Targeted drugs tailored against genes and signaling proteins have formed the new era termed Targeted Therapies. Although the field is relatively young, since only about 5 years ago clinical trials started showing promise, there have are already been significant setbacks due to drug resistance caused by point mutations, alterations in gene expression or complete loss of target proteins with disease progression. Although new drugs are continuously designed and tried, it seems inevitable that genetic and signal protein targets pose too broad flexibility and variability, often changing target characteristics and thus escape treatments turning “magic bullets” into rather “wondering bullets”. This is especially true in cancer, where old and new targeted therapies continue to fail and the most recent ones do not offer much improvement on clinical outcome parameters. Metabolic targeted therapies are aimed at control points of the metabolic network by targeting particular enzymes of major macromolecule synthesis pathways in cancer. This review summarizes the potential benefits of targeted therapies in the metabolic network as applied with genetic and proteomic approaches. The metabolic target approach is most efficient if and when pathway flux information is available for drug target development using the stable isotope based dynamic metabolic profile (SIDMAP) of tumor cells, in vitro or in vivo.
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References
A. Baron T. Migita D. Tang M. Loda (2004) ArticleTitleFatty acid synthase: a metabolic oncogene in prostate cancer? J. Cell. Biochem. 91 47–53 Occurrence Handle10.1002/jcb.10708 Occurrence Handle1:CAS:528:DC%2BD2cXlvV2gsQ%3D%3D Occurrence Handle14689581
P.A. Boekhorst B. Lowenberg J. van Kapel K. Nooter P. Sonneveld (1995) ArticleTitleMultidrug resistant cells with high proliferative capacity determine response to therapy in acute myeloid leukemia Leukemia 9 1025–1031 Occurrence Handle7541095
J. Boren M. Cascante S. Marin et al. (2001) ArticleTitleGleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells J. Biol. Chem. 276 37747–37753 Occurrence Handle1:CAS:528:DC%2BD3MXotFOrsbY%3D Occurrence Handle11489902
L.G. Boros J. Puigjaner M. Cascante et al. (1997) ArticleTitleOxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation Cancer Res. 57 4242–4248 Occurrence Handle1:CAS:528:DyaK2sXmsFChu74%3D Occurrence Handle9331084
L.G. Boros S. Bassilian S. Lim W.N. Lee (2001a) ArticleTitleGenistein inhibits non-oxidative ribose synthesis in MIA pancreatic adenocarcinoma cells: a new mechanism of controlling tumor growth Pancreas 22 1–7 Occurrence Handle10.1097/00006676-200101000-00001 Occurrence Handle1:STN:280:DC%2BD3M7hs1aisQ%3D%3D
L.G. Boros K. Lapis B. Szende et al. (2001b) ArticleTitleWheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells Pancreas 23 141–147 Occurrence Handle10.1097/00006676-200108000-00004 Occurrence Handle1:STN:280:DC%2BD38%2FislGqsA%3D%3D
L.G. Boros W.N. Lee V.L. Go (2002a) ArticleTitleA metabolic hypothesis of cell growth and death in pancreatic cancer Pancreas 24 26–33 Occurrence Handle10.1097/00006676-200201000-00004
L.G. Boros M. Cascante W.N. Lee (2002b) ArticleTitleMetabolic profiling of cell growth and death in cancer: applications in drug discovery Drug Discov. Today 7 364–372 Occurrence Handle10.1016/S1359-6446(02)02179-7 Occurrence Handle1:CAS:528:DC%2BD38XhvVWhsbg%3D
L.G. Boros D.J. Brackett G.G. Harrigan (2003a) ArticleTitleMetabolic biomarker and kinase drug target discovery in cancer using stable isotope-based dynamic metabolic profiling (SIDMAP) Curr. Cancer Drug Targets 3 445–453 Occurrence Handle10.2174/1568009033481769 Occurrence Handle1:CAS:528:DC%2BD3sXhtVSmurjI
L.G. Boros M.P. Steinkamp J.C. Fleming W.N. Lee M. Cascante E.J. Neufeld (2003b) ArticleTitleDefective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA) Blood 102 3556–3561 Occurrence Handle10.1182/blood-2003-05-1537 Occurrence Handle1:CAS:528:DC%2BD3sXptVymtro%3D
L.G. Boros M. Cascante W.-N.P. Lee (2003c) Stable isotope-based dynamic metabolic profiling in disease and health G.G. Harrigan R. Goodacre (Eds) Metabolic profiling: its role in biomarker discovery and gene function analysis Kluwer Academic Publishers Boston
Boros L.G. (2004). Metabolic profile of inflammatory breast cancer: aiding diagnosis and treatment. George Washington University and the IBC Research Foundation co-sponsored “IBC Mini Symposium” hosted by George Washington University: http://www.ibcresearch.org/ibcminisymposium/
S.W. Cowan-Jacob V. Guez G. Fendrich et al. (2004) ArticleTitleImatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment Mini Rev. Med. Chem. 4 285–299 Occurrence Handle10.2174/1389557043487321 Occurrence Handle1:CAS:528:DC%2BD2cXisVKhur8%3D Occurrence Handle15032675
J.E. Dancey B. Freidlin (2003) ArticleTitleTargeting epidermal growth factor receptor – Are we missing the mark? Lancet 362 62–64 Occurrence Handle10.1016/S0140-6736(03)13810-X Occurrence Handle1:CAS:528:DC%2BD3sXltF2is7w%3D Occurrence Handle12853203
P. Danzon A. Towse (2002) ArticleTitleThe economics of gene therapy and of pharmacogenetics Value Health 5 5–13 Occurrence Handle10.1046/j.1524-4733.2002.51081.x Occurrence Handle11873384
E. Eigenbrodt M. Reinacher U. Scheefers-Borchel H. Scheefers R. Friis (1992) ArticleTitleDouble role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells Crit. Rev. Oncog. 3 91–115 Occurrence Handle1:CAS:528:DyaK2cXhtVens7w%3D Occurrence Handle1532331
R. Green (2003) ArticleTitleMystery of thiamine-responsive megaloblastic anemia unlocked Blood 102 3464–3465 Occurrence Handle10.1182/blood-2003-09-3025 Occurrence Handle1:CAS:528:DC%2BD3sXptVymsLg%3D
J.L. Griffin (2004) ArticleTitleMetabolic profiles to define the genome: can we hear the phenotypes? Philos. Trans. R. Soc. Lond. B Biol. Sci. 359 857–871 Occurrence Handle10.1098/rstb.2003.1411 Occurrence Handle1:CAS:528:DC%2BD2cXmt1yms70%3D Occurrence Handle15306403
V. Guillemard H.U. Saragovi (2004) ArticleTitleNovel approaches for targeted cancer therapy Curr. Cancer Drug Targets 4 313–326 Occurrence Handle10.2174/1568009043332989 Occurrence Handle1:CAS:528:DC%2BD2cXkvFyjsrk%3D Occurrence Handle15180497
W.K. Hofmann M. Komor D. Hoelzer O.G. Ottmann (2004) ArticleTitleMechanisms of resistance to STI571 (Imatinib) in Philadelphia-chromosome positive acute lymphoblastic leukemia Leuk. Lymphoma 45 655–660 Occurrence Handle10.1080/10428190310001625755 Occurrence Handle1:CAS:528:DC%2BD3sXpvV2lsbw%3D Occurrence Handle15160936
W. Hu J.J. Kavanagh (2003) ArticleTitleAnticancer therapy targeting the apoptotic pathway Lancet Oncol. 4 721–729 Occurrence Handle10.1016/S1470-2045(03)01277-4 Occurrence Handle1:CAS:528:DC%2BD3sXps1OgsL0%3D Occurrence Handle14662428
F.P. Kuhajda (2000) ArticleTitleFatty-acid synthase and human cancer: new perspectives on its role in tumor biology Nutrition 16 202–208 Occurrence Handle10.1016/S0899-9007(99)00266-X Occurrence Handle1:CAS:528:DC%2BD3cXhsFGqu7w%3D Occurrence Handle10705076
S. Matzku H. Krempel H.P. Weckenmann V. Schirrmacher H. Sinn H. Stricker (1990) ArticleTitleTumor targeting with antibody-coupled liposomes: failure to achieve accumulation in xenografts and spontaneous liver metastases. Cancer Immunol. Immunother. 31 285–291 Occurrence Handle10.1007/BF01740936 Occurrence Handle1:STN:280:By%2BA38bmtFE%3D Occurrence Handle2376046
E.R. Nemecek D.C. Matthews (2003) ArticleTitleUse of radiolabeled antibodies in the treatment of childhood acute leukemia Pediatr. Transplant. 3 89–94 Occurrence Handle10.1034/j.1399-3046.7.s3.14.x
H.C. Pitot J.P. Jost (1967) ArticleTitleControl of biochemical expression in morphologically related cells in vivo and in vitro Natl. Cancer Inst. Monogr. 26 145–166 Occurrence Handle1:STN:280:CCeD1M%2FlsVY%3D Occurrence Handle4294465
C.M. Rudin J. Holmlund G.F. Fleming et al. (2001) ArticleTitlePhase I Trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer Clin. Cancer Res. 7 1214–1220 Occurrence Handle1:CAS:528:DC%2BD3MXktlemu7g%3D Occurrence Handle11350886
C. Schmidt (2004) ArticleTitleMetabolomics takes its place as latest up-and-coming “omic” science J. Natl. Cancer Inst. 96 732–734 Occurrence Handle15150298
A.G. Schwartz L. Pashko J.M. Whitcomb (1986) ArticleTitleInhibition of tumor development by dehydroepiandrosterone and related steroids Toxicol. Pathol. 14 357–362 Occurrence Handle1:CAS:528:DyaL2sXitVOruro%3D Occurrence Handle3024302
N.P. Shah C. Tran F.Y. Lee P. Chen D. Norris C.L. Sawyers (2004) ArticleTitleOverriding imatinib resistance with a novel ABL kinase inhibitor Science 305 399–401 Occurrence Handle10.1126/science.1099480 Occurrence Handle1:CAS:528:DC%2BD2cXls1egtrY%3D Occurrence Handle15256671
E.L. Sievers (2000) ArticleTitleTargeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates Cancer Chemother. Pharmacol. 46 S18–S22 Occurrence Handle1:CAS:528:DC%2BD3cXks1Oksrc%3D Occurrence Handle10950142
T.A. Smith (1998) ArticleTitleFDG uptake, tumor characteristics and response to therapy: a review Nucl. Med. Commun. 19 97–105 Occurrence Handle1:CAS:528:DyaK1cXhsF2gt7g%3D Occurrence Handle9548192
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Boros, L.G. Metabolic targeted therapy of cancer: current tracer technologies and future drug design strategies in the old metabolic network. Metabolomics 1, 11–15 (2005). https://doi.org/10.1007/s11306-005-1103-7
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DOI: https://doi.org/10.1007/s11306-005-1103-7