Receptors for Targeting Growth Factors for Treatment of Cancers

  • Devashree Jahagirdar
  • Sharwari Ghodke
  • Akshay Mergu
  • Aishwarya Nikam
  • Padma V. Devarajan
  • Ratnesh JainEmail author
  • Prajakta DandekarEmail author
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 39)


Growth factor receptors (GFR) are expressed on cell membranes or in the cytoplasm and play a major role in cell growth, survival, angiogenesis, and metastasis. Tumor growth and cell survival are composed of dodging apoptotic signals in cancer cells. The growth of cells is further supported by angiogenesis and metastasis to distant organs. Elevated expression of growth factor receptors contributes to the development of drug resistance. Therefore, therapeutics to target GFRs is a potentially attractive molecular approach to treat cancer more effectively. In this review, we have discussed the contribution of growth factor receptors to cancer development and thereby their subsequent molecular targets for novel drugs developed leading to inhibition of growth factor receptor-mediated pathways.


Receptor-ligand interaction Recognition domain Extracellular domain Transformation Drug target 



Bone morphogenetic protein


Cell cycle-regulated kinases


Colorectal cancer




Extracellular domain


Epithelial-mesenchymal transition


Fibroblast growth factor




Grb2-associated binding protein


Growth arrest specific protein


Glioblastoma multiforme


Growth hormone


Gemcitabine monophosphate


Human umbilical vein endothelial cells




Insulin-like growth factor


Iron oxide nanoparticles


Immunoglobulin-like plexin-transcription


Insulin receptor


Juxtamembrane domains


Jun N-terminal kinase


Monoclonal antibodies


Mitogen-activated protein kinase


Matrix metalloproteinases


Magnetic resonance imaging


Mesoporous silica nanoparticles


Mammalian target of rapamycin


Microvessel density


Nuclear factor kappa-light-chain-Enhancer of activated β cells


Amino-triphenyl dicarboxylate-bridged Zr4+ metal-organic framework nanoparticles


Platelet-derived growth factor




Phospho-inositol 3 kinase


Placental growth factor




Protein tyrosine kinase


Ribosomal protein S6 kinase 2


Receptor tyrosine kinase


Stem cell factor


Structural domain of semaphorins


Src-homology-2 domain


Src-homology-2 domain


Secreted protein acidic and rich in cysteine


Superparamagnetic iron oxide


Signal transducer and activator of transcription


Transforming growth factor


Transmembrane domain


Tumor necrosis factor


Vascular endothelial growth factor


  1. 1.
    Cross M, Dexter TM. Growth factors in development, transformation, and tumorigenesis. Cell. 1991;64(2):271–80.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Nakanishi T, Markwald R, Baldwin H, Keller B, Srivastava D, Yamagishi H. Extracellular matrix remodeling in vascular development and disease. In: Etiology and morphogenesis of congenital heart disease: from gene function and cellular interaction to morphology; 2016. Springer, Tokyo.Google Scholar
  3. 3.
    Zhang X, Nie D, Chakrabarty S. Growth factors in tumor microenvironment. Front Biosci. 2010;15:151.PubMedCentralCrossRefGoogle Scholar
  4. 4.
    Tannock IF. Conventional cancer therapy: promise broken or promise delayed? Lancet. 1998;351:SII9–SII16.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Xiao Y, Tian Q, He J, Huang M, Yang C, Gong L. MiR-503 inhibits hepatocellular carcinoma cell growth via inhibition of insulin-like growth factor 1 receptor. Onco Targets Ther. 2016;9:3535.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Gonzalez A, Broussas M, Beau-Larvor C, Haeuw JF, Boute N, Robert A, et al. A novel antagonist anti-cMet antibody with antitumor activities targeting both ligand-dependent and ligand-independent c-Met receptors. Int J Cancer. 2016;139(8):1851–63.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Birchmeier C, Birchmeier W, Gherardi E, Woude GFV. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4(12):915.PubMedCrossRefGoogle Scholar
  8. 8.
    Matsumoto K, Umitsu M, De Silva DM, Roy A, Bottaro DP. Hepatocyte growth factor/MET in cancer progression and biomarker discovery. Cancer Sci. 2017;108(3):296–307.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Rampa C, Tian E, Våtsveen TK, Buene G, Slørdahl TS, Børset M, et al. Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients. Biomark Res. 2014;2(1):8.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Pavelic J, Krizanac S, Kapitanovic S, Pavelic L, Samarzija M, Pavicic F, et al. The consequences of insulin-like growth factors/receptors dysfunction in lung cancer. Am J Respir Cell Mol Biol. 2005;32(1):65–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Heldin C-H. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11(1):97.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Massagué J. TGFβ in cancer. Cell. 2008;134(2):215–30.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist. 2000;5(Suppl 1):37–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014;34(2):280–300.PubMedCrossRefGoogle Scholar
  15. 15.
    Savage NM, Johnson RC, Gotlib J, George TI. Myeloid and lymphoid neoplasms with FGFR1 abnormalities: diagnostic and therapeutic challenges. Am J Hematol. 2013;88(5):427–30.PubMedCrossRefGoogle Scholar
  16. 16.
    Jin M, Kleinberg A, Cooke A, Gokhale PC, Foreman K, Dong H, et al. Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy. Bioorg Med Chem Lett. 2011;21(4):1176–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res. 2006;12(12):3657–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Safaie Qamsari E, Safaei Ghaderi S, Zarei B, Dorostkar R, Bagheri S, Jadidi-Niaragh F, et al. The c-Met receptor: implication for targeted therapies in colorectal cancer. Tumor Biol. 2017;39(5):1010428317699118.CrossRefGoogle Scholar
  19. 19.
    Gandino L, Longati P, Medico E, Prat M, Comoglio PM. Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. J Biol Chem. 1994;269(3):1815–20.PubMedGoogle Scholar
  20. 20.
    Cecchi F, Rabe DC, Bottaro DP. The hepatocyte growth factor receptor: structure, function and pharmacological targeting in cancer. Curr Signal Transduction Ther. 2011;6(2):146–51.CrossRefGoogle Scholar
  21. 21.
    Adriaenssens E, Vanhecke E, Saule P, Mougel A, Page A, Romon R, et al. Nerve growth factor is a potential therapeutic target in breast cancer. Cancer Res. 2008;68(2):346–51.PubMedCrossRefGoogle Scholar
  22. 22.
    Sachs M, Brohmann H, Zechner D, Müller T, Hülsken J, Walther I, et al. Essential role of Gab1 for signaling by the c-Met receptor in vivo. J Cell Biol. 2000;150(6):1375–84.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell. 1994;77(2):261–71.PubMedCrossRefGoogle Scholar
  24. 24.
    Montagner A, Yart A, Dance M, Perret B, Salles J-P, Raynal P. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J Biol Chem. 2005;280(7):5350–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Heukers R, Altintas I, Raghoenath S, De Zan E, Pepermans R, Roovers RC, et al. Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles. Biomaterials. 2014;35(1):601–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Alibakhshi A, Kahaki FA, Ahangarzadeh S, Yaghoobi H, Yarian F, Arezumand R, et al. Targeted cancer therapy through antibody fragments-decorated nanomedicines. J Control Release. 2017;268:323–34.PubMedCrossRefGoogle Scholar
  27. 27.
    Yang Z, Duan J, Wang J, Liu Q, Shang R, Yang X, et al. Superparamagnetic iron oxide nanoparticles modified with polyethylenimine and galactose for siRNA targeted delivery in hepatocellular carcinoma therapy. Int J Nanomedicine. 2018;13:1851.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Zhang H, Wang Y, Bai M, Wang J, Zhu K, Liu R, et al. Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor si RNA. Cancer Sci. 2018;109(3):629–41.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kalus W, Zweckstetter M, Renner C, Sanchez Y, Georgescu J, Grol M, et al. Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions. EMBO J. 1998;17(22):6558–72.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Keyhanfar M, Booker GW, Whittaker J, Wallace JC, Forbes BE. Precise mapping of an IGF-I-binding site on the IGF-1R. Biochem J. 2007;401(1):269–77.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Cabail MZ, Li S, Lemmon E, Bowen ME, Hubbard SR, Miller WT. The insulin and IGF1 receptor kinase domains are functional dimers in the activated state. Nat Commun. 2015;6:6406.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Lee J, Pilch PF. The insulin receptor: structure, function, and signaling. Am J Phys Cell Phys. 1994;266(2):C319–C34.CrossRefGoogle Scholar
  33. 33.
    De Meyts P, Sajid W, Palsgaard J, Theede A-M, Gauguin L, Aladdin H, et al. Insulin and IGF-I receptor structure and binding mechanism. In: Mechanisms of insulin action. Springer; 2007. p. 1–32. Landes Bioscience, Austin.Google Scholar
  34. 34.
    Abdullahi AD, Abdualkader AM, Abdulsamat NB, Ingale K. Application of group-based QSAR and molecular docking in the design of insulin-like growth factor antagonists. Trop J Pharm Res. 2015;14(6):941–51.CrossRefGoogle Scholar
  35. 35.
    Jafari R, Majidi Zolbanin N, Majidi J, Atyabi F, Yousefi M, Jadidi-Niaragh F, et al. Anti-Mucin1 Aptamer-conjugated Chitosan nanoparticles for targeted co-delivery of Docetaxel and IGF-1R siRNA to SKBR3 metastatic breast cancer cells. Iran Biomed J. 2019;23:21.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Shali H, Shabani M, Pourgholi F, Hajivalili M, Aghebati-Maleki L, Jadidi-Niaragh F, et al. Co-delivery of insulin-like growth factor 1 receptor specific siRNA and doxorubicin using chitosan-based nanoparticles enhanced anticancer efficacy in A549 lung cancer cell line. Artif Cells Nanomed Biotechnol. 2018;46(2):293–302.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhou H, Qian W, Uckun FM, Wang L, Wang YA, Chen H, et al. IGF1 receptor targeted theranostic nanoparticles for targeted and image-guided therapy of pancreatic cancer. ACS Nano. 2015;9(8):7976–91.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Zhang Q, Pan J, Lubet RA, Wang Y, You M. Targeting the insulin-like growth factor-1 receptor by picropodophyllin for lung cancer chemoprevention. Mol Carcinog. 2015;54(S1):E129–E37.PubMedCrossRefGoogle Scholar
  39. 39.
    Magnusson PU, Looman C, Åhgren A, Wu Y, Claesson-Welsh L, Heuchel RL. Platelet-derived growth factor receptor-β constitutive activity promotes angiogenesis in vivo and in vitro. Arterioscler Thromb Vasc Biol. 2007;27(10):2142–9.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Batut J, Schmierer B, Cao J, Raftery LA, Hill CS, Howell M. Two highly related regulatory subunits of PP2A exert opposite effects on TGF-β/Activin/Nodal signalling. Development. 2008;135(17):2927–37.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Bai A, Meetze K, Vo NY, Kollipara S, Govek E, Winston WM, et al. GP369, an FGFR2-IIIb specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res. 2010;70:7630. canres. 1489.2010.PubMedCrossRefGoogle Scholar
  42. 42.
    Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, et al. Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-β type I receptor kinase inhibitor. Cancer Res. 2006;66(13):6714–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Shim AH-R, Liu H, Focia PJ, Chen X, Lin PC, He X. Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proc Natl Acad Sci. 2010;107(25):11307–12.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen X, Liu H, Focia PJ, Shim AH-R, He X. Structure of macrophage colony stimulating factor bound to FMS: diverse signaling assemblies of class III receptor tyrosine kinases. Proc Natl Acad Sci. 2008;105(47):18267–72.PubMedCrossRefGoogle Scholar
  45. 45.
    Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell. 2007;130(2):323–34.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Liu H, Leo C, Chen X, Wong BR, Williams LT, Lin H, et al. The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim Biophys Acta-Proteins and Proteomics. 2012;1824(7):938–45.CrossRefGoogle Scholar
  47. 47.
    Chen P-H, Chen X, He X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim Biophys Acta-Proteins and Proteomics. 2013;1834(10):2176–86.CrossRefGoogle Scholar
  48. 48.
    Ekman S, Thuresson ER, Heldin C-H, RoÈnnstrand L. Increased mitogenicity of an αβ heterodimeric PDGF receptor complex correlates with lack of RasGAP binding. Oncogene. 1999;18(15):2481.PubMedCrossRefGoogle Scholar
  49. 49.
    Heidaran M, Pierce J, Jensen R, Matsui T, Aaronson S. Chimeric alpha-and beta-platelet-derived growth factor (PDGF) receptors define three immunoglobulin-like domains of the alpha-PDGF receptor that determine PDGF-AA binding specificity. J Biol Chem. 1990;265(31):18741–4.PubMedGoogle Scholar
  50. 50.
    Yang Y, Yuzawa S, Schlessinger J. Contacts between membrane proximal regions of the PDGF receptor ectodomain are required for receptor activation but not for receptor dimerization. Proc Natl Acad Sci. 2008;105(22):7681–6.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Heldin C-H, Östman A, Rönnstrand L. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta-reviews on cancer. 1998;1378(1):F79–F113.CrossRefGoogle Scholar
  52. 52.
    Baxter RM, Secrist JP, Vaillancourt RR, Kazlauskas A. Full activation of the platelet-derived growth factor β-receptor kinase involves multiple events. J Biol Chem. 1998;273(27):17050–5.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Hubbard SR. Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5(6):464.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Deng ZJ, Liang M, Toth I, Monteiro MJ, Minchin RF. Molecular interaction of poly (acrylic acid) gold nanoparticles with human fibrinogen. ACS Nano. 2012;6(10):8962–9.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Rejeeth C, Vivek R, NipunBabu V, Sharma A, Ding X, Qian K. Cancer nanomedicine: from PDGF targeted drug delivery. MedChemComm. 2017;8(11):2055–9.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Patil R, Portilla-Arias J, Ding H, Inoue S, Konda B, Hu J, et al. Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly (β-L-malic acid). Pharm Res. 2010;27(11):2317–29.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Miller K, Dixit S, Bredlau A-L, Moore A, McKinnon E, Broome A-M. Delivery of a drug cache to glioma cells overexpressing platelet-derived growth factor receptor using lipid nanocarriers. Nanomedicine. 2016;11(6):581–95.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ninomiya K, Yamashita T, Kawabata S, Shimizu N. Targeted and ultrasound-triggered drug delivery using liposomes co-modified with cancer cell-targeting aptamers and a thermosensitive polymer. Ultrason Sonochem. 2014;21(4):1482–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Pietras K, Rubin K, Sjöblom T, Buchdunger E, Sjöquist M, Heldin C-H, et al. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002;62(19):5476–84.PubMedGoogle Scholar
  60. 60.
    Wieser R, Wrana J, Massague J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 1995;14(10):2199–208.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Charng M-J, Kinnunen P, Hawker J, Brand T, Schneider MD. FKBP-12 recognition is dispensable for signal generation by type I transforming growth factor-β receptors. J Biol Chem. 1996;271(38):22941–4.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Souchelnytskyi S, Ten Dijke P, Miyazono K, Heldin C. Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses. EMBO J. 1996;15(22):6231–40.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Heldin C-H, Moustakas A. Signaling receptors for TGF-β family members. Cold Spring Harb Perspect Biol. 2016;8(8):a022053.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298(5600):1912–34.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Saitoh M, Nishitoh H, Amagasa T, Miyazono K, Takagi M, Ichijo H. Identification of important regions in the cytoplasmic juxtamembrane domain of type I receptor that separate signaling pathways of transforming growth factor-β. J Biol Chem. 1996;271(5):2769–75.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Zhang B, Halder SK, Zhang S, Datta PK. Targeting transforming growth factor-β signaling in liver metastasis of colon cancer. Cancer Lett. 2009;277(1):114–20.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ehrlich M, Gutman O, Knaus P, Henis YI. Oligomeric interactions of TGF-β and BMP receptors. FEBS Lett. 2012;586(14):1885–96.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Radaev S, Zou Z, Huang T, Lafer EM, Hinck AP, Sun PD. Ternary complex of TGF-β1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily. J Biol Chem. 2010;285:14806. jbc.M109.079921.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-β receptor. Nature. 1994;370(6488):341.CrossRefGoogle Scholar
  70. 70.
    Wang T, Li B-Y, Danielson PD, Shah PC, Rockwell S, Lechleider RJ, et al. The immunophilin FKBP12 functions as a common inhibitor of the TGFβ family type I receptors. Cell. 1996;86(3):435–44.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Chen YG, Liu F, Massagué J. Mechanism of TGFβ receptor inhibition by FKBP12. EMBO J. 1997;16(13):3866–76.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Huse M, Chen Y-G, Massagué J, Kuriyan J. Crystal structure of the cytoplasmic domain of the type I TGF β receptor in complex with FKBP12. Cell. 1999;96(3):425–36.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Huse M, Muir TW, Xu L, Chen Y-G, Kuriyan J, Massagué J. The TGFβ receptor activation process: an inhibitor-to substrate-binding switch. Mol Cell. 2001;8(3):671–82.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Gotoh N, Laks S, Nakashima M, Lax I, Schlessinger J. FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts. FEBS Lett. 2004;564(1–2):14–8.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK, et al. Synthesis and activity of new aryl-and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. J Med Chem. 2003;46(19):3953–6.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Bae Y, Nishiyama N, Fukushima S, Koyama H, Yasuhiro M, Kataoka K. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem. 2005;16(1):122–30.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proc Natl Acad Sci. 2007;104(9):3460–5.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Zhou Q, Li Y, Zhu Y, Yu C, Jia H, Bao B, et al. Co-delivery nanoparticle to overcome metastasis promoted by insufficient chemotherapy. J Control Release. 2018;275:67–77.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Zhou C, Li J, Lin L, Shu R, Dong B, Cao D, et al. A targeted transforming growth factor-beta (TGF-β) blocker, TTB, inhibits tumor growth and metastasis. Oncotarget. 2018;9(33):23102.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Nacif M, Shaker O. Targeting transforming growth factor-β (TGF-β) in cancer and non-neoplastic diseases. J Cancer Ther. 2014;5(07):735.CrossRefGoogle Scholar
  81. 81.
    Toth K, Dhar D, Wold WS. Oncolytic (replication-competent) adenoviruses as anticancer agents. Expert Opin Biol Ther. 2010;10(3):353–68.PubMedCrossRefGoogle Scholar
  82. 82.
    Hu Z, Zhang Z, Guise T, Seth P. Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-β receptor II–Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum Gene Ther. 2010;21(11):1623–9.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153(1):13–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437(2):169–83.PubMedCrossRefGoogle Scholar
  85. 85.
    De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992;255(5047):989–91.PubMedCrossRefGoogle Scholar
  86. 86.
    Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin C-H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994;269(43):26988–95.PubMedGoogle Scholar
  87. 87.
    Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2:a006502.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, De Vos AM. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci. 1997;94(14):7192–7.PubMedCrossRefGoogle Scholar
  89. 89.
    D’andrea LD, Del Gatto A, Pedone C, Benedetti E. Peptide-based molecules in angiogenesis. Chem Biol Drug Des. 2006;67(2):115–26.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Finetti F, Basile A, Capasso D, Di Gaetano S, Di Stasi R, Pascale M, et al. Functional and pharmacological characterization of a VEGF mimetic peptide on reparative angiogenesis. Biochem Pharmacol. 2012;84(3):303–11.PubMedCrossRefGoogle Scholar
  91. 91.
    Sen CK, Khanna S, Venojarvi M, Trikha P, Ellison EC, Hunt TK, et al. Copper-induced vascular endothelial growth factor expression and wound healing. Am J Phys Heart Circ Phys. 2002;282(5):H1821–H7.Google Scholar
  92. 92.
    Martin F, Linden T, Katschinski DM, Oehme F, Flamme I, Mukhopadhyay CK, et al. Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood. 2005;105(12):4613–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Feng W, Ye F, Xue W, Zhou Z, Kang YJ. Copper regulation of hypoxia-inducible factor-1 activity. Mol Pharmacol. 2009;75(1):174–82.PubMedCrossRefGoogle Scholar
  94. 94.
    Zhou Y, Bourcy K, Kang YJ. Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway. Cardiovasc Res. 2009;84(1):54–63.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Christinger HW, Fuh G, de Vos AM, Wiesmann C. The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J Biol Chem. 2004;279(11):10382–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM. Crystal structure at 1.7 Å resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell. 1997;91(5):695–704.PubMedCrossRefGoogle Scholar
  97. 97.
    Li B, Fuh G, Meng G, Xin X, Gerritsen ME, Cunningham B, et al. Receptor-selective variants of human vascular endothelial growth factor GENERATION AND CHARACTERIZATION. J Biol Chem. 2000;275(38):29823–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Davis TL, Walker JR, Loppnau P, Butler-Cole C, Allali-Hassani A, Dhe-Paganon S. Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase A3 (EphA3). Structure. 2008;16(6):873–84.PubMedCrossRefGoogle Scholar
  99. 99.
    Zou J, Wang YD, Ma FX, Xiang ML, Shi B, Wei YQ, et al. Detailed conformational dynamics of juxtamembrane region and activation loop in c-Kit kinase activation process. Proteins. 2008;72(1):323–32.PubMedCrossRefGoogle Scholar
  100. 100.
    Chan PM, Ilangumaran S, La Rose J, Chakrabartty A, Rottapel R. Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region. Mol Cell Biol. 2003;23(9):3067–78.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life. 2009;61(9):915–22.PubMedCrossRefGoogle Scholar
  102. 102.
    Walter M, Lucet IS, Patel O, Broughton SE, Bamert R, Williams NK, et al. The 2.7 Å crystal structure of the autoinhibited human c-Fms kinase domain. J Mol Biol. 2007;367(3):839–47.PubMedCrossRefGoogle Scholar
  103. 103.
    Shein SA, Kuznetsov II, Abakumova TO, Chelushkin PS, Melnikov PA, Korchagina AA, et al. VEGF-and VEGFR2-targeted liposomes for cisplatin delivery to glioma cells. Mol Pharm. 2016;13(11):3712–23.PubMedCrossRefGoogle Scholar
  104. 104.
    Zhang Y, Schwerbrock NM, Rogers AB, Kim WY, Huang L. Codelivery of VEGF siRNA and gemcitabine monophosphate in a single nanoparticle formulation for effective treatment of NSCLC. Mol Ther. 2013;21(8):1559–69.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Zhu R, Wang Z, Liang P, He X, Zhuang X, Huang R, et al. Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated SiO2@ LDH for anti-neuroblastoma therapy. Acta Biomater. 2017;63:163–80.PubMedCrossRefGoogle Scholar
  106. 106.
    Chen W-H, Sung SY, Fadeev M, Cecconello A, Nechushtai R, Willner I. Targeted VEGF-triggered release of an anti-cancer drug from aptamer-functionalized metal–organic framework nanoparticles. Nanoscale. 2018;10(10):4650–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Coutelle O, Schiffmann L, Liwschitz M, Brunold M, Goede V, Hallek M, et al. Dual targeting of Angiopoietin-2 and VEGF potentiates effective vascular normalisation without inducing empty basement membrane sleeves in xenograft tumours. Br J Cancer. 2015;112(3):495.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcinogenesis. Biochim Biophys Acta-Molecular Cell Research. 2012;1823(4):850–60.CrossRefGoogle Scholar
  109. 109.
    Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev. 2005;16(2):179–86.PubMedCrossRefGoogle Scholar
  110. 110.
    Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, et al. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271(25):15292–7.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family, part II. J Biol Chem. 2006;281(23): 15694–15700PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Eswarakumar V, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16(2):139–49.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Ornitz DM, Herr AB, Nilsson M, Westman J, Svahn C-M, Waksman G. FGF binding and FGF receptor activation by synthetic heparan-derived di-and trisaccharides. Science. 1995;268(5209):432–6.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Thisse B, Thisse C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol. 2005;287(2):390–402.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Citores L, Khnykin D, Sorensen V, Weschle J, Klingenberg O, Wiedlocha A, et al. Modulation of intracellular transport of acidic fibroblast growth factor by mutations in the cytoplasmic receptor domain. J Cell Sci. 2001;114(9):1677–89.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Knights V, Cook SJ. De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol Ther. 2010;125(1):105–17.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Mohammadi M, Honegger A, Rotin D, Fischer R, Bellot F, Li W, et al. A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1. Mol Cell Biol. 1991;11(10):5068–78.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Powers C, McLeskey S, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer. 2000;7(3):165–97.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Mohammadi M, Dikic I, Sorokin A, Burgess W, Jaye M, Schlessinger J. Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol Cell Biol. 1996;16(3):977–89.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Furdui CM, Lew ED, Schlessinger J, Anderson KS. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell. 2006;21(5):711–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Tiong KH, Mah LY, Leong C-O. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis. 2013;18(12):1447–68.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Kouhara H, Hadari Y, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell. 1997;89(5):693–702.PubMedCrossRefGoogle Scholar
  124. 124.
    Ong S, Hadari Y, Gotoh N, Guy G, Schlessinger J, Lax I. Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci. 2001;98(11):6074–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Foehr ED, Raffioni S, Fuji R, Bradshaw RA. FGF signal transduction in PC12 cells: comparison of the responses induced by endogenous and chimeric receptors. Immunol Cell Biol. 1998;76(5):406–13.PubMedCrossRefGoogle Scholar
  126. 126.
    Szlachcic A, Zakrzewska M, Lobocki M, Jakimowicz P, Otlewski J. Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy. Drug Des Devel Ther. 2016;10:2547.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Bhide RS, Lombardo LJ, Hunt JT, Cai Z-w, Barrish JC, Galbraith S, et al. The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinases. Mol Cancer Ther. 2010;9:369. 1535-7163. MCT-09-0472.PubMedCrossRefGoogle Scholar
  128. 128.
    Martin LP, Sill M, Shahin MS, Powell M, DiSilvestro P, Landrum LM, et al. A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2014;132(3):526–30.PubMedCrossRefGoogle Scholar
  129. 129.
    Balis FM, Thompson PA, Mosse YP, Blaney SM, Minard CG, Weigel BJ, et al. First-dose and steady-state pharmacokinetics of orally administered crizotinib in children with solid tumors: a report on ADVL0912 from the Children’s Oncology Group Phase 1/Pilot Consortium. Cancer Chemother Pharmacol. 2017;79(1):181–7.PubMedCrossRefGoogle Scholar
  130. 130.
    Abou-Alfa GK, Meyer T, Cheng A-L, El-Khoueiry AB, Rimassa L, Ryoo B-Y, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Tolcher AW, Sarantopoulos J, Patnaik A, Papadopoulos K, Lin C-C, Rodon J, et al. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor. Clin Oncol. 2007;25:1390.CrossRefGoogle Scholar
  132. 132.
    Di Cosimo S, Sathyanarayanan S, Bendell JC, Cervantes A, Stein MN, Braña I, et al. Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial. Clin Cancer Res. 2015;21(1):49–59.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Wen PY, Yung WA, Lamborn KR, Dahia PL, Wang Y, Peng B, et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res. 2006;12(16):4899–907.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Shirley M. Olaratumab: first global approval. Drugs. 2017;77(1):107–12.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Younus J, Verma S, Franek J, Coakley N. Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate–resistant patients: recommendations and evidence. Curr Oncol. 2010;17(4):4.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro-Oncology. 2016;18(8):1146–56.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One. 2014;9(3):e90353.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Pinter T, Klippel Z, Cesas A, Croitoru A, Decaestecker J, Gibbs P, et al. A phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim in patients receiving first-line FOLFOX/bevacizumab or FOLFIRI/bevacizumab for locally advanced or metastatic colorectal cancer: final results of the pegfilgrastim and anti-VEGF evaluation study (PAVES). Clin Colorectal Cancer. 2017;16(2):103–14. e3.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Zhang Y, Han C, Li J, Zhang L, Wang L, Ye S, et al. Efficacy and safety for Apatinib treatment in advanced gastric cancer: a real world study. Sci Rep. 2017;7(1):13208.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Qin S. Phase III study of apatinib in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. Am Soc Clin Oncol. 2014;32:15:4003–4003.CrossRefGoogle Scholar
  141. 141.
    Kuo T, Cabebe E, Koong A, Norton J, Kunz P, Ford J, et al. An update of a phase I/II study of the VEGF receptor tyrosine kinase inhibitor vatalanib and gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2008;26(15_suppl):15571.CrossRefGoogle Scholar
  142. 142.
    Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(3):286–96.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Perez-Garcia J, Muñoz-Couselo E, Soberino J, Racca F, Cortes J. Targeting FGFR pathway in breast cancer. Breast. 2018;37:126–33.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Sobhani N, Ianza A, D’Angelo A, Roviello G, Giudici F, Bortul M, et al. Current status of fibroblast growth factor receptor-targeted therapies in breast cancer. Cell. 2018;7(7):76.CrossRefGoogle Scholar
  145. 145.
    Vergote I, Teneriello M, Powell MA, Miller DS, Garcia AA, Mikheeva ON, et al. A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: angiopoietin-2 as a predictive marker for clinical outcomes. Am Soc Clin Oncol. 2013;31:15:5520–5520.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Devashree Jahagirdar
    • 1
  • Sharwari Ghodke
    • 2
  • Akshay Mergu
    • 2
  • Aishwarya Nikam
    • 1
  • Padma V. Devarajan
    • 3
  • Ratnesh Jain
    • 2
    Email author
  • Prajakta Dandekar
    • 3
    Email author
  1. 1.Department of Pharmaceutical Sciences & TechnologyInstitute of Chemical TechnologyMumbaiIndia
  2. 2.Department of Chemical EngineeringInstitute of Chemical TechnologyMumbaiIndia
  3. 3.Department of Pharmaceutical SciencesInsitute of Chemical Technology, Deemed University, Elite Status and Centre of Excellence, Government of MaharashtraMumbaiIndia

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