Skip to main content
SpringerLink
Log in

Theranostic Approaches for Pathway-Activated Systems in Oncology

  • Chapter
  • First Online:
Book cover Personalized Pathway-Activated Systems Imaging in Oncology

Abstract

Theranostics is a novel concept that refers to the integration of diagnostics with therapeutics in order to generate personalized therapies and is emerging as a promising precise therapeutic paradigm. In oncology, the approach is aimed at more accurate diagnosis of cancer, optimization of patient selection to identify those most likely to benefit from a proposed specific therapy allowing the generation of effective therapeutics that enhance patient survival. Perhaps the most promising target to date for theranostics is the deregulation of cancer cell metabolism, involving the uptake of glucose and glutamate, two key nutrients that are necessary to convert into glucosamine to stimulate protein biosynthesis for the growth and survival of cancer cells. We have recently developed a novel technology whereby the chelator ethylenedicysteine (EC) conjugates with glucosamine to create a vehicle platform (ECG), which mimics N-acetylglucosamine (GlcNAc) that targets highly proliferative cancer cells. Moreover, ECG can be further conjugated to diagnostic/therapeutic metals (rhenium, Re, and platinum, Pt) that function as a new theranostic agent suitable for personalized medicine, targeting key pathways in cancer cells such as highly metabolic diffuse large B-cell lymphoma (DLBCL). This chapter summarizes key signaling pathways linked to dysregulated glucose metabolism in DLBCL and how deregulated glucose metabolism can be utilized for developing innovative new technologies with theranostic applications to eradicate cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alexander DD, Mink PJ, Adami HO, Chang ET, Cole P, Mandel JS, et al. The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int J Cancer. 2007;120(Suppl 12):1–39. Epub 2007/04/04. doi:10.1002/ijc.22719. PubMed PMID: 17405121.

  2. Johnson PW. Survival from non-Hodgkin lymphoma in England and Wales up to 2001. Br J Cancer. 2008;99(Suppl 1):S107–9. PubMed PMID: 18813239.

    Google Scholar 

  3. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107(1):265–76. PubMed PMID: 16150940.

    Google Scholar 

  4. Wang M, Burau KD, Fang S, Wang H, Du XL. Ethnic variations in diagnosis, treatment, socioeconomic status, and survival in a large population-based cohort of elderly patients with non-Hodgkin lymphoma. Cancer. 2008;113:3231. PubMed PMID: 18937267.

    Google Scholar 

  5. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96. PubMed PMID: 18287387.

    Google Scholar 

  6. Coiffier B. Current strategies for the treatment of diffuse large B cell lymphoma. Curr Opin Hematol. 2005;12(4):259–65. PubMed PMID: 15928481.

    Google Scholar 

  7. Coiffier B. Treatment of non-Hodgkin’s lymphoma: a look over the past decade. Clin Lymphoma Myeloma. 2006;7(Suppl 1):S7–13. PubMed PMID: 17101073.

    Google Scholar 

  8. Lossos IS. Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Oncol. 2005;23(26):6351–7. PubMed PMID: 16155019.

    Google Scholar 

  9. Volpe G, Vitolo U, Carbone A, Pastore C, Bertini M, Botto B, et al. Molecular heterogeneity of B-lineage diffuse large cell lymphoma. Genes Chromosomes Cancer. 1996;16(1):21–30. PubMed PMID: 9162193.

    Google Scholar 

  10. Jost PJ, Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood. 2007;109(7):2700–7. PubMed PMID: 17119127.

    Google Scholar 

  11. Lam LT, Wright G, Davis RE, Lenz G, Farinha P, Dang L, et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood. 2008;111(7):3701–13. PubMed PMID: 18160665.

    Google Scholar 

  12. Sagaert X, De Wolf-Peeters C, Noels H, Baens M. The pathogenesis of MALT lymphomas: where do we stand? Leukemia. 2007;21(3):389–96. PubMed PMID: 17230229.

    Google Scholar 

  13. Feuerhake F, Kutok JL, Monti S, Chen W, LaCasce AS, Cattoretti G, et al. NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood. 2005;106(4):1392–9. PubMed PMID: 15870177.

    Google Scholar 

  14. Staudt LM, Dave S. The biology of human lymphoid malignancies revealed by gene expression profiling. Adv Immunol. 2005;87:163–208. PubMed PMID: 16102574.

    Google Scholar 

  15. Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V, et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood. 2005;106(9):3183–90. PubMed PMID: 16046532.

    Google Scholar 

  16. Iqbal J, Greiner TC, Patel K, Dave BJ, Smith L, Ji J, et al. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia. 2007;21:2332. PubMed PMID: 17625604.

    Google Scholar 

  17. Moskowitz CH, Zelenetz AD, Kewalramani T, Hamlin P, Lessac-Chenen S, Houldsworth J, et al. Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL. Blood. 2005;106(10):3383–5. PubMed PMID: 16091454.

    Google Scholar 

  18. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11. PubMed PMID: 10676951.

    Google Scholar 

  19. Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–62. PubMed PMID: 12975453.

    Google Scholar 

  20. Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2003;100(17):9991–6. PubMed PMID: 12900505.

    Google Scholar 

  21. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2005;105(5):1851–61. PubMed PMID: 15550490.

    Google Scholar 

  22. Rosenwald A, Staudt LM. Gene expression profiling of diffuse large B-cell lymphoma. Leuk Lymphoma. 2003;44(Suppl 3):S41–7. PubMed PMID: 15202524.

    Google Scholar 

  23. Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G, et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell. 2007;12(3):280–92. PubMed PMID: 17785208.

    Google Scholar 

  24. Parekh S, Polo JM, Shaknovich R, Juszczynski P, Lev P, Ranuncolo SM, et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood. 2007;110(6):2067–74. PubMed PMID: 17545502.

    Google Scholar 

  25. Polo JM, Juszczynski P, Monti S, Cerchietti L, Ye K, Greally JM, et al. Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas. Proc Natl Acad Sci U S A. 2007;104(9):3207–12. PubMed PMID: 17360630.

    Google Scholar 

  26. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23:23–68. PubMed PMID: 15771565.

    Google Scholar 

  27. Zhang G. Tumor necrosis factor family ligand-receptor binding. Curr Opin Struct Biol. 2004;14(2):154–60. PubMed PMID: 15093829.

    Google Scholar 

  28. Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4(4):360–7. PubMed PMID: 15251129.

    Google Scholar 

  29. Shivakumar L, Ansell S. Targeting B-lymphocyte stimulator/B-cell activating factor and a proliferation-inducing ligand in hematologic malignancies. Clin Lymphoma Myeloma. 2006;7(2):106–8. PubMed PMID: 17026820.

    Google Scholar 

  30. Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. J Clin Invest. 2005;115(10):2625–32. PubMed PMID: 16200195.

    Google Scholar 

  31. Lin-Lee YC, Pham LV, Tamayo AT, Fu L, Zhou HJ, Yoshimura LC, et al. Nuclear localization in the biology of the CD40 receptor in normal and neoplastic human B lymphocytes. J Biol Chem. 2006;281(27):18878–18887. PubMed PMID: 16644731.

    Google Scholar 

  32. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Terry N, Reid PS, et al. A CD40 Signalosome anchored in lipid rafts leads to constitutive activation of NF-kappaB and autonomous cell growth in B cell lymphomas. Immunity. 2002;16(1):37–50. Epub 2002/02/05. doi: S1074761301002588 [pii]. PubMed PMID: 11825564.

    Google Scholar 

  33. Zhou HJ, Pham LV, Tamayo AT, Lin-Lee YC, Fu L, Yoshimura LC, et al. Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma. Blood. 2007;110(6):2121–2127. Epub 2007/06/15. doi: blood-2007-02-073080 [pii] 10.1182/blood-2007-02-073080. PubMed PMID: 17567982; PubMed Central PMCID: PMC1976364.

  34. Pham LV, Tamayo AT, Yoshimura LC, Lin-Lee YC, Ford RJ. Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood. 2005;106(12):3940–3947. Epub 2005/08/16. doi: 2005–03-1167 [pii] 10.1182/blood-2005-03-1167. PubMed PMID: 16099873; PubMed Central PMCID: PMC1895110.

  35. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003;171(1):88–95. Epub 2003/06/21. PubMed PMID: 12816986.

    Google Scholar 

  36. Pham LV, Tamayo AT, Zhou H-J, Lin-Lee Y-C, Fu L, Bueso-Ramos C, Medeiros LJ, Ford RJ. Networking NFkB signaling modules from canonical and alternative NFkB pathways regulate growth and survival in large B cell lymphomas. submitted for publication. 2008.

    Google Scholar 

  37. Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell. 2007;128(2):369–381. PubMed PMID: 17254973.

    Google Scholar 

  38. Dejardin E. The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol. 2006;72(9):1161–1179. PubMed PMID: 16970925.

    Google Scholar 

  39. Perkins ND. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 2007;8(1):49–62. PubMed PMID: 17183360.

    Google Scholar 

  40. Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006;2006(357):re13. PubMed PMID: 17047224.

    Google Scholar 

  41. Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008;132(3):344–362. PubMed PMID: 18267068.

    Google Scholar 

  42. Scheidereit C. IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene. 2006;25(51):6685–6705. PubMed PMID: 17072322.

    Google Scholar 

  43. Xiao G, Rabson AB, Young W, Qing G, Qu Z. Alternative pathways of NF-kappaB activation: a double-edged sword in health and disease. Cytokine Growth Factor Rev. 2006;17(4):281–293. PubMed PMID: 16793322.

    Google Scholar 

  44. Ishikawa H, Carrasco D, Claudio E, Ryseck RP, Bravo R. Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2. J Exp Med. 1997;186(7):999–1014. PubMed PMID: 9314550.

    Google Scholar 

  45. Beinke S, Ley SC. Functions of NF-kappaB1 and NF-kappaB2 in immune cell biology. Biochem J. 2004;382(Pt 2):393–409. PubMed PMID: 15214841.

    Google Scholar 

  46. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2(4):301–310. PubMed PMID: 12001991.

    Google Scholar 

  47. Neri A, Chang CC, Lombardi L, Salina M, Corradini P, Maiolo AT, et al. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell. 1991;67(6):1075–1087. PubMed PMID: 1760839.

    Google Scholar 

  48. Gardam S, Sierro F, Basten A, Mackay F, Brink R. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity. 2008;28(3):391–401. PubMed PMID: 18313334.

    Google Scholar 

  49. Cancro MP. Living in context with the survival factor BAFF. Immunity. 2008;28(3):300–301. PubMed PMID: 18342003.

    Google Scholar 

  50. Sasaki Y, Calado DP, Derudder E, Zhang B, Shimizu Y, Mackay F, et al. NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells. Proc Natl Acad Sci U S A. 2008;105(31):10883–10888. PubMed PMID: 18663224.

    Google Scholar 

  51. Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007;12(2):115–130. PubMed PMID: 17692804.

    Google Scholar 

  52. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12(2):131–144. PubMed PMID: 17692805.

    Google Scholar 

  53. Gilmore TD. Multiple myeloma: lusting for NF-kappaB. Cancer Cell. 2007;12(2):95–97. PubMed PMID: 17692798.

    Google Scholar 

  54. Zarnegar B, Yamazaki S, He JQ, Cheng G. Control of canonical NF-kappaB activation through the NIK-IKK complex pathway. Proc Natl Acad Sci U S A. 2008;105(9):3503–3508. PubMed PMID: 18292232.

    Google Scholar 

  55. Kim SW, Oleksyn DW, Rossi RM, Jordan CT, Sanz I, Chen L, et al. Protein kinase C-associated kinase is required for NF-kappaB signaling and survival in diffuse large B-cell lymphoma cells. Blood. 2008;111(3):1644–1653. PubMed PMID: 18025152.

    Google Scholar 

  56. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105(36):13520–13525. Epub 2008/09/04. doi: 0804295105 [pii] 10.1073/pnas.0804295105. PubMed PMID: 18765795; PubMed Central PMCID: PMC2533222.

  57. Homig-Holzel C, Hojer C, Rastelli J, Casola S, Strobl LJ, Muller W, et al. Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. J Exp Med. 2008;205(6):1317–1329. PubMed PMID: 18490492.

    Google Scholar 

  58. Serfling E, Berberich-Siebelt F, Avots A, Chuvpilo S, Klein-Hessling S, Jha MK, et al. NFAT and NF-kappaB factors-the distant relatives. Int J Biochem Cell Biol. 2004;36(7):1166–1170. PubMed PMID: 15109564.

    Google Scholar 

  59. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003;17(18):2205–2232. PubMed PMID: 12975316.

    Google Scholar 

  60. Fu L, Lin-Lee YC, Pham LV, Tamayo A, Yoshimura L, Ford RJ. Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood. 2006;107(11):4540–4548. Epub 2006/02/25. doi: 2005–10-4042 [pii] 10.1182/blood-2005-10-4042. PubMed PMID: 16497967; PubMed Central PMCID: PMC1895801.

  61. Duncliffe KN, Bert AG, Vadas MA, Cockerill PN. A T cell-specific enhancer in the interleukin-3 locus is activated cooperatively by Oct and NFAT elements within a DNase I-hypersensitive site. Immunity. 1997;6(2):175–185. PubMed PMID: 9047239.

    Google Scholar 

  62. Hawwari A, Burrows J, Vadas MA, Cockerill PN. The human IL-3 locus is regulated cooperatively by two NFAT-dependent enhancers that have distinct tissue-specific activities. J Immunol. 2002;169(4):1876–1886. PubMed PMID: 12165512.

    Google Scholar 

  63. Cockerill PN. NFAT is well placed to direct both enhancer looping and domain-wide models of enhancer function. Sci Signal. 2008;1(13):pe15. PubMed PMID: 18385038.

    Google Scholar 

  64. Cockerill PN. Mechanisms of transcriptional regulation of the human IL-3/GM-CSF locus by inducible tissue-specific promoters and enhancers. Crit Rev Immunol. 2004;24(6):385–408. PubMed PMID: 15777160.

    Google Scholar 

  65. Banine F, Bartlett C, Gunawardena R, Muchardt C, Yaniv M, Knudsen ES, et al. SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation. Cancer Res. 2005;65(9):3542–3547. PubMed PMID: 15867346.

    Google Scholar 

  66. Bert AG, Johnson BV, Baxter EW, Cockerill PN. A modular enhancer is differentially regulated by GATA and NFAT elements that direct different tissue-specific patterns of nucleosome positioning and inducible chromatin remodeling. Mol Cell Biol. 2007;27(8):2870–2885. PubMed PMID: 17283044.

    Google Scholar 

  67. Wurster AL, Pazin MJ. BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells. Mol Cell Biol. 2008. PubMed PMID: 18852284.

    Google Scholar 

  68. Bajpai R, Matulis SM, Wei C, Nooka AK, Von Hollen HE, Lonial S, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2015. doi:10.1038/onc.2015.464. PubMed PMID: 26640142.

  69. Tsytsykova AV, Rajsbaum R, Falvo JV, Ligeiro F, Neely SR, Goldfeld AE. Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc Natl Acad Sci U S A. 2007;104(43):16850–16855. PubMed PMID: 17940009.

    Google Scholar 

  70. Johnson BV, Bert AG, Ryan GR, Condina A, Cockerill PN. Granulocyte-macrophage colony-stimulating factor enhancer activation requires cooperation between NFAT and AP-1 elements and is associated with extensive nucleosome reorganization. Mol Cell Biol. 2004;24(18):7914–7930. PubMed PMID: 15340054.

    Google Scholar 

  71. Bengsch B, Wherry EJ. The importance of cooperation: partnerless NFAT induces T cell exhaustion. Immunity. 2015;42(2):203–205. doi: 10.1016/j.immuni.2015.01.023. PubMed PMID: 25692694.

  72. Fehr T, Lucas CL, Kurtz J, Onoe T, Zhao G, Hogan T, et al. A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo. Blood. 2010;115(6):1280–1287. doi: 10.1182/blood-2009-07-230680. PubMed PMID: 20007805; PubMed Central PMCID: PMC2826238.

  73. Abe BT, Shin DS, Mocholi E, Macian F. NFAT1 supports tumor-induced anergy of CD4(+) T cells. Cancer Res. 2012;72(18):4642–4651. doi: 10.1158/0008-5472.CAN-11-3775. PubMed PMID: 22865456; PubMed Central PMCID: PMC3445721.

  74. Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME, et al. The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells. Immunity. 2015;42(2):265–278. doi: 10.1016/j.immuni.2015.01.006. PubMed PMID: 25680272; PubMed Central PMCID: PMC4346317.

  75. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008;181(7):4832–4839. PubMed PMID: 18802087; PubMed Central PMCID: PMC2645436.

    Google Scholar 

  76. Lozano T, Villanueva L, Durantez M, Gorraiz M, Ruiz M, Belsue V, et al. Inhibition of FOXP3/NFAT interaction enhances T cell function after TCR stimulation. J Immunol. 2015;195(7):3180–3189. doi: 10.4049/jimmunol.1402997. PubMed PMID: 26324768.

  77. Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE. Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8(+) cytolytic T cell responses. Immunity. 2016;44(2):274–286. doi: 10.1016/j.immuni.2016.01.018. PubMed PMID: 26885856; PubMed Central PMCID: PMC4760122.

  78. Sagiv-Barfi I, Kohrt HE, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A. 2015;112(9):E966–E972. doi: 10.1073/pnas.1500712112. PubMed PMID: 25730880; PubMed Central PMCID: PMC4352777.

  79. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539–2549. doi: 10.1182/blood-2013-06-507947. PubMed PMID: 23886836; PubMed Central PMCID: PMC3795457.

  80. Li C, Thompson MA, Tamayo AT, Zuo Z, Lee J, Vega F, et al. Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma. Oncotarget. 2012. Epub 2012/03/27. doi:463 [pii]. PubMed PMID: 22447839.

    Google Scholar 

  81. Gromer S, Urig S, Becker K. The thioredoxin system--from science to clinic. Med Res Rev. 2004;24(1):40–89. Epub 2003/11/05. doi: 10.1002/med.10051. PubMed PMID: 14595672.

  82. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000;267(20):6102–6109. Epub 2000/09/30. doi: ejb1701 [pii]. PubMed PMID: 11012661.

    Google Scholar 

  83. Powis G, Kirkpatrick DL. Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol. 2007;7(4):392–397. Epub 2007/07/06. doi: S1471–4892(07)00091–4 [pii] 10.1016/j.coph.2007.04.003. PubMed PMID: 17611157.

  84. Baker AF, Koh MY, Williams RR, James B, Wang H, Tate WR, et al. Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1alpha-induced gene in pancreatic cancer. Pancreas. 2008;36(2):178–186. Epub 2008/04/01. doi: 10.1097/MPA.0b013e31815929fe00006676-200803000-00012 [pii]. PubMed PMID: 18376310.

  85. Welsh SJ, Bellamy WT, Briehl MM, Powis G. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res. 2002;62(17):5089–5095. Epub 2002/09/05. PubMed PMID: 12208766.

    Google Scholar 

  86. Tonissen KF, Di Trapani G. Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy. Mol Nutr Food Res. 2009;53(1):87–103. Epub 2008/11/04. doi: 10.1002/mnfr.200700492. PubMed PMID: 18979503.

  87. Tome ME, Johnson DB, Rimsza LM, Roberts RA, Grogan TM, Miller TP, et al. A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis. Blood. 2005;106(10):3594–3601. Epub 2005/08/06. doi: 2005–02-0487 [pii] 10.1182/blood-2005-02-0487. PubMed PMID: 16081686; PubMed Central PMCID: PMC1895056.

  88. Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol. 2000;164(12):6287–6295. Epub 2000/06/08. doi: ji_v164n12p6287 [pii]. PubMed PMID: 10843682.

    Google Scholar 

  89. Stoltzman CA, Peterson CW, Breen KT, Muoio DM, Billin AN, Ayer DE. Glucose sensing by MondoA:Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression. Proc Natl Acad Sci U S A. 2008;105(19):6912–6917. Epub 2008/05/07. doi: 0712199105 [pii] 10.1073/pnas.0712199105. PubMed PMID: 18458340; PubMed Central PMCID: PMC2383952.

  90. Stoltzman CA, Kaadige MR, Peterson CW, Ayer DE. MondoA senses non-glucose sugars: regulation of thioredoxin-interacting protein (TXNIP) and the hexose transport curb. J Biol Chem. 2011;286(44):38027–38034. Epub 2011/09/13. doi: M111.275503 [pii] 10.1074/jbc.M111.275503. PubMed PMID: 21908621; PubMed Central PMCID: PMC3207397.

  91. Zhou J, Yu Q, Chng WJ. TXNIP (VDUP-1, TBP-2): a major redox regulator commonly suppressed in cancer by epigenetic mechanisms. Int J Biochem Cell Biol. 2011;43(12):1668–1673. Epub 2011/10/04. doi: S1357–2725(11)00257–3 [pii] 10.1016/j.biocel.2011.09.005. PubMed PMID: 21964212.

  92. Yoshioka J, Chutkow WA, Lee S, Kim JB, Yan J, Tian R, et al. Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury. J Clin Invest. 2012;122(1):267–279. Epub 2011/12/29. doi: 44927 [pii] 10.1172/JCI44927. PubMed PMID: 22201682; PubMed Central PMCID: PMC3248280.

  93. Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA, Marks PA, et al. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci U S A. 2002;99(18):11700–11705. Epub 2002/08/22. doi: 10.1073/pnas.182372299182372299 [pii]. PubMed PMID: 12189205; PubMed Central PMCID: PMC129332.

  94. Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood. 2011;118(10):2830–2839. Epub 2011/07/08. doi: blood-2010-07-294827 [pii] 10.1182/blood-2010-07-294827. PubMed PMID: 21734239.

  95. Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21(9):1050–1063. Epub 2007/04/18. doi: gad.1524107 [pii] 10.1101/gad.1524107. PubMed PMID: 17437993; PubMed Central PMCID: PMC1855231.

  96. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–349. Epub 2011/01/21. doi: nature09784 [pii] 10.1038/nature09784. PubMed PMID: 21248841.

  97. Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011;17(9):2613–2618. Epub 2011/03/04. doi: 1078–0432.CCR-10-2156 [pii] 10.1158/1078-0432.CCR-10-2156. PubMed PMID: 21367748.

  98. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109(10):3879–3884. Epub 2012/02/22. doi: 1121343109 [pii] 10.1073/pnas.1121343109. PubMed PMID: 22343534.

  99. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–185. Epub 2010/01/19. doi: ng.518 [pii] 10.1038/ng.518. PubMed PMID: 20081860; PubMed Central PMCID: PMC2850970.

  100. Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117(8):2451–2459. Epub 2010/12/31. doi: blood-2010-11-321208 [pii] 10.1182/blood-2010-11-321208. PubMed PMID: 21190999; PubMed Central PMCID: PMC3062411.

  101. Jeong M, Piao ZH, Kim MS, Lee SH, Yun S, Sun HN, et al. Thioredoxin-interacting protein regulates hematopoietic stem cell quiescence and mobilization under stress conditions. J Immunol. 2009;183(4):2495–2505. Epub 2009/07/25. doi: jimmunol.0804221 [pii] 10.4049/jimmunol.0804221. PubMed PMID: 19625652.

  102. Sloan EJ, Ayer DE. Myc, mondo, and metabolism. Genes Cancer. 2010;1(6):587–596. doi: 10.1177/1947601910377489. PubMed PMID: 21113411; PubMed Central PMCID: PMC2992335.

  103. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, Metabolism, and Cancer. Cancer Discovery. 2015;5(10):1024–1039. doi: 10.1158/2159-8290.CD-15-0507. PubMed PMID: 26382145; PubMed Central PMCID: PMC4592441.

  104. Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121(20):4021–4031; quiz 250. doi: 10.1182/blood-2012-10-460063. PubMed PMID: 23449635; PubMed Central PMCID: PMC3709650.

  105. Zhang X, Chen X, Lin J, Lwin T, Wright G, Moscinski LC, et al. Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene. 2012;31(24):3002–3008. doi: 10.1038/onc.2011.470. PubMed PMID: 22002311; PubMed Central PMCID: PMC3982396.

  106. Zhang X, Zhao X, Fiskus W, Lin J, Lwin T, Rao R, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell. 2012;22(4):506–523. doi: 10.1016/j.ccr.2012.09.003. PubMed PMID: 23079660; PubMed Central PMCID: PMC3973134.

  107. Zhao X, Lwin T, Zhang X, Huang A, Wang J, Marquez VE, et al. Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia. 2013;27(12):2341–2350. doi: 10.1038/leu.2013.94. PubMed PMID: 23538750; PubMed Central PMCID: PMC4015113.

  108. Pham LV, Tamayo AT, Li C, Bueso-Ramos C, Ford RJ. An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas. Blood. 2010;116(19):3899–3906. Epub 2010/07/29. doi: blood-2009-12-257378 [pii] 10.1182/blood-2009-12-257378. PubMed PMID: 20664054; PubMed Central PMCID: PMC2981542.

  109. Kelkar SS, Reineke TM. Theranostics: combining imaging and therapy. Bioconjug Chem. 2011;22(10):1879–1903. Epub 2011/08/13. doi: 10.1021/bc200151q. PubMed PMID: 21830812.

  110. Fernandez-Fernandez A, Manchanda R, McGoron AJ. Theranostic applications of nanomaterials in cancer: drug delivery, image-guided therapy, and multifunctional platforms. Appl Biochem Biotechnol. 2011;165(7–8):1628–1651. Epub 2011/09/29. doi: 10.1007/s12010-011-9383-z. PubMed PMID: 21947761; PubMed Central PMCID: PMC3239222.

  111. Koppenol WH, Bounds PL, Dang CV. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325–337. Epub 2011/04/22. doi: nrc3038 [pii] 10.1038/nrc3038. PubMed PMID: 21508971.

  112. Kubota K. From tumor biology to clinical PET: a review of positron emission tomography (PET) in oncology. Ann Nucl Med. 2001;15(6):471–486. Epub 2002/02/08. PubMed PMID: 11831394.

    Google Scholar 

  113. Weber WA, Schwaiger M, Avril N. Quantitative assessment of tumor metabolism using FDG-PET imaging. Nucl Med Biol. 2000;27(7):683–687. Epub 2000/11/25. doi: S0969–8051(00)00141–4 [pii]. PubMed PMID: 11091112.

    Google Scholar 

  114. Cheson BD. Role of functional imaging in the management of lymphoma. J Clin Oncol. 2011;29(14):1844–1854. Epub 2011/04/13. doi: JCO.2010.32.5225 [pii] 10.1200/JCO.2010.32.5225. PubMed PMID: 21482982.

  115. Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25(5):571–578. Epub 2007/01/24. doi: JCO.2006.08.2305 [pii] 10.1200/JCO.2006.08.2305. PubMed PMID: 17242397.

  116. Hutchings M, Barrington SF. PET/CT for therapy response assessment in lymphoma. J Nucl Med. 2009;50 Suppl 1:21S–30S. Epub 2009/04/22. doi: jnumed.108.057190 [pii] 10.2967/jnumed.108.057190. PubMed PMID: 19380407.

  117. Spaepen K, Stroobants S, Dupont P, Van Steenweghen S, Thomas J, Vandenberghe P, et al. Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-Hodgkin’s lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods? J Clin Oncol. 2001;19(2):414–419. Epub 2001/02/24. PubMed PMID: 11208833.

    Google Scholar 

  118. Jerusalem G, Beguin Y, Fassotte MF, Najjar F, Paulus P, Rigo P, et al. Persistent tumor 18F-FDG uptake after a few cycles of polychemotherapy is predictive of treatment failure in non-Hodgkin's lymphoma. Haematologica. 2000;85(6):613–618. Epub 2000/06/28. PubMed PMID: 10870118.

    Google Scholar 

  119. Yang DH, Min JJ, Song HC, Jeong YY, Chung WK, Bae SY, et al. Prognostic significance of interim (1)F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma. Eur J Cancer. 2011;47(9):1312–8. Epub 2011/02/22. doi: S0959–8049(11)00038–4 [pii]10.1016/j.ejca.2010.12.027. PubMed PMID: 21334197.

  120. Cox MC, Ambrogi V, Lanni V, Cavalieri E, Pelliccia S, Scopinaro F, et al. Use of interim [(18)F]fluorodeoxyglucose-positron emission tomography is not justified in diffuse large B-cell lymphoma during first-line immunochemotherapy. Leuk Lymphoma. 2012;53(2):263–269. Epub 2011/08/19. doi: 10.3109/10428194.2011.614704. PubMed PMID: 21846184.

  121. Rajagopalan KN, DeBerardinis RJ. Role of glutamine in cancer: therapeutic and imaging implications. J Nucl Med. 2011;52(7):1005–1008. Epub 2011/06/18. doi: jnumed.110.084244 [pii] 10.2967/jnumed.110.084244. PubMed PMID: 21680688.

  122. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427–433. Epub 2010/06/24. doi: S0968–0004(10)00091–5 [pii] 10.1016/j.tibs.2010.05.003. PubMed PMID: 20570523; PubMed Central PMCID: PMC2917518.

  123. Hanover JA, Krause MW, Love DC. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim Biophys Acta. 2010;1800(2):80–95. Epub 2009/08/04. doi: S0304–4165(09)00207–4 [pii] 10.1016/j.bbagen.2009.07.017. PubMed PMID: 19647043; PubMed Central PMCID: PMC2815088.

  124. Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011;80:825–858. Epub 2011/03/12. doi: 10.1146/annurev-biochem-060608-102511. PubMed PMID: 21391816.

  125. Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ. Critical role of O-GlcNAc transferase in prostate cancer invasion, angiogenesis and metastasis. J Biol Chem. 2012. Epub 2012/01/26. doi: M111.302547 [pii] 10.1074/jbc.M111.302547. PubMed PMID: 22275356.

  126. Krzeslak A, Forma E, Bernaciak M, Romanowicz H, Brys M. Gene expression of O-GlcNAc cycling enzymes in human breast cancers. Clin Exp Med. 2011. Epub 2011/05/14. doi: 10.1007/s10238-011-0138-5. PubMed PMID: 21567137.

  127. Ozcan S, Andrali SS, Cantrell JE. Modulation of transcription factor function by O-GlcNAc modification. Biochim Biophys Acta. 2010;1799(5–6):353–364. Epub 2010/03/06. doi: S1874–9399(10)00047–7 [pii] 10.1016/j.bbagrm.2010.02.005. PubMed PMID: 20202486; PubMed Central PMCID: PMC2881704.

  128. Rogacka D, Piwkowska A, Jankowski M, Kocbuch K, Dominiczak MH, Stepinski JK, et al. Expression of GFAT1 and OGT in podocytes: transport of glucosamine and the implications for glucose uptake into these cells. J Cell Physiol. 2010;225(2):577–584. Epub 2010/05/28. doi: 10.1002/jcp.22242. PubMed PMID: 20506529.

  129. Uldry M, Ibberson M, Hosokawa M, Thorens B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 2002;524(1–3):199–203. Epub 2002/07/24. doi: S0014579302030582 [pii]. PubMed PMID: 12135767.

    Google Scholar 

  130. Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 2010;24(24):2784–2799. Epub 2010/11/26. doi: gad.1985910 [pii] 10.1101/gad.1985910. PubMed PMID: 21106670; PubMed Central PMCID: PMC3003197.

  131. Yang DJ, Kim CG, Schechter NR, Azhdarinia A, Yu DF, Oh CS, et al. Imaging with 99mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents. Radiology. 2003;226(2):465–473. doi: 10.1148/radiol.2262011811. PubMed PMID: 12563141.

  132. Yang D, Yukihiro M, Yu DF, Ito M, Oh CS, Kohanim S, et al. Assessment of therapeutic tumor response using 99mtc-ethylenedicysteine-glucosamine. Cancer Biother Radiopharm. 2004;19(4):443–456. Epub 2004/09/30. doi: 10.1089/cbr.2004.19.443. PubMed PMID: 15453959.

  133. Yang DJ, Kong F-L, Oka T, Bryant JL. Molecular imaging kits for hexosamine biosynthetic pathway in oncology. Curr Med Chem. 2012;19(20):3310–4.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Lan V. Pham, Jerry L. Bryant & Richard J. Ford

  2. Vyripharm Biopharmaceuticals, University of Texas Health Science Center, Houston, TX, USA

    David Yang

Authors
  1. Lan V. Pham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerry L. Bryant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard J. Ford
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lan V. Pham .

Editor information

Editors and Affiliations

  1. School of Medicine, Yokohama City University, Yokohama, Japan

    Tomio Inoue

  2. Vyripharm Biopharmaceuticals, University of Texas Health Science Center, Houston, Texas, USA

    David Yang

  3. Renji Hospital / Department of Nuclear Medicine, Shanghai Jiao Tong University, Shanghai, China

    Gang Huang

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Pham, L.V., Bryant, J.L., Yang, D., Ford, R.J. (2017). Theranostic Approaches for Pathway-Activated Systems in Oncology. In: Inoue, T., Yang, D., Huang, G. (eds) Personalized Pathway-Activated Systems Imaging in Oncology. Springer, Singapore. https://doi.org/10.1007/978-981-10-3349-0_2

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-3349-0_2

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-3348-3

  • Online ISBN: 978-981-10-3349-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation