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Clinical Cancer Research 13, 3771, July 1, 2007. doi: 10.1158/1078-0432.CCR-06-2921
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Molecular Pathways

Targeting the Phosphatidylinositol 3-Kinase Pathway in Multiple Myeloma

Hashem Younes1, Xavier Leleu2, Evdoxia Hatjiharissi2, Anne-Sophie Moreau2, Teru Hideshima2, Paul Richardson2, Kenneth C. Anderson2 and Irene M. Ghobrial2

Authors' Affiliations: 1 Department of Internal Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania and 2 Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Irene M. Ghobrial, Dana-Farber Cancer Institute, 44 Binney Street, Mayer 548A, Boston, MA 02115. Phone: 617-632-4198; E-mail: irene_ghobrial{at}dfci.harvard.edu.

Abstract

Multiple myeloma is a plasma cell neoplasm with a median survival of 3 to 5 years. Recent advances have improved patient outlook, but the disease remains incurable. Therefore, continued efforts to develop new therapies that target aberrant signaling pathways are needed. The phosphatidylinositol 3-kinase pathway regulates apoptosis, cell cycle regulation, and tumor proliferation. This pathway is constitutively activated in multiple myeloma and its inhibition induces apoptosis. Advances in understanding the signaling cascades mediating proliferation and survival of multiple myeloma cells have markedly improved the treatment of this disease. In this article, we review the role of the phosphatidylinositol 3-kinase/Akt pathway in the pathogenesis of multiple myeloma and the potential therapeutic implications of targeting this pathway in the treatment of multiple myeloma.

Background

Multiple myeloma is the second most common hematologic malignancy, with 15,000 new cases per year (1), and remains incurable with a median survival of 3 to 5 years (2). In multiple myeloma, plasma cells localize in the bone marrow, a microenvironment which supports their survival and growth (3). One of the signaling pathways whose deregulation may play an oncogenic role in multiple myeloma and several other cancers is the phosphatidylinositol 3-kinase (PI3K) pathway (4–7). The PI3K pathway regulates apoptosis, cell cycle regulation, and tumor proliferation (6). This cascade is constitutively activated in multiple myeloma and its inhibition induces apoptosis (8). In addition, the PI3K pathway also plays a major role in migration of plasma cells (9). In this article, we review the role of the PI3K/Akt pathway in the oncogenesis of multiple myeloma and the potential therapeutic implications of targeting this pathway in the novel treatment strategies.

The PI3K Pathway

PI3Ks are a large and complex family of lipid kinases that phosphorylate the 3'-OH group of the inositol ring in inositol phospholipids (4). The family contains three classes, with multiple subunits and isoforms (10). Class I PI3Ks catalyze the phosphorylation of multiple phosphatidylinositols, mainly PtdIns(4,5)P2 (sometimes referred to as PIP2), which is converted to PtdIns(3,4,5)P3 (called PIP3; ref. 10). Based on the receptor used to transmit their signals, class I PI3Ks are subdivided into two subgroups: IA and IB. Subgroup IA is activated by tyrosine kinase–coupled receptors, whereas subgroup IB uses G protein–coupled receptors. Because subgroup IA is clearly involved in oncogenesis, our discussion will be restricted to this subgroup (10). At the molecular level, class I PI3Ks are heterodimers which consist of a regulatory p85 subunit, a phosphoprotein substrate for many cytoplasmic and receptor tyrosine kinases (RTK), and a catalytic p110 subunit. Both subunits are encoded by a different set of three genes ({alpha}, ß, and {gamma}), which are also subject to alternate splicing, thereby yielding multiple variants (4, 10).

In normal cells, the PI3K pathway is under tight regulation by various mechanisms (11). The inactive p85-p110 complex present in the cytoplasm of resting cells is activated through ligands binding a RTK on the plasma membrane. This interaction drives the p85-p110 complex to the cytoplasmic tail of this RTK receptor and leads to activation of the PI3K kinase, either by a direct interaction between an SH2 domain of p85 regulatory subunit of the complex with consensus phosphotyrosine residues on RTK or by indirect interaction through IRS1/IRS2 signaling intermediates. The net result is activation of the PI3K complex due both to the close proximity of the p110 catalytic subunit with its lipid substrates in the cell membrane and relief of an inhibitory effect of p85 on p110 associated with the RTK-p85 interaction and the resulting p85-p110 complex conformational changes (11).

PtdIns(3,4,5)P3 (PIP3) generation, which functions as a second messenger activating multiple downstream pathways, is the main consequence of PI3K activation. The basic function of PIP3 is the recruitment to the inner membrane and activation of pleckstrin homology domain–containing proteins. Most important among these proteins is Akt, the cellular homologue of the retroviral oncogene v-Akt, which is also known as protein kinase B (12, 13). Akt encodes a serine/threonine kinase composed of an NH2-terminal pleckstrin homology domain, a central catalytic domain, and a short COOH-terminal regulatory domain (14, 15). Akt activation involves two steps: translocation to the plasma membrane and phosphorylation at Thr308 and Ser473 residues (13, 15). Phosphorylation at Thr308, a necessary and sufficient step at Akt activation, is mediated by 3-phosphoinositide–dependent protein kinase 1, another pleckstrin homology domain–containing kinase on the inner leaflet of the plasma membrane (7, 16). Maximal Akt activation requires phosphorylation at Ser473 residue by a poorly characterized 3-phosphoinositide–dependent protein kinase 1 (ref. 16; Fig. 1 ).


Figure 1
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  		Fig. 1. Schematic of the PI3K pathway and downstream proteins regulating cell cycle and proliferation. Inhibitors of this pathway include direct inhibitors of the PI3K pathway such as perifosine, enzastaurin, and mTOR inhibitors (CCI-779 and RAD001), as well as indirect inhibitors such as Hsp90 inhibitors (KOS-953 and 17-AAG) and IL-6 and IGF-IR inhibitors.

 
Akt activation mediates multiple biological activities including increased survival, proliferation, and growth of tumor cells (7, 17, 18). Another speculated Akt effect is related to tumor-induced angiogenesis (19). The effect of Akt on survival of cancer cells is related to its antiapoptotic properties (20). Dominant-negative alleles of Akt block cell survival even in the presence of many mediators of survival such as insulin-like growth factor I (IGF-I; ref. 21). This effect of Akt is likely multifactorial because Akt directly phosphorylates several components of the cell death machinery (21). For example, phosphorylation of BAD (a proapoptotic member of the Bcl-2 family) prevents its binding and inactivation of the survival factor Bcl-XL (22–24). Similarly, Akt phosphorylates and inhibits the catalytic activity of caspase-9, a known proapoptotic protease (23, 24). A third mechanism of Akt antiapoptotic effect is mediated by phosphorylation of FKHR, a member of the Forkhead family of transcription factors, which inhibits the nuclear translocation and activation of proapoptotic FKHR gene target proteins, such as Bim and Fas ligands (14, 22, 23). In addition to its direct antiapoptotic effect, Akt influences indirectly two central regulators of cell death, nuclear factor {kappa}B and p53 (13, 14, 24). Nuclear factor {kappa}B is a known mediator promoting cell survival in response to many survival stimuli. It is indirectly activated by Akt through direct phosphorylation and activation of I{kappa}B kinase, thereby inducing degradation of the nuclear factor-{kappa}B inhibitor (I{kappa}B; refs. 22, 24). The effect on p53 is mediated by the phosphorylation and activation of the p53-binding protein murine double minute-2, a ubiquitin ligase–containing proteasome, resulting in the degradation of the proapoptotic tumor suppressor p53 (ref. 22; Fig. 1).

In addition to its cell survival effect, Akt also enhances proliferation and growth of tumor cells (25, 26) via its effects on cell cycle regulation by modulating cyclin D1, an important factor in the G1-S phase transition of the cell. Through phosphorylation and inhibition of cyclin D1, Akt prevents its degradation and leads to its accumulation in the cell (26). Akt kinase also mediates phosphorylation and activation of mammalian target of rapamycin (mTOR; ref. 25). A serine/threonine kinase that serves as a molecular sensor regulating protein synthesis in response to availability of nutrients, mTOR regulates biogenesis by activating p70 ribosomal S6 kinase and enhancing translation (27). Another mTOR effect is inhibition of 4E-binding protein 1 (PHAS-I), a translational repressor. Enhanced mRNA translation results in up-regulation of multiple proteins involved in cell cycle progression from G1 to S phase (27). The mTOR pathway plays a role in pathogenesis of multiple solid tumors and hematologic malignancies including multiple myeloma (refs. 21, 28–30; Fig. 1).

PI3K Pathway and Human Cancer

Studies have shown that multiple genes encoding proteins involved in the PI3K pathway are mutated in human cancers (31, 32). The earliest and most compelling evidence of the involvement of the PI3K pathway in human cancer came from studies involving deletion of phosphatase and tensin homologue (PTEN) tumor suppressor gene in multiple cancer types (33, 34). PTEN protein product is a phosphatase that has a dual activity toward both phosphotyrosine and phospholipid substrates. Dephosphorylation of PI3K products, mainly PIP3, by PTEN leads to the decreased level of this phospholipid and a concomitant reduction in Akt activity (34). Conversely, the loss of PTEN expression has been detected in many cancers (34, 35). A high incidence of hematopoietic tumors and lymphoid hyperplasia was observed in PTEN-knockout mice, suggesting a role of PTEN in regulating hematopoietic cell proliferation, cell death, and malignant transformation (33, 34).

Multiple Myeloma and the Role of PI3K Pathway

Myeloma is a B-cell malignancy characterized by excess monoclonal plasma cells in the bone marrow. Multiple studies have shown that the PI3K pathway is involved in the development of multiple myeloma (25). Specifically, previous studies showed that interleukin-6 (IL-6) stimulates growth and survival of multiple myeloma cells, at least in part, via the PI3K/Akt pathway (36). Similarly, IGF-I is a growth factor for multiple myeloma, which also activates the PI3K pathway (25, 37, 38). mTOR, a major survival checkpoint regulator downstream of Akt, has shown significant antiapoptotic activity in multiple myeloma (25, 29). It is a serine/threonine kinase that enhances the phosphorylation and subsequent activation of p70 ribosomal S6 kinase and 4E-binding protein 1, associated with multiple myeloma cell proliferation and survival (29).

Clinical Translational Advances

Agents that target the PI3K pathway in multiple myeloma. Improved understanding of the pathways involved in multiple myeloma cell transformation has led to the development of several new treatment approaches. PI3K/Akt pathway inhibitors are already being studied in phase II trials, whereas others are still in phase I trials or preclinical studies showing antitumor activity. PI3K/Akt pathway inhibitors can be divided into direct versus indirect inhibitors of specific members of the pathway.

Direct inhibitors of the PI3K/Akt pathway. These include the Akt inhibitor perifosine, the PKC inhibitor enzastaurin, and the mTOR inhibitors RAD001 and CCI-779.

Akt inhibitors. Due to its central role in the proliferation, survival, migration, and drug resistance of multiple myeloma cells in vitro, Akt represents a promising target for novel therapies. Perifosine [(1,1-dimethyl-4 [(octadecyloxy)hydroxyphosphinyl]oxy)-piperidinium inner salt, NSC 639966; Keryx Biopharmaceuticals] is a novel oral Akt inhibitor that belongs to a class of lipid-related compounds called alkylphospholipids. Perifosine was found to inhibit phosphorylation of Akt (at both Ser473 and Thr308 positions) and its downstream molecules, FKHRL1 and glycogen synthase kinase 3{alpha}/ß, in a time- and dose-dependent fashion (39). It triggered significant cytotoxicity against multiple myeloma cells, both in vitro and in vivo, even in the presence of stromal cells that induce drug resistance (39). This cytotoxic effect was mediated via caspase-8, caspase-9, and poly(ADP-ribose) polymerase cleavage and was associated with c-jun NH2-terminal kinase activation (39). In addition, perifosine enhances the antitumor activity of multiple other agents such as bortezomib and dexamethasone (39). A phase II clinical trial to test the efficacy of perifosine treatment in patients with relapsed multiple myeloma is ongoing. To date, it has been well tolerated with a favorable side effect profile, which includes mainly nausea, vomiting, and fatigue, but no myelosuppression or neuropathy (40). The multiple myeloma trial is ongoing and has already shown early activity, specifically in combination with dexamethasone (40). A follow-up study of the combination of perifosine and bortezomib based on synergistic antitumor cytotoxicity in vitro is now being initiated.

Protein kinase C inhibitors. Protein kinases C (PKC) family proteins are composed of 11 members of serine threonine kinases that mediate proliferation, survival, migration, and angiogenesis in many malignancies (41). These proteins directly activate the PI3K pathway through Akt protein. Enzastaurin [H-pyrrole-2,5-dione,3-(1-methyl-1H-indol-3-yl)-4-(1-[-1(2-pyridinylmethyl)-4-piperidinyl]-1H-indol-3-yl), LY317615; Eli Lilly and Company] is an acyclic bisindolylmaleimide, an oral PKCß selective inhibitor. It suppresses not only PKC signaling but also the PI3K/Akt pathway, thereby inhibiting tumor-induced angiogenesis as well as tumor cell survival and proliferation (42). Enzastaurin also suppresses vascular endothelial growth factor–induced angiogenesis in animal models, indicating that it suppresses tumor growth through multiple mechanisms (42, 43). In multiple myeloma, PKC overexpression has been associated with t(4;14) translocation (44). Importantly, PKC signaling pathways have been implicated in multiple myeloma cell proliferation, apoptosis, and migration (43, 45). Studies conducted by our group and others have shown that enzastaurin specifically inhibits membrane, cytosolic, and nuclear phosphorylation of homologous PKC isoform residues, as well as associated kinase activity, induced by the major PKC activator 12-O-tetradecanoylphorbol-13-acetate (tumor-promoting phorbol ester; refs. 46, 47). Consequently, it also abrogates 12-O-tetradecanoylphorbol-13-acetate–induced phosphorylation of signaling molecules downstream of PKC, including myristolated alanine-rich C kinase substrate (47). Importantly, in multiple myeloma cells, enzastaurin also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells; costimulation with the extracellular matrix protein fibronectin, vascular endothelial growth factor, or IL-6; and multiple myeloma patient serum. In addition, enzastaurin inhibited multiple myeloma cell adhesion as well as vascular endothelial growth factor– and IGF-I–triggered multiple myeloma cell migration (47). Finally and most importantly, tumor growth, survival, and angiogenesis were abrogated by enzastaurin in an in vivo xenograft model of human multiple myeloma (47). Enzastaurin has been tested in clinical trials in diffuse large-cell lymphoma and glioblastoma and showed promising activity in lymphoma with minimal side effects, including fatigue, peripheral edema, and nausea (48). A phase II trial of enzastaurin in patients with relapsed/refractory multiple myeloma is planned to start in 2007.

mTOR inhibitors. Rapamycin has been in clinical use for more than two decades as an immunosuppressive agent to prevent allograft rejection. The delineation of the role of mTOR in the pathogenesis of many malignancies led to the use of rapamycin and several other analogues as anticancer agents (49–51). Specifically, two rapamycin analogues have been tested in preclinical and clinical studies in multiple myeloma: CCI-779 and RAD001 (52, 53). CCI-779 (temsirolimus, Wyeth) has shown in vitro and in vivo activity against multiple myeloma cell lines, specifically those with PTEN mutations (54, 55). Similarly, RAD001 (everolimus, Novartis) inhibits proliferation at nanomolar concentrations against a broad range of multiple myeloma cells in vitro (52). It also has antitumor activity in a severe combined immunodeficient/nonobese diabetic mouse model of human multiple myeloma (52). Importantly, the combination of rapamycin with other novel agents used in multiple myeloma, such as lenalidomide and 17-allylamino-17-demethoxygeldanamycin (17-AAG), has shown synergistic activity in vitro (56, 57). In addition, rapamycin has shown strong antiangiogenic activity even at low concentrations (53, 58). Interestingly, rapamycin also showed inhibitory activity on osteoclasts in vitro, indicating that it may inhibit in vivo bone lytic lesion formation in multiple myeloma (57). A phase II study of i.v. CCI-779 once a week in patients with relapsed multiple myeloma has shown exciting responses (59). In addition, a phase II trial of oral RAD001 is currently being conducted in patients with relapsed and refractory multiple myeloma. Based on preclinical studies, a phase II trial of RAD001 in combination with lenalidomide and another phase I/II clinical trial of CCI-779 in combination with bortezomib are currently under way in patients with relapsed/refractory multiple myeloma.

Indirect inhibitors of the PI3K pathway. These include IL-6 and IGF-I inhibitors as well as heat shock protein-90 (Hsp90) inhibitors.

IL-6 inhibitors. IL-6 is one of the major cytokines that induce proliferation and survival in multiple myeloma. It activates multiple signaling pathways mediating proliferation, including the PI3K, Ras/mitogen-activated protein kinase/extracellular signal–regulated kinase kinase/extracellular signal–regulated kinase, and Janus-activated kinase/signal transducers and activators of transcription cascades (36). Monoclonal antibodies targeting IL-6 and the IL-6 receptor have shown preclinical antitumor cytostatic activity in multiple myeloma in vitro and transient antimyeloma activity in vivo (60). However, clinical trials using anti–IL-6 monoclonal antibody failed to achieve clinical activity in multiple myeloma (60). More recently, superantagonists to the IL-6 receptor have shown strong antimyeloma activity in vitro, specifically Sant7 (61). Sant7 showed activity even in the dexamethasone-resistant multiple myeloma cell lines. In addition, it showed synergistic activity in vitro when combined with dexamethasone and significantly potentiated the activity of dexamethasone in vivo in a humanized severe combined immunodeficient multiple myeloma model (61). Taken together, these studies provide the framework for studying Sant7 in clinical trials in multiple myeloma.

IGF-I inhibitors. IGF-I is another major regulator of cell survival and activation of PI3K and mitogen-activated protein kinase in multiple myeloma. The IGF-I receptor (IGF-IR) is highly expressed on various hematologic cell lines as well as patient multiple myeloma cells (62). IGF-I triggers multiple myeloma cell proliferation and drug resistance; conversely, a small-molecule IGF-IR tyrosine kinase inhibitor, NVP-ADW742, has shown significant cytotoxicity in vitro and in vivo in multiple myeloma (62). In addition, IGF-IR inhibition decreased phosphorylation and activation of multiple key kinases and kinase targets involved in the PI3K/Akt pathway, including Akt, I{kappa}B kinase, FKHRL1, p70S6 kinase, and glycogen synthase kinase 3{alpha}/ß. In addition, IGF-IR inhibition of multiple myeloma cells sensitized the cells to other anticancer agents including doxorubicin and melphalan (62). These results provide the rationale for undergoing clinical trials of IGF-IR inhibitors for the treatment of multiple myeloma patients.

Hsp90 inhibitors. Hsp90 is a ubiquitous molecular chaperone involved in the proper folding of a variety of intracellular proteins involved in proliferation and survival of tumor cells, including bcr/abl chimeric kinases, cell-surface receptors like HER2/neu, and receptors of androgens and estrogens (63). Studies in multiple myeloma have shown that heat shock proteins are involved in multiple intracellular tumor proliferation/survival pathways including the PI3K/Akt pathway (64). More specifically, small-molecule Hsp90 inhibitors (such as geldanamycin, a benzoquinone ansamycin antibiotic produced by the bacterium Streptomyces hygroscopicus, and its analogue 17-AAG) suppressed multiple myeloma cell proliferation and survival both in vitro and in vivo (64). Growth inhibition was associated with suppression of signaling events triggered by IGF-I and IL-6 at multiple levels, including suppression of cell-surface receptor expression (IGF-IR) and inhibition of downstream PI3K signaling mediators such as Akt and I{kappa}B kinase (65). Multiple anti-Hsp90 compounds (17-AAG, KOS-953, and IPI-504) are currently being tested in phase I and II clinical trials in patients with multiple myeloma. KOS-953 is a novel form of 17-AAG, which, based on preclinical studies, has been combined with bortezomib in clinical trials and has already shown promising activity even in patients whose multiple myeloma is resistant to bortezomib (66).

Conclusion

In summary, the PI3K pathway is a critical regulator of cell survival and proliferation in multiple myeloma. Several PI3K cascade inhibitors show significant preclinical activity, and clinical trials show early promising activity. These novel agents include direct inhibitors of the pathway such as perifosine, enzastaurin, CCI-779, and RAD001. In addition, indirect inhibitors of the pathway such as IL-6 and IGF-IR inhibitors and Hsp90 inhibitors also inhibit signaling through the PI3K/Akt pathway. The combination of inhibitors of this pathway along with other novel therapeutic agents has great promise to improve patient outcome in multiple myeloma.

Footnotes

Grant support: The Leukemia and Lymphoma Society, Lymphoma Research Foundation, and American Society of Clinical Oncology Career Development Award (I.M. Ghobrial).

Received 12/11/06; accepted 1/ 5/07.

References

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  2. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860–73.[Free Full Text]
  3. Hideshima T, Chauhan D, Podar K, Schlossman RL, Richardson P, Anderson KC. Novel therapies targeting the myeloma cell and its bone marrow microenvironment. Semin Oncol 2001;28:607–12.[CrossRef][Medline]
  4. Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci 2001;114:1439–45.[Abstract]
  5. Chang F, Lee JT, Navolanic PM, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003;17:590–603.[CrossRef][Medline]
  6. Martinez-Gac L, Alvarez B, Garcia Z, Marques M, Arrizabalaga M, Carrera AC. Phosphoinositide 3-kinase and Forkhead, a switch for cell division. Biochem Soc Trans 2004;32:360–1.[CrossRef][Medline]
  7. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004;30:193–204.[CrossRef][Medline]
  8. Zhang J, Choi Y, Mavromatis B, Lichtenstein A, Li W. Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene 2003;22:6289–95.[CrossRef][Medline]
  9. Tai YT, Podar K, Mitsiades N, et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-{kappa}B signaling. Blood 2003;101:2762–9.[Abstract/Free Full Text]
  10. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.[CrossRef][Medline]
  11. Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM. Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110{alpha} catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 1998;18:1379–87.[Abstract/Free Full Text]
  12. Marte BM, Downward J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 1997;22:355–8.[CrossRef][Medline]
  13. Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2001;2:760–8.[CrossRef][Medline]
  14. Hemmings BA. Akt signaling: linking membrane events to life and death decisions. Science 1997;275:628–30.[Free Full Text]
  15. Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 2001;114:2903–10.[Medline]
  16. Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt. Cell 2002;111:293–303.[CrossRef][Medline]
  17. Lu Y, Wang H, Mills GB. Targeting PI3K-AKT pathway for cancer therapy. Rev Clin Exp Hematol 2003;7:205–28.[Medline]
  18. Toker A, Yoeli-Lerner M. Akt signaling and cancer: surviving but not moving on. Cancer Res 2006;66:3963–6.[Abstract/Free Full Text]
  19. Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 2002;90:1243–50.[Abstract/Free Full Text]
  20. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9:59–71.[Medline]
  21. Mitsiades CS, Mitsiades N, Koutsilieris M. The Akt pathway: molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 2004;4:235–56.[CrossRef][Medline]
  22. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005;55:178–94.[Abstract/Free Full Text]
  23. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene 2003;22:8983–98.[CrossRef][Medline]
  24. Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004;15:177–82.[CrossRef][Medline]
  25. Pene F, Claessens YE, Muller O, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002;21:6587–97.[CrossRef][Medline]
  26. Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006;20:911–28.[CrossRef][Medline]
  27. Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. 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;4:1533–40.[Abstract/Free Full Text]
  28. Choo AY, Blenis J. TORgeting oncogene addiction for cancer therapy. Cancer Cell 2006;9:77–9.[CrossRef][Medline]
  29. Pene F, Claessens YE, Muller O, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002;21:6587–97.[CrossRef][Medline]
  30. Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer 2004;91:1420–4.[CrossRef][Medline]
  31. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005;94:29–86.[CrossRef][Medline]
  32. Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995;64:280–5.[Medline]
  33. Mills GB, Lu Y, Fang X, et al. The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Semin Oncol 2001;28:125–41.[CrossRef][Medline]
  34. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 1999;96:4240–5.[Abstract/Free Full Text]
  35. Hyun T, Yam A, Pece S, et al. Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood 2000;96:3560–8.[Abstract/Free Full Text]
  36. Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001;20:5991–6000.[CrossRef][Medline]
  37. Hideshima T, Podar K, Chauhan D, Anderson KC. Cytokines and signal transduction. Best Pract Res Clin Haematol 2005;18:509–24.[Medline]
  38. Descamps G, Pellat-Deceunynck C, Szpak Y, Bataille R, Robillard N, Amiot M. The magnitude of Akt/phosphatidylinositol 3'-kinase proliferating signaling is related to CD45 expression in human myeloma cells. J Immunol 2004;173:4953–9.[Abstract/Free Full Text]
  39. 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;107:4053–62.[Abstract/Free Full Text]
  40. Richardson P, Lonial S, Jakubowiak J, et al. A multicenter phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (Dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM) [abstract 3582]. Blood 2006;108:124A–5A.
  41. Serova M, Ghoul A, Benhadji KA, et al. Preclinical and clinical development of novel agents that target the protein kinase C family. Semin Oncol 2006;33:466–78.[CrossRef][Medline]
  42. Graff JR, McNulty AM, Hanna KR, et al. The protein kinase Cß-selective inhibitor, enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 2005;65:7462–9.[Abstract/Free Full Text]
  43. Podar K, Tai YT, Davies FE, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 2001;98:428–35.[Abstract/Free Full Text]
  44. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101:4569–75.[Abstract/Free Full Text]
  45. Podar K, Tai YT, Lin BK, et al. Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with ß1 integrin- and phosphatidylinositol 3-kinase-dependent PKC{alpha} activation. J Biol Chem 2002;277:7875–81.[Abstract/Free Full Text]
  46. Rizvi MA, Ghias K, Davies KM, et al. Enzastaurin (LY317615), a protein kinase Cß inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines. Mol Cancer Ther 2006;5:1783–9.[Abstract/Free Full Text]
  47. Podar K, Raab MS, Zhang J, et al. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl). Blood 2007;109:1669–77.[Abstract/Free Full Text]
  48. Carducci MA, Musib L, Kies MS, et al. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase Cß inhibitor, in patients with advanced cancer. J Clin Oncol 2006;24:4092–9.[Abstract/Free Full Text]
  49. Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer 2004;100:657666.
  50. Peralba JM, DeGraffenried L, Friedrichs W, et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 2003;9:2887–92.[Abstract/Free Full Text]
  51. Cortot A, Armand JP, Soria JC. PI3K-AKT-mTOR pathway inhibitors. Bull Cancer 2006;93:19–26.[Medline]
  52. Mitsiades N, McMullan C, Poulaki V, et al. The mTOR inhibitor RAD001 (everolimus) is active against multiple myeloma cells in vitro and in vivo [abstract 1496]. Blood 2004;104:418a.
  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;104:4181–7.[Abstract/Free Full Text]
  54. Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002;62:5027–34.[Abstract/Free Full Text]
  55. Gera JF, Mellinghoff IK, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 2004;279:2737–46.[Abstract/Free Full Text]
  56. 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;104:4188–93.[Abstract/Free Full Text]
  57. Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res 2006;12:6826–35.[Abstract/Free Full Text]
  58. Brader S, Eccles SA. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004;90:2–8.[Medline]
  59. Farag S, Zhang S, Miller M, et al. Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): preliminary results. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No 18S (June 20 Supplement). 2006.
  60. Trikha M, Corringham R, Klein B, Rossi JF. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 2003;9:4653–65.[Abstract/Free Full Text]
  61. Tassone P, Neri P, Burger R, et al. Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu in vivo model of human multiple myeloma. Clin Cancer Res 2005;11:4251–8.[Abstract/Free Full Text]
  62. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 2004;5:221–30.[CrossRef][Medline]
  63. Picard D. Heat-shock protein 90, a chaperone for folding and regulation. Cell Mol Life Sci 2002;59:1640–8.[CrossRef][Medline]
  64. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107:1092–100.[Abstract/Free Full Text]
  65. Chen Y, Ding J. Heat shock protein 90: novel target for cancer therapy. Ai Zheng 2004;23:968–74.[Medline]
  66. Chanan-Khan AA, Richardson PG, Alsina M, et al. Phase 1 clinical trial of KOS-953 + bortezomib (BZ) in relapsed refractory multiple myeloma (MM) [abstract 362]. Blood 2005;106:109a.



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