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Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies

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The phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.

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References and Recommended Reading

  1. Bjornsti MA, Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004, 4:335–348.

    Article  PubMed  CAS  Google Scholar 

  2. Sansal I, Sellers WR: The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004, 22:2954–2963.

    Article  PubMed  CAS  Google Scholar 

  3. Cully M, You H, Levine AJ, Mak TW: Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006, 6:184–192. This article provides an excellent overview of the PI3-K pathway, with special reference to oncology.

    Article  PubMed  CAS  Google Scholar 

  4. Downward J: PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004, 15:177–182.

    Article  PubMed  CAS  Google Scholar 

  5. Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell 2006, 124:471–484.

    Article  PubMed  CAS  Google Scholar 

  6. Cantley LC: The phosphoinositide 3-kinase pathway. Science 2002, 296:1655–1657.

    Article  PubMed  CAS  Google Scholar 

  7. Bader AG, Kang S, Zhao L, Vogt PK: Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005, 5:921–929.

    Article  PubMed  CAS  Google Scholar 

  8. Conde E, Angulo B, Tang M, et al.: Molecular context of the EGFR mutations: evidence for the activation of mTOR/S6K signaling. Clin Cancer Res 2006, 12:710–717.

    Article  PubMed  CAS  Google Scholar 

  9. O'Reilly KE, Rojo F, She Q et al.: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006, 66:1500–1508.

    Article  PubMed  CAS  Google Scholar 

  10. Alessi DR, Andjelkovic M, Caudwell B, et al.: Mechanism of activation of protein kinase B by insulin and IGF-1. Embo J 1996, 15:6541–6551.

    PubMed  CAS  Google Scholar 

  11. Kharas MG, Fruman DA: ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors. Cancer Res 2005, 65:2047–2053.

    Article  PubMed  CAS  Google Scholar 

  12. Rodriguez-Viciana P, Warne PH, Dhand R, et al.: Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994, 370:527–532.

    Article  PubMed  CAS  Google Scholar 

  13. Thompson JE, Thompson CB: Putting the Rap on Akt. J Clin Oncol 2004, 22:4217–4226.

    Article  PubMed  CAS  Google Scholar 

  14. Nicholson KM, Anderson NG: The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002, 14:381–395.

    Article  PubMed  CAS  Google Scholar 

  15. Brazil DP, Hemmings BA: Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 2001, 26:657–664.

    Article  PubMed  CAS  Google Scholar 

  16. Bader AG, Kang S, Vogt PK: Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A 2006, 103:1475–1479.

    Article  PubMed  CAS  Google Scholar 

  17. Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol 2002, 3:221–227.

    Article  PubMed  CAS  Google Scholar 

  18. Luo Z, Saha AK, Xiang X, Ruderman NB: AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci 2005, 26:69–76.

    Article  PubMed  CAS  Google Scholar 

  19. Brunn GJ, Hudson CC, Sekulic A, et al.: Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997, 277:99–101.

    Article  PubMed  CAS  Google Scholar 

  20. Burnett PE, Barrow RK, Cohen NA, et al.: RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A 1998, 95:1432–1437.

    Article  PubMed  CAS  Google Scholar 

  21. Gingras AC, Raught B, Sonenberg N: Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001, 15:807–826.

    Article  PubMed  CAS  Google Scholar 

  22. Hay N, Sonenberg N: Upstream and downstream of mTOR. Genes Dev 2004, 18:1926–1945.

    Article  PubMed  CAS  Google Scholar 

  23. Gingras AC, Gygi SP, Raught B, et al.: Regulation of 4EBP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999, 13:1422–1437.

    PubMed  CAS  Google Scholar 

  24. Schmelzle T, Hall MN: TOR, a central controller of cell growth. Cell 2000, 103:253–262.

    Article  PubMed  CAS  Google Scholar 

  25. Grolleau A, Bowman J, Pradet-Balade B, et al.: Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J Biol Chem 2002, 277:22175–22184.

    Article  PubMed  CAS  Google Scholar 

  26. Hudson CC, Liu M, Chiang GG, et al.: Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002, 22:7004–7014.

    Article  PubMed  CAS  Google Scholar 

  27. Thomas GV, Tran C, Mellinghoff IK, et al.: Hypoxiainducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006, 12:122–127.

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  29. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictormTOR complex. Science 2005, 307:1098–1101.

    Article  PubMed  CAS  Google Scholar 

  30. Hennessy BT, Smith DL, Ram PT, et al.: Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005, 4:988–1004.

    Article  PubMed  CAS  Google Scholar 

  31. Ali IU, Schriml LM, Dean M: Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 1999, 91:1922–1932.

    Article  PubMed  CAS  Google Scholar 

  32. Brognard J, Clark AS, Ni Y, Dennis PA: Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001, 61:3986–3997.

    PubMed  CAS  Google Scholar 

  33. Granville CA, Memmott RM, Gills JJ, Dennis PA: Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res 2006, 12:679–689. A detailed discussion and review of the drugs in various phases of development for the PI3-K/mTOR pathway.

    Article  PubMed  CAS  Google Scholar 

  34. Vlahos CJ, Matter WF, Hui KY, Brown RF: A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994, 269:5241–5248.

    PubMed  CAS  Google Scholar 

  35. Uddin S, Hussain AR, Al-Hussein KA, et al.: Inhibition of phosphatidylinositol 3'-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin Cancer Res 2005, 11:3102–3108.

    Article  PubMed  CAS  Google Scholar 

  36. Shi Y, Yan H, Frost P, et al.: Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005, 4:1533–1540.

    Article  PubMed  CAS  Google Scholar 

  37. Hideshima T, Catley L, Yasui H, et al.: Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006, 107:4053–4062.

    Article  PubMed  CAS  Google Scholar 

  38. Crul M, Rosing H, de Klerk GJ, et al.: Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 2002, 38:1615–1621.

    Article  PubMed  CAS  Google Scholar 

  39. Van Ummersen L, Binger K, Volkman J, et al.: A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 2004, 10:7450–7456.

    Article  PubMed  Google Scholar 

  40. Sehgal SN, Baker H, Vezina C: Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 1975, 28:727–732.

    CAS  Google Scholar 

  41. Vezina C, Kudelski A, Sehgal SN: Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975, 28:721–726.

    CAS  Google Scholar 

  42. Sehgal SN: Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998, 31:335–340.

    Article  PubMed  CAS  Google Scholar 

  43. Vignot S, Faivre S, Aguirre D, Raymond E: mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005, 16:525–537.

    Article  PubMed  CAS  Google Scholar 

  44. Recher C, Beyne-Rauzy O, Demur C, et al.: Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005, 105:2527–2534.

    Article  PubMed  CAS  Google Scholar 

  45. Teachey DT, Obzut DA, Cooperman J, et al.: The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood 2006, 107:1149–1155.

    Article  PubMed  CAS  Google Scholar 

  46. Rizzieri DR, Feldman E, Moore JO: A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies [abstract]. Blood 2005, 106:2980.

    Google Scholar 

  47. Witzig TE, Geyer SM, Ghobrial I, et al.: Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005, 23:5347–5356. The first trial to demonstrate clinical activity of the mTOR inhibitors in lymphoma.

    Article  PubMed  CAS  Google Scholar 

  48. Hipp S, Ringshausen I, Oelsner M, et al.: Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica 2005, 90:1433–1434.

    PubMed  CAS  Google Scholar 

  49. Witzig TE, Ansell SM, Geyer SM, et al.: Anti-tumor activity of low-dose single agent CCI-779 for relapsed mantle cell lymphoma: a phase II trial in the North Central Cancer Treatment Group [abstract 6503]. Proc Am Soc Clin Oncol 2005, 23:561s.

    Google Scholar 

  50. Majewski M, Korecka M, Joergensen J, et al.: Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograftprotecting doses. Transplantation 2003, 75:1710–1717.

    Article  PubMed  CAS  Google Scholar 

  51. Majewski M, Korecka M, Kossev P, et al.: The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: a potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci U S A 2000, 97:4285–4290.

    Article  PubMed  CAS  Google Scholar 

  52. Raje N, Kumar S, Hideshima T, et al.: Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 2004, 104:4188–4193.

    Article  PubMed  CAS  Google Scholar 

  53. Frost P, Moatamed F, Hoang B, et al.: In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004, 104:4181–4187.

    Article  PubMed  CAS  Google Scholar 

  54. Molhoek KR, Brautigan DL, Slingluff CL Jr: Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor rapamycin. J Transl Med 2005, 3:39.

    Article  PubMed  CAS  Google Scholar 

  55. Beuvink I, Boulay A, Fumagalli S, et al.: The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005, 120:747–759.

    Article  PubMed  CAS  Google Scholar 

  56. Xu Q, Thompson JE, Carroll M: mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood 2005, 106:4261–4268.

    Article  PubMed  CAS  Google Scholar 

  57. Wendel HG, De Stanchina E, Fridman JS, et al.: Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004, 428:332–337.

    Article  PubMed  CAS  Google Scholar 

  58. Smith PG, Wang F, Wilkinson KN, et al.: The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKTdependent apoptosis in diffuse large B-cell lymphoma. Blood 2005, 105:308–316.

    Article  PubMed  CAS  Google Scholar 

  59. Lal L, Li Y, Smith J, et al.: Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells. Blood 2005, 105:1669–1677.

    Article  PubMed  CAS  Google Scholar 

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  1. Mayo Clinic, Stabile 628, 200 First Street SW, 55905, Rochester, MN, USA

    Thomas E. Witzig MD

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  1. Thomas E. Witzig MD
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  2. Scott H. Kaufmann MD, PhD
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Witzig, T.E., Kaufmann, S.H. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr. Treat. Options in Oncol. 7, 285–294 (2006). https://doi.org/10.1007/s11864-006-0038-1

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