, Yaromina A, Dorfler A, Eicheler W, et al. EGFR-TK inhibition before radiotherapy reduces tumour volume but does not improve local control: differential response of cancer stem cells and nontumourigenic cells? Radiother Oncol 2007;83:316-25. (Pubitemid 46915543)
24. Zips D. Tumour growth and response to radiation. In: Joiner M, van der Kogel JA, editors. Basic clinical radiobiology. London: Hodder Arnold; 2009. p. 78-101.
25. Dings RP, Loren M, Heun H, McNiel E, Griffioen AW, Mayo KH, et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res 2007;13:3395-402. (Pubitemid 46944928)
26. McGee MC, Hamner JB, Williams RF, Rosati SF, Sims TL, Ng CY, et al. Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation. Int J Radiat Oncol Biol Phys 2010;76:1537-45.
27. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004;5:429-41. (Pubitemid 38610245)
28. Horsman MR, Siemann DW. Pathophysiologic effects of vasculartargeting agents and the implications for combination with conventional therapies. Cancer Res 2006;66:11520-39. (Pubitemid 46094158)
29. Coderre JA, Morris GM, Micca PL, Hopewell JW, Verhagen I, Kleiboer BJ, et al. Late effects of radiation on the central nervous system: role of vascular endothelial damage and glial stem cell survival. Radiat Res 2006;166:495-503. (Pubitemid 44353433)
30. Zips D, Eicheler W, Geyer P, Hessel F, Dorfler A, Thames HD, et al. Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition. Cancer Res 2005;65:5374-9. (Pubitemid 40827351)
31. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15:232-9.
32. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220-31.
33. Morello F, Perino A, Hirsch E. Phosphoinositide 3-kinase signalling in the vascular system. Cardiovasc Res 2009;82:261-71.
34. Castellino RC, Durden DL. Mechanisms of disease: the PI3K-Akt- PTEN signaling node-an intercept point for the control of angiogenesis in brain tumors. Nat Clin Pract Neurol 2007;3:682-93. (Pubitemid 350238060)
35. Jiang BH, Zheng JZ, Aoki M, Vogt PK. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci U S A 2000;97:1749-53. (Pubitemid 30118514)
36. Denning G, Jean-Joseph B, Prince C, Durden DL, Vogt PK. A short Nterminal sequence of PTEN controls cytoplasmic localization and is required for suppression of cell growth. Oncogene 2007;26:3930-40. (Pubitemid 46884301)
37. Marone R, Erhart D, Mertz AC, Bohnacker T, Schnell C, Cmiljanovic V, et al. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol Cancer Res 2009;7:601-13.
38. Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, et al. NVPBEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 2009;8:2204-10.
39. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008;7:1851-63.
40. Cho DC, Cohen MB, Panka DJ, Collins M, Ghebremichael M, Atkins MB, et al. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin Cancer Res 2010;16:3628-38.
41. Manara MC, Nicoletti G, Zambelli D, Ventura S, Guerzoni C, Landuzzi L, et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res 2010;16:530-40.
42. Schnell CR, Stauffer F, Allegrini PR, O'Reilly T, McSheehy PM, Dartois C, et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008;68:6598-607.
43. Sun JF, Phung T, Shiojima I, Felske T, Upalakalin JN, Feng D, et al. Microvascular patterning is controlled by fine-tuning the Akt signal. Proc Natl Acad Sci U S A 2005;102:128-33. (Pubitemid 40094440)
44. Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C, et al. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 2006;10:159-70. (Pubitemid 44175906)