Conclusions

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

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Enthusiasm for the development of molecularly targeted agents has been spurred by the clinical successes of trastuzumab and imatinib mesylate, and the more recent approvals of gefitinib, cetuximab, and bevacizumab. One of the lessons learned from the development of these agents is the importance of target selection. Appropriate targets are the aberrant pathways or molecules upon which the cancer cell is critically dependent. The challenge here is whether targeting a single pathway or molecule will impact tumor burden given the redundancies in signaling pathways and the molecular heterogeneity inherent in the tumor cell population. In light of this problem, an approach that might prove effective is the targeting of convergence points of multiple signaling pathways, such as Akt. Modulation of such targets may provide more complete inhibition than those farther upstream, such as cell surface receptors. Of course, the potential benefits of such an approach will have to be balanced by careful evaluation of potential toxicities, as such points of signaling confluence are utilized in multiple cellular functions, including those in normal cell populations. Nevertheless, given the importance of signaling through PI3K/Akt in prostate cancer, targeting components of this pathway, either alone or in combination with cytotoxic agents or other targeted therapeutics, holds substantial promise.

Molecularly targeted agents that alter pathways critical to cancer cell survival and progression will undoubtedly compose, either alone or in combination, the foundation for future chemotherapeutic strategies for HRPC. The rate at which these strategies can mature and be translated to the clinical setting will rely in part on the identification and validation of appropriate targets, the consideration of more global signaling profiles or signatures in tumor cells that will facilitate the identification of critical pathways that can be targeted in combination, utilization of modern drug discovery/medicinal chemistry resources, access of clinician-scientists to new investigational agents developed by these resources, development of innovative means to identify patients who harbor a relevant target, and to assess drug responses in these patients, and on substantive and informative interactions among basic scientists and clinicians.

References

1. Oefelein MG, Resnick MI (2003) Effective testosterone suppression for patients with prostate cancer: Is there a best castration? Urology 62:207-213.

2. Goktas S, Crawford ED (1999) Optimal hormonal therapy for advanced prostatic carcinoma. Semin Oncol 26:162-173.

3. David AK, Khwaja R, Hudes GR (2003) Treatments for improving survival of patients with prostate cancer. Drugs Aging 20:683-699.

4. Small EJ, Vogelzang NJ (1997) Second-line hormonal therapy for advanced prostate cancer: A shifting paradigm. J Clin Oncol 15:382-388.

5. Roth BJ (1999) Androgen-independent prostate cancer: Not so chemorefrac-tory after all. Semin Oncol 26:43-50.

6. Scherr D, Swindle PW, Scardino PT (2003) National Comprehensive Cancer Network guidelines for the management of prostate cancer. Urology 61: 14-24.

7. Smaletz O, Scher HI, Small EJ, et al. (2002) Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 20:3972-3982.

8. Kamradt JM, Pienta KJ (2001) Prostate cancer chemotherapy: Closing out a century and opening a new one. In: Chung LWK, Isaacs WB, Simons JW, eds. Prostate Cancer: Biology, Genetics and the New Therapeutics. Human Press, Inc., Totowa, NJ, pp. 415-431.

9. Goodin S, Rao KV DiPaola RS (2002) State-of-the-art treatment of metastatic hormone-refractory prostate cancer. Oncologist 7:360-370.

10. Solit DB, Kelly WK (2002) Chemotherapy for androgen-independent prostate cancer. In: Kantoff PW, Carroll PR, D'Amico AV eds. Prostate Cancer: Principles and Practice. Lippincott, Williams and Wilkins, Philadelphia, PA, pp. 665-681.

11. Martel CL, Gumerlock PH, Meyers FJ, Lara PN (2003) Current strategies in the management of hormone refractory prostate cancer. Cancer Treat Rev 29:171-187.

12. Trump D, Lau YK (2003) Chemotherapy of prostate cancer: Present and future. Curr Urol Rep 4:229-232.

13. Stearns ME, Tew KD (1988) Estramustine binds MAP-2 to inhibit microtubule assembly in vitro. J Cell Sci 89(Pt 3):331-342.

14. Tew KD, Glusker JP, Hartley-Asp B, Hudes G, Speicher LA (1992) Preclinical and clinical perspectives on the use of estramustine as an antimi-totic drug. Pharmacol Ther 56:323-339.

15. Obasaju C, Hudes GR (2001) Paclitaxel and docetaxel in prostate cancer. Hematol Oncol Clin North Am 15:525-545.

16. Slamon DJ, Leyland-Jones B, Shak S, et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792.

17. Druker BJ, Sawyers CL, Kantarjian H, et al. (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038-1042.

18. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052-1056.

19. Chan TO, Rittenhouse SE, Tsichlis PN (1999) AKT/PKB and other D3 phos-phoinositide-regulated kinases: Kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 68:965-1014.

20. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: A play in three Akts. Genes Dev 13:2905-2927.

21. Toker A, Cantley LC (1997) Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387:673-676.

22. Storz P, Toker A (2002) 3'-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling. Front Biosci 7:886-902.

23. Scheid MP, Woodgett JR (2003) Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 546:108-112.

24. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296: 1655-1657.

25. Hill MM, Hemmings BA (2002) Inhibition of protein kinase B/Akt. Implications for cancer therapy. Pharmacol Therap 93:243-251.

26. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82-85.

27. Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240-4245.

28. Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387-390.

29. Wang SI, Parsons R, Ittmann M (1998) Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin Cancer Res 4:811-815.

30. Whang YE, Wu X, Suzuki H, et al. (1998) Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 95:5246-5250.

31. McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR (1999) Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 59: 4291-4296.

32. Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J (1998) Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 58:2720-2723.

33. Abate-Shen C, Shen MM (2000) Molecular genetics of prostate cancer. Genes Dev 14:2410-2434.

34. DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI (2003) Pathological and molecular aspects of prostate cancer. Lancet 361:955-964.

35. Djakiew D (2000) Dysregulated expression of growth factors and their receptors in the development of prostate cancer. Prostate 42:150-160.

36. Page C, Lin HJ, Jin Y, et al. (2000) Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res 20:407-416.

37. Graff JR, Konicek BW, McNulty AM, et al. (2000) Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 275:24500-24505.

38. Paweletz CP, Charboneau L, Bichsel VE, et al. (2001) Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 20: 1981-1989.

39. Malik SN, Brattain M, Ghosh PM, et al. (2002) Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 8:1168-1171.

40. Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C, Pandolfi PP (2001) Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 27:222-224.

41. Majumder PK, Yeh JJ, George DJ, et al. (2003) Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: The MPAKT model. Proc Natl Acad Sci USA 100:7841-7846.

42. Kwabi-Addo B, Giri D, Schmidt K, et al. (2001) Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA 98:11563-11568.

43. Kim MJ, Cardiff RD, Desai N, et al. (2002) Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci USA 99:2884-2889.

44. Backman SA, Ghazarian D, So K, et al. (2004) Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten. Proc Natl Acad Sci USA 101:1725-1730.

45. Wang S, Gao J, Lei Q, et al. (2003) Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4:209-221.

46. Dimmeler S, Zeiher AM (2000) Akt takes center stage in angiogenesis signaling. Circ Res 86:4-5.

47. Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1:707-717.

48. Wu K, Wang C, D'Amico M, et al. (2002) Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: Association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways. Mol Cancer Ther 1:695-706.

49. Hayakawa J, Ohmichi M, Kurachi H, et al. (2000) Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res 60:5988-5994.

50. Mabuchi S, Ohmichi M, Kimura A, et al. (2002) Inhibition of phosphoryla-tion of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to pacli-taxel. J Biol Chem 277:33490-33500.

51. Yip-Schneider MT, Wiesenauer CA, Schmidt CM (2003) Inhibition of the phosphatidylinositol 3'-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac. JGastrointest Surg 7:354-363.

52. Kraus AC, Ferber I, Bachmann SO, et al. (2002) In vitro chemo- and radioresistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene 21:8683-8695.

53. Krystal GW, Sulanke G, Litz J (2002) Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. Mol Cancer Ther 1:913-922.

54. O'Gorman DM, McKenna SL, McGahon AJ, Knox KA, Cotter TG (2000) Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals. Leukemia 14:602-611.

Neri LM, Borgatti P, Tazzari PL, et al. (2003) The phosphoinositide 3-kinase/ AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol Cancer Res 1:234-246.

Beresford SA, Davies MA, Gallick GE, Donato NJ (2001) Differential effects of phosphatidylinositol-3/Akt-kinase inhibition on apoptotic sensitization to cytokines in LNCaP and PCc-3 prostate cancer cells. J Interferon Cytokine Res 21:313-322.

West KA, Sianna Castillo S, Dennis PA (2002) Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat 5:234-248. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103: 211-225.

Barton J, Blackledge G, Wakeling A (2001) Growth factors and their receptors: New targets for prostate cancer therapy. Urology 58:114-122. Fabbro D, Parkinson D, Matter A (2002) Protein tyrosine kinase inhibitors: New treatment modalities? Curr Opin Pharmacol 2:374-381. Scher HI, Sarkis A, Reuter V et al. (1995) Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms. Clin Cancer Res 1:545-550. Olapade-Olaopa EO, Moscatello DK, MacKay EH, et al. (2000) Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer. Br J Cancer 82:186-194.

Hudes GR (2002) Signaling inhibitors in the treatment of prostate cancer.

Invest New Drugs 20:159-172.

Signoretti S, Montironi R, Manola J, et al. (2000) Her-2-neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst 92:1918-1925.

Osman I, Scher HI, Drobnjak M, et al. (2001) HER-2/neu (p185neu) protein expression in the natural or treated history of prostate cancer. Clin Cancer Res 7:2643-2647.

Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C (1999) From HER2/ Neu signal cascade to androgen receptor and its coactivators: A novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA 96:5458-5463. Wen Y, Hu MC, Makino K, et al. (2000) HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 60:6841-6845.

Ratan HL, Gescher A, Steward WP, Mellon JK (2003) ErbB receptors: Possible therapeutic targets in prostate cancer? BJU Int 92:890-895.

69. Agus DB, Scher HI, Higgins B, et al. (1999) Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models. Cancer Res 59:4761-4764.

70. Morris MJ, Reuter VE, Kelly WK, et al. (2002) HER-2 profiling and targeting in prostate carcinoma. Cancer 94:980-986.

71. Albanell J, Codony J, Rovira A, Mellado B, Gascon P (2003) Mechanism of action of anti-HER2 monoclonal antibodies: Scientific update on trastuzumab and 2C4. Adv Exp Med Biol 532:253-268.

72. Mendoza N, Phillips GL, Silva J, Schwall R, Wickramasinghe D (2002) Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer. Cancer Res 62:5485-5488.

73. Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG (2000) Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6:4885-4892.

74. Lorusso PM (2003) Phase I studies of ZD1839 in patients with common solid tumors. Semin Oncol 30:21-29.

75. Mellinghoff IK, Tran C, Sawyers CL (2002) Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts. Cancer Res 62:5254-5259.

76. Bergsten E, Uutela M, Li X, et al. (2001) PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol 3:512-516.

77. LaRochelle WJ, Jeffers M, McDonald WF, et al. (2001) PDGF-D, a new protease-activated growth factor. Nat Cell Biol 3:517-521.

78. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283-1316.

79. Fudge K, Wang CY, Stearns ME (1994) Immunohistochemistry analysis of platelet-derived growth factor A and B chains and platelet-derived growth factor alpha and beta receptor expression in benign prostatic hyperplasias and Gleason-graded human prostate adenocarcinomas. Mod Pathol 7: 549-554.

80. Chott A, Sun Z, Morganstern D, et al. (1999) Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. Am J Pathol 155:1271-1279.

81. Fudge K, Bostwick DG, Stearns ME (1996) Platelet-derived growth factor A and B chains and the alpha and beta receptors in prostatic intraepithelial neoplasia. Prostate 29:282-286.

82. Ko YJ, Small EJ, Kabbinavar F, et al. (2001) A multi-institutional phase ii study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. Clin Cancer Res 7: 800-805.

83. Shawver LK, Schwartz DP, Mann E, et al. (1997) Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide. Clin Cancer Res 3:1167-1177.

84. Buchdunger E, Cioffi CL, Law N, et al. (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295: 139-145.

85. Uehara H, Kim SJ, Karashima T, et al. (2003) Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 95:458-470.

86. Kaplan DR, Miller FD (1997) Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 9:213-221.

87. Weeraratna AT, Arnold JT, George DJ, DeMarzo A, Isaacs JT (2000) Rational basis for Trk inhibition therapy for prostate cancer. Prostate 45:140-148.

88. Dionne CA, Camoratto AM, Jani JP, et al. (1998) Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin Cancer Res 4:1887-1898.

89. George DJ, Dionne CA, Jani J, et al. (1999) Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res 59:2395-2401.

90. Weeraratna AT, Dalrymple SL, Lamb JC, et al. (2001) Pan-trk inhibition decreases metastasis and enhances host survival in experimental models as a result of its selective induction of apoptosis of prostate cancer cells. Clin Cancer Res 7:2237-2245.

91. Choy M, Rafii S (2001) Role of angiogenesis in the progression and treatment of prostate cancer. Cancer Invest 19:181-191.

92. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L (2003) VEGF-receptor signal transduction. Trends Biochem Sci 28:488-494.

93. Gerber HP, McMurtrey A, Kowalski J, et al. (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidyli-nositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/ KDR activation. J Biol Chem 273:30336-30343.

94. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401-409.

95. Ferrer FA, Miller LJ, Lindquist R, et al. (1999) Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology 54:567-572.

96. Chevalier S, Defoy I, Lacoste J, et al. (2002) Vascular endothelial growth factor and signaling in the prostate: More than angiogenesis. Mol Cell Endocrinol 189:169-179.

97. Borgstrom P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N (1998) Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo. Prostate 35:1-10.

98. Melnyk O, Zimmerman M, Kim KJ, Shuman M (1999) Neutralizing anti-vascular endothelial growth factor antibody inhibits further growth of established prostate cancer and metastases in a pre-clinical model. J Urol 161:960-963.

99. Fox WD, Higgins B, Maiese KM, et al. (2002) Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res 8:3226-3231.

100. Gordon MS, Margolin K, Talpaz M, et al. (2001) Phase I safety and phar-macokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843-850.

101. Picus J (2004) Docetaxel/Bevacizumab (avastin) in prostate cancer. Cancer Invest 22(Suppl 1):60 (Abstract 46).

102. Wedge SR, Ogilvie DJ, Dukes M, et al. (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645-4655.

103. Ciardiello F, Caputo R, Damiano V et al. (2003) Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyro-sine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 9:1546-1556.

104. Fong TA, Shawver LK, Sun L, et al. (1999) SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59:99-106.

105. Rothenberg ML, Berlin JD, Cropp GF, et al. (2001) Phase I/II study of SU5416 in combination with irinotecan/5-FU/LV (IFL) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 20:75a (Abstract 298).

106. Unknown (2002) Trials terminated (News Update). Appl Clin Trials 11:16.

107. Hancock JF (2003) Ras proteins: Different signals from different locations. Nat Rev Mol Cell Biol 4:373-384.

108. Shields JM, Pruitt K, McFall A, Shaub A, Der CJ (2000) Understanding Ras: 'It ain't over 'til it's over'. Trends Cell Biol 10:147-154.

109. Bos JL (1989) ras oncogenes in human cancer: A review. Cancer Res 49: 4682-4689.

110. Carter BS, Epstein JI, Isaacs WB (1990) ras gene mutations in human prostate cancer. Cancer Res 50:6830-6832.

111. Gumerlock PH, Poonamallee UR, Meyers FJ, deVere White RW (1991) Activated ras alleles in human carcinoma of the prostate are rare. Cancer Res 51:1632-1637.

112. Moul JW, Friedrichs PA, Lance RS, Theune SM, Chang EH (1992) Infrequent RAS oncogene mutations in human prostate cancer. Prostate 20:327-338.

113. Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ (1999) Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 59:279-284.

114. Bakin RE, Gioeli D, Sikes RA, Bissonette EA, Weber MJ (2003) Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res 63:1981-1989.

115. Holmlund JT, Monia BP, Kwoh TJ, Dorr FA (1999) Toward antisense oligonucleotide therapy for cancer: ISIS compounds in clinical development. Curr Opin Mol Ther 1:372-385.

116. Cunningham CC, Holmlund JT, Geary RS, et al. (2001) A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. Cancer 92:1265-1271.

117. Adjei AA, Dy GK, Erlichman C, et al. (2003) A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res 9:115-123.

118. Monia BP, Johnston JF, Sasmor H, Cummins LL (1996) Nuclease resistance and antisense activity of modified oligonucleotides targeted to Ha-ras. J Biol Chem 271:14533-14540.

119. Geiger T, Muller M, Monia BP, Fabbro D (1997) Antitumor activity of a C-raf antisense oligonucleotide in combination with standard chemothera-peutic agents against various human tumors transplanted subcutaneously into nude mice. Clin Cancer Res 3:1179-1185.

120. Tolcher AW, Reyno L, Venner PM, et al. (2002) A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res 8:2530-2535.

121. Kohl NE (1999) Farnesyltransferase inhibitors. Preclinical development. Ann N Y Acad Sci 886:91-102.

122. Sepp-Lorenzino L, Tjaden G, Moasser MM, et al. (2001) Farnesyl: Protein transferase inhibitors as potential agents for the management of human prostate cancer. Prostate Cancer Prostatic Dis 4:33-43.

123. Shi B, Yaremko B, Hajian G, et al. (2000) The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo. Cancer Chemother Pharmacol 46:387-393.

124. Liu M, Bryant MS, Chen J, et al. (1998) Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 58:4947-4956.

125. Nielsen LL, Shi B, Hajian G, et al. (1999) Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 ade-novirus) in preclinical cancer models. Cancer Res 59:5896-5901.

126. Sirotnak FM, Sepp-Lorenzino L, Kohl NE, Rosen N, Scher HI (2000) A peptidomimetic inhibitor of ras functionality markedly suppresses growth of human prostate tumor xenografts in mice. Prospects for long-term clinical utility. Cancer Chemother Pharmacol 46:79-83.

127. Haas N, Peereboom D, Rangnanathan S, Thistle A, Greenberg R (2002) Phase II trial of R115777, an inhibitor of farnesyltransferase, in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 21:181a (Abstract 721).

128. Mills GB, Kohn E, Lu Y, et al. (2003) Linking molecular diagnostics to molecular therapeutics: Targeting the PI3K pathway in breast cancer. Semin Oncol 30:93-104.

129. Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2:1093-1103.

130. Sato S, Fujita N, Tsuruo T (2002) Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21: 1727-1738.

131. Shao RG, Shimizu T, Pommier Y (1997) 7-Hydroxystaurosporine (UCN-01) induces apoptosis in human colon carcinoma and leukemia cells independently of p53. Exp Cell Res 234:388-397.

132. Senderowicz AM (2002) The cell cycle as a target for cancer therapy: Basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01. Oncologist 7(Suppl 3):12-19.

133. Song X, Lin HP, Johnson AJ, et al. (2002) Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells. J Natl Cancer Inst 94:585-591.

134. Zhu J, Song X, Lin HP, et al. (2002) Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J Natl Cancer Inst 94:1745-1757.

135. Kulp SK, Yang YT, Hung CC, et al. (2004) 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 64: 1444-1451.

136. Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr (1998) Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 95:7772-7777.

137. Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: Identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344(Pt 2): 427-431.

138. Dutcher JP (2004) Mammalian target of rapamycin (mTOR) inhibitors. Curr Oncol Rep 6:111-115.

139. Tolcher AW (2004) Novel therapeutic molecular targets for prostate cancer: The mTOR signaling pathway and epidermal growth factor receptor. J Urol 171:S41-43 (discussion S44).

140. Neshat MS, Mellinghoff IK, Tran C, et al. (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98:10314-10319.

141. Podsypanina K, Lee RT, 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.

142. Shi Y, Gera J, Hu L, et al. (2002) Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62: 5027-5034.

143. Yu K, Toral-Barza L, Discafani C, et al. (2001) mTOR, a novel target in breast cancer: The effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249-258.

144. Hidalgo M, Rowinsky EK (2000) The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19:6680-6686.

145. Mousses S, Wagner U, Chen Y, et al. (2001) Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 20: 6718-6723.

146. Grunwald V, DeGraffenried L, Russel D, Friedrichs WE, Ray RB, Hidalgo M (2002) Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 62:6141-6145.

147. van der Poel HG, Hanrahan C, Zhong H, Simons JW (2003) Rapamycin induces Smad activity in prostate cancer cell lines. Urol Res 30:380-386.

148. Gao N, Zhang Z, Jiang BH, Shi X (2003) Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun 310:1124-1132.

149. Gera JF, Mellinghoff IK, Shi Y, et al. (2004) AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 279:2737-2746.

150. Huang S, Houghton PJ (2003) Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3:371-377.

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