Therapeutic Implications

The marked chemotherapy and radiation resistance of gliomas has focused attention on the means by which signaling aberrations underlying gliomagenesis contribute to resistance to cell death. In this regard, the PI3-kinase pathway is recognized for supporting cellular proliferation and survival, thereby promoting both malignant transformation and resistance to therapy.

Several lines of investigation identify PI3-kinase as a regulator of cellular responses to ionizing radiation. Biochemical inhibitors of PI3-kinase, LY294002, and wortmannin, enhance the anti-neoplastic effects of radiation [64-66], and recent data indicate that PKB/ Akt mediates LY294002-mediated radiosensitization [82]. Ionizing radiation has been shown to activate PKB/Akt and p70S6K in epithelial tumors in vitro, however this has not been shown to be the case in malignant glioma cell lines (Nakamura and Haas-Kogan, unpublished data).

In addition to direct effects on tumor cells, PKB/ Akt mediates responses of vascular endothelium to ionizing radiation [67]. PI3-kinase inhibition may provide a means of targeting elements in the tumor microenvironment such as vascular endothelium [68]. Thus, PI3-kinase inhibition may have anti-neoplastic effects through direct tumor killing as well as through disruption of the supportive microenvironmental components such as vascularization [69].

The importance of PKB/Akt function in survival after cytotoxic therapy is highlighted by the evidence that mutant receptor tyrosine kinases such as EGFRvIII exert cytoprotective effects through PI3-kinase [70] (Fig. 13.2). However, the effectiveness of EGFR tyrosine kinase inhibitors may be compromised by compensatory signaling through PTEN loss and/or PKB/Akt activation [71,72]. Combinations of signaling inhibitors, based on growing insights into glioma genetic pathogenesis, may help circumvent these escape mechanisms. Although such combinations may appear redundant, the ability of dysregulated PI3-kinase signaling to rescue cells from cytotoxic therapies may be one molecular explanation for the modest clinical efficacy of signaling inhibitors [73].

Redundant activation of PI3-kinase from alternate growth factor receptors may also provide a means of rescuing malignant gliomas from EGFR inhibition. For example, insulin-like growth factor receptor-I (IGFR-I) has been shown to maintain PI3-kinase signaling in the face of AG1478, the EGFR inhibitor and in fact co-suppression of IGFR-I and EGFR produced greater cytotoxicity compared to individual receptor inhibition [74]. These data further confirm that therapeutic signaling inhibition will be delivered as polychemotherapy, and increasing recognition of the molecular basis of resistance will improve our ability to intelligently incorporate signaling inhibitors into multimodality therapy. The same complexity and cross talk of signaling cascades contributing to drug resistance may also protect tumors from alternate mechanisms of cell death. EGFR inhibitors AG1478 and PD153035 can protect malignant gliomas from hypoxia-induced cell death [75].

Signaling through mTOR represents another potential target for molecular-based therapeutics. Phase I studies of CCI-779, an ester of rapamycin that inhibits mTOR, are ongoing for malignant gliomas [76]. mTOR and its downstream effector eIF4E may be particularly important targets because recent data indicate that they mediate resistance to therapy and treatment with rapamycin sensitizes lymphomas to chemotherapy [77]. Furthermore, tumors with activated PKB/Akt display particular sensitivity to mTOR inhibition [78]. In glioma, mTOR inhibition may have multiple inhibitory effects. Rapamycin radiosensitizes U87 in vivo [79], a finding that suggests improved efficacy when combining mTOR inhibition with radiotherapy. Recent data also indicate that mTOR inhibition alone using the rapamycin derivative RAD001 reduces glioma invasiveness and VEGF secretion [80].

Recent data suggest the possibility of targeting eIF4E as a strategy. Kentsis, et al. described the suppression of eIF4E-mediated transformation by the guanosine ribonucleoside analog ribavirin [81].

Increasing recognition of the redundancy of inputs into the PI3-kinase pathway and the cross talk between signaling pathways emphasizes the need to rationally coordinate signaling inhibitors for maximal efficacy. In vitro and in vivo data defining compensatory mechanisms after single-agent signaling inhibition should be used to offer more appropriate combinatorial therapy.

FIGURE 13.2 Schema of some signaling inhibitors currently in clinical trials. A variety of mechanisms are available to suppress aberrant signaling through growth factor receptors and the PI3-kinase pathway. STI-571, ZD1839, and OSI-774 inhibit tyrosine kinase activity, while R115777 is a farnesyl transferase inhibitor suppressing the necessary post-translational processing of Ras, and CCI-779, a rapamycin analog, inhibits mTOR. See Plate 13.2 in Color Plate Section.

FIGURE 13.2 Schema of some signaling inhibitors currently in clinical trials. A variety of mechanisms are available to suppress aberrant signaling through growth factor receptors and the PI3-kinase pathway. STI-571, ZD1839, and OSI-774 inhibit tyrosine kinase activity, while R115777 is a farnesyl transferase inhibitor suppressing the necessary post-translational processing of Ras, and CCI-779, a rapamycin analog, inhibits mTOR. See Plate 13.2 in Color Plate Section.


1. Alessi, D. R., Andjelkovic, M., Caudwell, B. et al. (1996). Mechanism of activation of protein kinase B by insulin and IGF-1. Embo J 15, 6541-6551.

2. Di Cristofano, A., Pesce, B., Cordon-Cardo, C., and Pandolfi, P. P. (1998). PTEN is essential for embryonic development and tumour suppression. Nat Genet 19, 348-355.

3. Habib, T., Hejna, J. A., Moses, R. E., and Decker, S. J. (1998). Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J Biol Chem 273, 18605-18609.

4. Ishihara, H., Sasaoka, T., Hori, H. et al. (1999). Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling. Biochem Biophys Res Commun 260, 265-272.

5. Choi, Y., Zhang, J., Murga, C. et al. (2002). PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. Oncogene 21, 5289-5300.

6. Stokoe, D., Stephens, L. R., Copeland, T. et al. (1997). Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277, 567-570.

7. Liang, J., Zubovitz, J., Petrocelli, T. et al. (2002). PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8, 1153-1160.

8. Datta, S. R., Dudek, H., Tao, X. et al. (1997). Akt phosphoryla-tion of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241.

9. Shtivelman, E., Sussman, J., and Stokoe, D. (2002). A role for PI3-kinase and PKB activity in the G2/M phase of the cell cycle. Curr Biol 12, 919-924.

10. Kandel, E. S., Skeen, J., Majewski, N. et al. (2002). Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. Mol Cell Biol 22, 7831-7841.

11. Downward, J. (1999). How BAD phosphorylation is good for survival. Nat Cell Biol 1, E33-35.

12. Cardone, M. H., Roy, N., Stennicke, H. R. et al. (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318-1321.

13. Rena, G., Guo, S., Cichy, S. C., Unterman, T. G., and Cohen, P. (1999). Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 274, 17179-17183.

14. Biggs, W. H., 3rd, Meisenhelder, J., Hunter, T., Cavenee, W. K., and Arden, K. (1999). Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 96, 7421-7426.

15. Wolfrum, C., Besser, D., Luca, E., and Stoffel, M. (2003). Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/ cytosolic localization. Proc Natl Acad Sci USA 100, 11624-11629.

16. Brunet, A., Bonni, A., Zigmond, M. J. et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868.

17. Remy, I., and Michnick, S. W. (2004). Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt. Mol Cell Biol 24, 1493-1504.

18. Maira, S. M., Galetic, I., Brazil, D. P. et al. (2001). Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294, 374-380.

19. Jefferies, H. B., Reinhard, C., Kozma, S. C., and Thomas, G. (1994). Rapamycin selectively represses translation of the

''polypyrimidine tract'' mRNA family. Proc Natl Acad Sci USA 91, 4441-4445.

20. Jefferies, H. B., Fumagalli, S., Dennis, P. B., Reinhard, C., Pearson, R. B., and Thomas, G. (1997). Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. Embo J 16, 3693-3704.

21. Shima, H., Pende, M., Chen, Y., Fumagalli, S., Thomas, G., and Kozma, S. C. (1998). Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. Embo J 17, 6649-6659.

22. Stolovich, M., Tang, H., Hornstein, E. et al. (2002). Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol Cell Biol 22, 8101-8113.

23. Tang, H., Hornstein, E., Stolovich, M. et al. (2001). Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol Cell Biol 21, 8671-8683.

24. Burnett, P. E., Barrow, R. K., Cohen, N. A. Snyder, S. H., and Sabatini, D. M. (1998). RAFT1 phosphorylation of the transla-tional regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95, 1432-1437.

25. Fingar, D. C., Richardson, C. J., Tee, A. R. Cheatham, L., Tsou, C., and Blenis, J. (2004). mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24, 200-216.

26. Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., and Thomas, G. (2001). Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102-1105.

27. Murakami, M., Ichisaka, T., Maeda, M. et al. (2004). mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 24, 6710-6718.

28. Hentges, K. E., Sirry, B., Gingeras, A. C. et al. (2001). FRAP/ mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc Natl Acad Sci USA 98, 13796-13801.

29. Inoki, K., Li, Y., Xu, T., and Guan, K. L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17, 1829-1834.

30. Oldham, S., Montagne, J., Radimerski, T., Thomas, G., and Hafen, E. (2000). Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev 14, 2689-2694.

31. Ishii, N., Maier, D., Merlo, A. et al. (1999). Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9, 469-479.

32. Haas-Kogan, D., Shalev, N., Wong, M., Mills, G., Yount, G., and Stokoe, D. (1998). Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 8, 1195-1198.

33. Chakravarti, A., Zhai, G., Suzuki, Y. et al. (2004). The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22, 1926-1933.

34. Smith, J. S., Tachibana, I., Passe, S. M. et al. (2001). PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93, 1246-1256.

35. Ermoian, R. P., Furniss, C. S., Lamborn, K. R. et al. (2002). Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res 8, 1100-1106.

36. Myers, M. P., Pass, I., Batty, I. H. et al. (1998). The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA 95, 13513-13518.

37. Ramaswamy, S., Nakamura, N., Vazquez, F. et al. (1999). Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci USA 96, 2110-2115.

38. Gottschalk, A. R., Basila, D., Wong, M. et al. (2001). p27Kip1 is required for PTEN-induced G1 growth arrest. Cancer Res 61, 2105-2111.

39. Adachi, J., Ohbayashi, K., Suzuki, T., and Sasaki, T. (1999). Cell cycle arrest and astrocytic differentiation resulting from PTEN expression in glioma cells. J Neurosurg 91, 822-830.

40. Davies, M. A., Koul, D., Dhesi, H. et al. (1999). Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res 59, 2551-2556.

41. Pore, N., Liu, S., Haas-Kogan, D. A., O'Rourke, D. M., and Maity, A. (2003). PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res 63, 236-241.

42. Tamura, M., Gu, J., Matsumoto, K., Aota, S., Parsons, R., and Yamada, K. M. (1998). Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280, 1614-1617.

43. Maier, D., Jones, G., Li, X. et al. (1999). The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells. Cancer Res 59, 5479-5482.

44. Raftopoulou, M., Etienne-Manneville, S., Self, A., Nicholls, S., and Hall, A. (2004). Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science 303, 1179-1181.

45. Taylor, V., Wong, M., Brandts, C. et al. (2000). 5'^phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol 20, 6860-6871.

46. Rodriguez-Viciana, P., Warne, P. H., Khwaja, A. et al. (1997). Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457-467.

47. Sonoda, Y., Ozawa, T., Hirose, Y. et al. (2001). Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res 61, 4956-4960.

48. Jiang, K., Sun, J., Cheng, J., Djeu, J. Y., Wei, S., and Sebti, S. (2004). Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 24, 5565-5576.

49. Sonoda, Y., Ozawa, T., Aldape, K. D., Deen, D. F., Berger, M. S., and Pieper, R. O. (2001). Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res 61, 6674-6678.

50. Rich, J. N., Guo, C., McLendon, R. E., Bigner, D. D., Wang, X. F., and Counter, C. M. (2001). A genetically tractable model of human glioma formation. Cancer Res 61, 3556-3560.

51. Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. E., and Fuller, G. N. (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25, 55-57.

52. Shi, Q., Bao, S., Maxwell, J. A. et al. (2004). Secreted protein acidic, rich in cysteine (SPARC) mediates cellular survival of gliomas through AKT activation. J Biol Chem.

53. Rajasekhar, V. K., Viale, A., Socci, N. D., Wiedmann, M., Hu, X., and Holland, E. C. (2003). Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 12, 889-901.

54. Alkarain, A., and Slingerland, J. (2004). Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Res 6, 13-21.

55. Catzavelos, C., Bhattacharya, N., Ung, Y. C. et al. (1997). Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med 3, 227-230.

56. Avdulov, S., Li, S., Michalek, V. et al. (2004). Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5, 553-563.

57. Riesterer, O., Zingg, D., Hummerjohann, J., Bodis, S., and Pruschy, M. (2004). Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells. Oncogene 23, 4624-4635.

58. Lazaris-Karatzas, A., Montine, K. S., and Sonenberg, N. (1990). Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 345, 544-547.

59. Ruggero, D., Montanaro, L., Ma, L. et al. (2004). The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10, 484-486.

60. Rosenwald, I. B., Lazaris-Karatzas, A., Sonenberg, N., and Schmidt, E. V. (1993). Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol 13, 7358-7363.

61. Rosenwald, I. B., Kaspar, R., Rousseau, D. et al. (1995). Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem 270, 21176-21180.

62. Rousseau, D., Kaspar, R., Rosenwald, I., Gehrke, L., and Sonenberg, N. (1996). Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc Natl Acad Sci USA 93, 1065-1070.

63. Topisirovic, I., Guzman, M. L., McConnell, M. J. et al. (2003). Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Mol Cell Biol 23, 8992-9002.

64. Gupta, A. K., Cerniglia, G. J., Mick, R. et al. (2003). Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys 56, 846-853.

65. Rosenzweig, K. E., Youmell, M. B., Palayoor, S. T., and Price, B. D. (1997). Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin Cancer Res 3, 1149-1156.

66. Shi, Y. Q., Blattmann, H., and Crompton, N. E. (2001). Wortmannin selectively enhances radiation-induced apoptosis in proliferative but not quiescent cells. Int J Radiat Oncol Biol Phys 49, 421-425

67. Zingg, D., Riesterer, O., Fabbro, D., Glanzmann, C., Bodis, S., and Pruschy, M. (2004). Differential activation of the phos-phatidylinositol 3'-kinase/Akt survival pathway by ionizing radiation in tumor and primary endothelial cells. Cancer Res 64, 5398-5406.

68. Geng, L., Tan, J., Himmelfarb, E. et al. (2004). A specific antagonist of the p110delta catalytic component of phosphatidylinositol 3'-kinase, IC486068, enhances radiation-induced tumor vascular destruction. Cancer Res 64, 4893-4899.

69. Edwards, E., Geng, L., Tan, J., Onishko, H., Donnelly, E., and Hallahan, D. E. (2002). Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 62, 4671-4677.

70. Li, B., Yuan, M., Kim, I. A., Chang, C. M., Bernhard, E. J., and Shu, H. K. (2004). Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 23, 4594-4602

71. Bianco, R., Shin, I., Ritter, C. A. et al. (2003). Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22, 2812-2822.

72. Li, B., Chang, C. M., Yuan, M., McKenna, W. G., and Shu, H. K. (2003). Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res 63, 7443-7450.

73. Fan, Q. W., Specht, K. M., Zhang, C., Goldenberg, D. D., Shokat, K. M., and Weiss, W. A. (2003). Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach. Cancer Res 63, 8930-8938.

74. Chakravarti, A., Loeffler, J. S., and Dyson, N. J. (2002). Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 62, 200-207.

75. Steinbach, J. P., Klumpp, A., Wolburg, H., and Weller, M. (2004). Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. Cancer Res 64, 1575-1578.

76. Chang, S. M., Kuhn, J., Wen, P. et al. (2004). Phase I/ pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs 22, 427-435.

77. Wendel, H. G., De Stanchina, E., Fridman, J. S. et al. (2004). Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332-337.

78. Podsypanina, K., Lee, R. T., Politis, C. et al. (2001). An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc Natl Acad Sci USA 98, 10320-10325.

79. Eshleman, J. S., Carlson, B. L., Mladek, A. C., Kastner, B. D., Shide, K. L., and Sarkaria, J. N. (2002). Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62, 7291-7297.

80. LaFortune, T., Liu, T.J., Yung, W.K.A. (1994). The anticancer effects of RAD001 on glioma cell lines. Neuro-Oncol 6, 332.

81. Kentsis, A., Topisirovic, I., Culjkovic, B., Shao, L., and Borden, K. L. (2004). Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA 101, 18105-18110.

82. Nakamura, J. L., Karlsson, A., Arvold, N. D. et al. (2005). PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol 71, 215-222.

PLATE 13.1 (Fig. 13.1)
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook

Post a comment