Engineering Therapeutic Alignments Between Immune Response and Molecularly Targeted Cancer Treatment

  • Ariel Fernández Stigliano


In this chapter we develop molecular design strategies to empower drug-based anticancer therapy by restoring the immune response to drug-induced antigenic activity. We focus on reengineering immunosuppressive anticancer drugs where the impact on the immune system is an undesirable outcome, betraying their own raison d’être. The goal is to remove the immunosuppressive effects through molecular redesign, more specifically, to restore the adaptive immune response and natural killer cell cytotoxicity compromised by the original drug treatment. The redesign strategy enables us to create synergies that may empower drug-based anticancer therapy, aligning the immune response with the molecularly targeted treatment while retaining the anticancer efficacy of the parental compound.


Anticancer Drug Adaptive Immune Response Stem Cell Factor Selectivity Filter Antigenic Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Druker BJ, Lydon NB (2000) Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105:3–7CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480CrossRefPubMedGoogle Scholar
  3. 3.
    Hodi FS, Friedlander P, Corless CL, Heinrich MC, Mac Rae S, Kruse A, Jagannathan J, Van den Abbeele AD, Velazquez EF, Demetri GD, Fisher DE (2007) Major response to imatinib mesylate in KIT mutated melanoma. J Clin Oncol 26:2046–2051CrossRefGoogle Scholar
  4. 4.
    Gnoni A, Marech I, Silvestris N, Vacca A, Lorusso V (2011) Dasatinib: an anti-tumor agent via Src inhibition. Curr Drug Targets 12:563–578CrossRefPubMedGoogle Scholar
  5. 5.
    Li J, Rix U, Fang B, Bai Y, Edwards A, Colinge J, Bennett KL, Gao J, Song L, Eschrich S, Superti-Furga G, Koomen J, Haura EB (2010) A chemical and phosphoproteomic characterization of dasatinib action in lung cancer. Nat Chem Biol 6:291–299CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Pichot CS, Hartig SM, Xia L, Arvanitis C, Monisvais D, Lee FY, Frost JA, Corey SJ (2009) Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer 101:38–47CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E (2009) Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer 101:263–268CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich MC (2006) Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 66:473–481CrossRefPubMedGoogle Scholar
  9. 9.
    Woodman SE, Trent JC, Stemke-Hale K, Lazar AJ, Pricl S, Pavan GM, Fermeglia M, Gopal YN, Yang D, Podoloff DA, Ivan D, Kim KB, Papadopoulos N, Hwu P, Mills GB, Davies MA (2009) Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 8:2079–2085CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Martin P, Oliver S, Kennedy SJ, Partridge E, Hutchison M, Clarke D, Giles P (2012) Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. Clin Ther 34:221–237CrossRefPubMedGoogle Scholar
  11. 11.
    Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (2011) Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 54:6342–6363CrossRefPubMedGoogle Scholar
  12. 12.
    Fernández A (2010) Transformative concepts for drug design: target wrapping. Springer, HeidelbergCrossRefGoogle Scholar
  13. 13.
    Seggewiss R, Loré K, Greiner E, Magnusson MK, Price DA, Douek DC, Dunbar CE, Wiestner A (2005) Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 105:2473–2480CrossRefPubMedGoogle Scholar
  14. 14.
    Weichsel RL, Dix C, Wooldridge L, Clement M, Fenton-May A, Sewell AK, Zezula J, Greiner E, Gostick E, Price DA, Einsele H, Seggewiss R (2008) Profound inhibition of antigen-specific T-cell effector functions by dasatinib. Clin Cancer Res 14:2484–2491CrossRefPubMedGoogle Scholar
  15. 15.
    Wölfl M, Langhammer F, Wiegering V, Eyrich M, Schlegel PG (2013) Dasatinib medication causing profound immunosuppression in a patient after haploidentical SCT: functional assays from whole blood as diagnostic clues. Bone Marrow Transplant 48:875–877CrossRefPubMedGoogle Scholar
  16. 16.
    Heine A, Held SA, Bringmann A, Holderried TA, Brossart P (2011) Immunomodulatory effects of anti-angiogenic drugs. Leukemia 25:899–905CrossRefPubMedGoogle Scholar
  17. 17.
    Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotech 29:1046–1051CrossRefGoogle Scholar
  18. 18.
    Wolf D, Tilg H, Rumpold H, Gastl G, Wolf AM (2007) The kinase inhibitor imatinib–an immunosuppressive drug? Curr Cancer Drug Targets 7:251–258CrossRefPubMedGoogle Scholar
  19. 19.
    Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Böhm A, Herndlhofer S, Tschachler E, Superti-Furga G, Jäger U, Valent P (2009) Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 39:1098–1109CrossRefPubMedGoogle Scholar
  20. 20.
    Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L, Seggewiss R, Porkka K, Mustjoki S (2010) Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood 116:772–782CrossRefPubMedGoogle Scholar
  21. 21.
    Ravandi F (2010) Dasatinib, an immunomodulator? Blood 116:673–674CrossRefPubMedGoogle Scholar
  22. 22.
    Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotech 26:127–132CrossRefGoogle Scholar
  23. 23.
    Crunkhorn S (2008) Anticancer drugs: redesigning kinase inhibitors. Nat Rev Drug Discov 7:120–121CrossRefGoogle Scholar
  24. 24.
    Demetri G (2007) Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest 117:3650–3653CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Fernández A, Sanguino A, Peng Z, Ozturk E, Chen J, Crespo A, Wulf S, Shavrin A, Qin C, Ma J, Trent J, Lin Y, Han HD, Mangala LS, Bankson JA, Gelovani J, Samarel A, Bornmann W, Sood AK, Lopez-Berestein G (2007) An anticancer c-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044–4054CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol/Hemat 77:12–19CrossRefGoogle Scholar
  27. 27.
    Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M (2014) Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 42:D199–D205CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Das J, Squibb B-M (2003) Cyclic protein tyrosine kinase inhibitors. US Patent 6,596,746Google Scholar
  29. 29.
    Crespo A, Fernández A (2007) Kinase packing defects as drug targets. Drug Discov Today 12:917–923CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Fernández A, Bornmann W, Lopez-Berestein G, Sanguino A, Peng Z, Sood AK, The board of regents of the University of Texas system (2013) Methods and composition of matter related to wrapping of dehydrons. US Patent 8,466,154Google Scholar
  31. 31.
    Fei F, Yu Y, Schmitt A, Rojewski MT, Chen B, Greiner J, Götz M, Guillaume P, Döhner H, Bunjes D, Schmitt M (2008) Dasatinib exerts an immunosuppressive effect on CD8 + T cells specific for viral and leukemia antigens. Experim Hematol 36:1297–1308CrossRefGoogle Scholar
  32. 32.
    Sondel P (2012) Unpublished results (personal communication)Google Scholar
  33. 33.
    Weber J (2008) Overcoming immunologic tolerance to melanoma: Targeting CTLA-4 with ipilimumab (MDX-010). Oncologist 13:16–25CrossRefPubMedGoogle Scholar
  34. 34.
    Gallo RC, Sarin PS, Gelmann EP, Robert-Guroff M, Richardson E, Kalyanaraman VS, Mann D, Sidhu GD, Stahl RE, Zolla-Pazner S, Leibowitch J, Popovic M (1983) Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220:865–867CrossRefPubMedGoogle Scholar
  35. 35.
    Haas DA, Bala K, Büsche G, Weidner-Glunde M, Santag S, Kati S, Gramolelli S, Damas M, Dittrich-Breiholz O, Kracht M, Rückert J, Varga Z, Keri G, Schulz TF (2013) The inflammatory kinase MAP4K4 promotes reactivation of kaposi’s sarcoma herpesvirus and enhances the invasiveness of infected endothelial cells. PLoS Pathog 9:e1003737CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Fernández A (2014) Synergizing immunotherapy with molecularly targeted anticancer treatment. Drug Discov Today 19:1427–1432CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.National Research Council–CONICETBuenos AiresArgentina
  2. 2.Former Karl F. Hasselmann Endowed Chair Professor of BioengineeringRice UniversityHoustonUSA

Personalised recommendations