Old and New Peptide Receptor Targets in Cancer: Future Directions

  • Jean Claude Reubi
Conference paper
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 194)


A precise definition of the tumor tissue targets to be selected for in vivo peptide receptor targeting, namely to know which peptide receptor is expressed in which type of cancer, is an important prerequisite for successful clinical application of this technology. In this short review, I give three selected examples of new and promising peptide receptor targets. In the somatostatin receptor field, based on in vitro receptor autoradiography experiments showing that much more sst2 binding sites are detected in tumors using a 177Lu-labeled sst2 antagonist than a 177Lu-labeled agonist, it can be proposed that, in addition to neuroendocrine tumors, nonneuroendocrine tumors with lower sst2 levels such as breast carcinomas, renal cell carcinomas, and non-Hodgkin lymphomas may become potential candidates for sst2 antagonist targeting. In the gastrin-releasing peptide receptor field, recent in vitro data show that not only tumor cells may overexpress gastrin-releasing peptide receptors but also neoangiogenic tumoral vessels, making tumors expressing high levels of gastrin-releasing peptide receptors in tumor vessels, such as ovarian or urinary tract cancers, attractive new candidates for gastrin-releasing peptide receptor targeting. In the incretin receptor field, it was found in vitro that, apart from glucagon-like peptide 1 receptors overexpressed in benign insulinomas, incretin receptors, especially the glucose-dependent insulinotropic polypeptide receptors, can be overexpressed in medullary thyroid cancers, an unexpected finding making also these tumors potential novel candidates for incretin receptor targeting. Due to the abundance of peptide receptors in various cancers, it may be possible in the future to define for each tumor type a corresponding overexpressed peptide receptor suitable for targeting.


Neuroendocrine Tumor Vascular Endothelial Growth Factor Receptor Medullary Thyroid Carcinoma Medullary Thyroid Cancer Urinary Tract Cancer 
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.



Glucagon-like peptide 1


Gastrin-releasing peptide


Vascular endothelial growth factor


Glucose-dependent insulinotropic polypeptide


  1. Bjenning C, Farrell AP, Holmgren S (1991) Bombesin-like immunoreactivity in skates and the in vitro effect of bombesin on coronary vessels from the longnose skate, Raja rhina. Regul Pept 35:207–219PubMedCrossRefGoogle Scholar
  2. Bunnett G (1994) Gastrin-releasing peptide. Gut peptides: biochemistry and physiology, New York pp 423–445Google Scholar
  3. Cescato R, Maina T, Nock B et al (2008) Bombesin receptor antagonists may be preferable to agonists for tumor targeting. J Nucl Med 49:318–326PubMedCrossRefGoogle Scholar
  4. Cescato R, Waser B, Fani M et al (2011) Evaluation of 177Lu-DOTA-SST2-antagonist versus 177Lu-DOTA-SST2-agonist binding in human cancers in vitro. J Nucl Med 52:1886–1890PubMedCrossRefGoogle Scholar
  5. Christ E, Wild D, Forrer F et al (2009) Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J Clin Endocrinol Metab 94:4398–4405PubMedCrossRefGoogle Scholar
  6. Clive S, Jodrell D, Webb D (2001) Gastrin-releasing peptide is a potent vasodilator in humans. Clin Pharmacol Ther 69:252–259PubMedCrossRefGoogle Scholar
  7. Ehses JA, Casilla VR, Doty T et al (2003) Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology 144:4433–4445PubMedCrossRefGoogle Scholar
  8. Fleischmann A, Waser B, Reubi JC (2007) Overexpression of gastrin-releasing peptide receptors in tumor-associated blood vessels of human ovarian neoplasms. Cell Oncol 29:421–433PubMedGoogle Scholar
  9. Fleischmann A, Waser B, Reubi JC (2009) High expression of gastrin-releasing peptide receptors in the vascular bed of urinary tract cancers: promising candidates for vascular targeting applications. Endocr Relat Cancer 16:623–633PubMedCrossRefGoogle Scholar
  10. Ginj M, Zhang H, Waser B et al (2006) Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci USA 103:16436–16441PubMedCrossRefGoogle Scholar
  11. Gugger M, Reubi JC (1999) GRP receptors in non-neoplastic and neoplastic human breast. Am J Pathol 155:2067–2076PubMedCrossRefGoogle Scholar
  12. Heuser M, Schlott T, Schally AV et al (2005) Expression of gastrin releasing Peptide receptor in renal cell carcinomas: a potential function for the regulation of neoangiogenesis and microvascular perfusion. J Urol 173:2154–2159PubMedCrossRefGoogle Scholar
  13. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439PubMedCrossRefGoogle Scholar
  14. Holst JJ, Vilsboll T, Deacon CF (2009) The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 297:127–136PubMedCrossRefGoogle Scholar
  15. Irwin N, Flatt PR (2009) Therapeutic potential for GIP receptor agonists and antagonists. Best Pract Res Clin Endocrinol Metab 23:499–512PubMedCrossRefGoogle Scholar
  16. Jensen JA, Carroll RE, Benya RV (2001) The case for gastrin-releasing peptide acting as a morphogen when it and its receptor are aberrantly expressed in cancer. Peptides 22:689–699PubMedCrossRefGoogle Scholar
  17. Kim JS, McKinnis VS, White SR (1997) Migration of guinea pig airway epithelial cells in response to bombesin analogues. Am J Respir Cell Mol Biol 16:259–266PubMedGoogle Scholar
  18. Kim SJ, Nian C, Widenmaier S et al (2008) Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol 28:1644–1656PubMedCrossRefGoogle Scholar
  19. Korner M, Stockli M, Waser B et al (2007) GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 48:736–743PubMedCrossRefGoogle Scholar
  20. Levine L, Licci JA 3rd, Townsend CM Jr et al (2003a) Expression of gastrin-releasing peptide receptors in endometrial cancer. J Am Coll Surg 196:898–904PubMedCrossRefGoogle Scholar
  21. Levine L, Lucci JA 3rd, Pazdrak B et al (2003b) Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. Cancer Res 63:3495–3502PubMedGoogle Scholar
  22. Luu TN, Chester AH, O’Neil GS et al (1993) Different responses of the human gastroepiploic and internal mammary arteries to vasoactive peptides. Am J Physiol 264:H583–H587PubMedGoogle Scholar
  23. Maecke HR, Reubi JC (2011) Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment. J Nucl Med 52:841–844PubMedCrossRefGoogle Scholar
  24. Mansi R, Wang X, Forrer F et al (2009) Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides. Clin Cancer Res 15:5240–5249PubMedCrossRefGoogle Scholar
  25. Mansi R, Wang X, Forrer F et al (2011) Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours. Eur J Nucl Med Mol Imaging 38:97–107PubMedCrossRefGoogle Scholar
  26. Markwalder R, Reubi JC (1999) Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res 59:1152–1159PubMedGoogle Scholar
  27. Oberg KE, Reubi JC, Kwekkeboom DJ et al (2010) Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology 139:742–753 753 e741PubMedCrossRefGoogle Scholar
  28. Reubi JC (2003) Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 24:389–427PubMedCrossRefGoogle Scholar
  29. Reubi JC (2007) Targeting CCK receptors in human cancers. Curr Top Med Chem 7:1239–1242PubMedCrossRefGoogle Scholar
  30. Reubi JC, Fleischmann A, Waser B et al (2011) Concomitant vascular GRP-receptor and VEGF-receptor expression in human tumors: molecular basis for dual targeting of tumoral vasculature. Peptides 32:1457–1462PubMedCrossRefGoogle Scholar
  31. Reubi JC, Macke HR, Krenning EP (2005) Candidates for peptide receptor radiotherapy today and in the future. J Nucl Med 46:67S–75SPubMedGoogle Scholar
  32. Reubi JC, Maecke HR (2008) Peptide-based probes for cancer imaging. J Nucl Med 49:1735–1738PubMedCrossRefGoogle Scholar
  33. Reubi JC, Waser B (2003) Concomitant expression of several peptide receptors in neuroendocrine tumors as molecular basis for in vivo multireceptor tumor targeting. Eur J Nucl Med 30:781–793CrossRefGoogle Scholar
  34. Waser B, Beetschen K, Pellegata NS et al (2011) Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology 94:291–301PubMedCrossRefGoogle Scholar
  35. Wild D, Caplin M, Christ E et al (2011a) Glucagon-like peptide-1 vs. somatostatin receptor targeting in malignant insulinomas. J Nucl Med 52:1073–1078PubMedCrossRefGoogle Scholar
  36. Wild D, Fani M, Behe M et al (2011b) First clinical evidence that imaging with somatostatin receptor antagonists is clinically feasible. J Nucl Med 52:1412–1417PubMedCrossRefGoogle Scholar
  37. Wild D, Mäcke H, Christ E et al (2008) Glucagon-like peptide 1-receptor scans to localize occult insulinomas. N Engl J Med 359:766–768PubMedCrossRefGoogle Scholar
  38. Yule KA, White SR (1999) Migration of 3T3 and lung fibroblasts in response to calcitonin gene-related peptide and bombesin. Exp Lung Res 25:261–273PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Division of Cell Biology and Experimental Cancer ResearchInstitute of Pathology, University of BerneBerneSwitzerland

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