Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

Abstract

Targeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the 'correct', biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.

Key Points

  • There is an urgent need to develop and use assays that accelerate the drug development and evaluation processes and, at the same time, reduce the drugs' costs

  • Radiolabeled drug analogs can be used to perform 'phase 0' (microdosing) studies at dose levels that have no significant toxic effects

  • Molecular imaging provides tools and assays that can address expression of the target protein, drug–target interactions, and tumor response in preclinical and clinical studies

  • The number of targets that can be studied noninvasively by molecular imaging is still limited

  • Development of new molecular imaging probes for MRI, PET and optical imaging is a highly active research area that will further extend the use of molecular imaging in the process of drug development

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intrapatient heterogeneity in the expression of αVβ3 integrin imaged by PET with the αVβ3 ligand [18F]galacto-RGD.
Figure 2: New approaches for imaging expression of the target protein.
Figure 3: Monitoring of target inhibition by PET imaging.
Figure 4: Monitoring of target inhibition by dynamic contrast-enhanced MRI.
Figure 5: Treatment monitoring with fluorodeoxyglucose (FDG) PET and CT in a patient with locally advanced distal esophageal cancer (arrows).

Similar content being viewed by others

References

  1. Sawyers C (2004) Targeted cancer therapy. Nature 432: 294–297

    Article  CAS  Google Scholar 

  2. Vogel CL et al. (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20: 719–726

    Article  CAS  Google Scholar 

  3. Shepherd FA et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132

    Article  CAS  Google Scholar 

  4. Atkins MB et al. (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22: 909–918

    Article  CAS  Google Scholar 

  5. Collins I and Workman P (2006) New approaches to molecular cancer therapeutics. Nat Chem Biol 2: 689–700

    Article  CAS  Google Scholar 

  6. Workman P et al. (2006) Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst 98: 580–598

    Article  CAS  Google Scholar 

  7. Perik PJ et al. (2006) Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 24: 2276–2282

    Article  CAS  Google Scholar 

  8. Ntziachristos V et al. (2005) Looking and listening to light: the evolution of whole-body photonic imaging. Nat Biotechnol 23: 313–320

    Article  CAS  Google Scholar 

  9. Cherry SR (2006) The 2006 Henry N. Wagner Lecture: Of mice and men (and positrons)--advances in PET imaging technology. J Nucl Med 47: 1735–1745

    CAS  PubMed  Google Scholar 

  10. Blodgett TM et al. (2007) PET/CT: form and function. Radiology 242: 360–385

    Article  Google Scholar 

  11. Linden HM et al. (2006) Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer. J Clin Oncol 24: 2793–2799

    Article  CAS  Google Scholar 

  12. Beer AJ et al. (2005) Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18f-galacto-RGD in cancer patients. J Nucl Med 46: 1333–1341

    CAS  PubMed  Google Scholar 

  13. Mintun MA et al. (1988) Breast cancer: PET imaging of estrogen receptors. Radiology 169: 45–48

    Article  CAS  Google Scholar 

  14. Larson SM et al. (2004) Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 45: 366–373

    CAS  PubMed  Google Scholar 

  15. Hofmann M et al. (2001) Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med 28: 1751–1757

    Article  CAS  Google Scholar 

  16. Schottelius M et al. (2004) First (18)F-labeled tracer suitable for routine clinical imaging of sst receptor-expressing tumors using positron emission tomography. Clin Cancer Res 10: 3593–3606

    Article  CAS  Google Scholar 

  17. Haubner R et al. (2005) Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]galacto-RGD. PLoS Med 2: 244–252

    Article  CAS  Google Scholar 

  18. Wu AM and Senter PD (2005) Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 23: 1137–1146

    Article  CAS  Google Scholar 

  19. Backer MV et al. (2007) Molecular imaging of VEGF receptors in angiogenic vasculature with single-chain VEGF-based probes. Nat Med 13: 504–509

    Article  CAS  Google Scholar 

  20. Sharma P et al. (2006) Nanoparticles for bioimaging. Adv Colloid Interface Sci 123–126: 471–485

    Article  Google Scholar 

  21. Gao X et al. (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22: 969–976

    Article  CAS  Google Scholar 

  22. Ntziachristos V et al. (2002) Fluorescence molecular tomography resolves protease activity in vivo. Nat Med 8: 757–760

    Article  CAS  Google Scholar 

  23. Hutchinson OC et al. (2003) Pharmacokinetics of radiolabelled anticancer drugs for positron emission tomography. Curr Pharm Des 9: 917–929

    Article  CAS  Google Scholar 

  24. Jayson GC et al. (2002) Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 94: 1484–1493

    Article  CAS  Google Scholar 

  25. Shani J and Wolf W (1977) A model for prediction of chemotherapy response to 5-fluorouracil based on the differential distribution of 5-[18F]fluorouracil in sensitive versus resistant lymphocytic leukemia in mice. Cancer Res 37: 2306–2308

    CAS  PubMed  Google Scholar 

  26. Hsueh WA et al. (2006) Predicting chemotherapy response to paclitaxel with 18F-fluoropaclitaxel and PET. J Nucl Med 47: 1995–1999

    CAS  PubMed  Google Scholar 

  27. Saleem A et al. (2003) Metabolic activation of temozolomide measured in vivo using positron emission tomography. Cancer Res 63: 2409–2415

    CAS  PubMed  Google Scholar 

  28. Saleem A et al. (2001) Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography. J Clin Oncol 19: 1421–1429

    Article  CAS  Google Scholar 

  29. Bergstrom M et al. (2003) Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development. Eur J Clin Pharmacol 59: 357–366

    Article  Google Scholar 

  30. Bading JR et al. (2003) Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats. Cancer Res 63: 3667–3674

    CAS  PubMed  Google Scholar 

  31. Nunn AD (2006) The cost of developing imaging agents for routine clinical use. Invest Radiol 41: 206–212

    Article  Google Scholar 

  32. Lee CC et al. (2005) Multistep synthesis of a radiolabeled imaging probe using integrated microfluidics. Science 310: 1793–1796

    Article  CAS  Google Scholar 

  33. Dehdashti F et al. (1999) Positron emission tomographic assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med 26: 51–56

    Article  CAS  Google Scholar 

  34. Haubner R et al. (2001) Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 61: 1781–1785

    CAS  PubMed  Google Scholar 

  35. Bremer C et al. (2001) In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med 7: 743–748

    Article  CAS  Google Scholar 

  36. Pal A et al. (2006) Molecular imaging of EGFR kinase activity in tumors with 124I-labeled small molecular tracer and positron emission tomography. Mol Imaging Biol 8: 262–277

    Article  CAS  Google Scholar 

  37. Smith-Jones PM et al. (2004) Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol 22: 701–706

    Article  CAS  Google Scholar 

  38. Smith-Jones PM et al. (2006) Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J Nucl Med 47: 793–796

    CAS  PubMed  PubMed Central  Google Scholar 

  39. O'Connor JP et al. (2007) DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 96: 189–195

    Article  CAS  Google Scholar 

  40. Thomas AL et al. (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23: 4162–4171

    Article  CAS  Google Scholar 

  41. Morgan B et al. (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 21: 3955–3964

    Article  CAS  Google Scholar 

  42. Paez JG et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500

    Article  CAS  Google Scholar 

  43. Leach MO et al. (2005) The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 92: 1599–1610

    Article  CAS  Google Scholar 

  44. Massoud TF et al. (2007) Reporter gene imaging of protein-protein interactions in living subjects. Curr Opin Biotechnol 18: 31–37

    Article  CAS  Google Scholar 

  45. Paulmurugan R et al. (2002) Noninvasive imaging of protein-protein interactions in living subjects by using reporter protein complementation and reconstitution strategies. Proc Natl Acad Sci USA 99: 15608–15613

    Article  CAS  Google Scholar 

  46. Luker KE et al. (2004) Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals. Proc Natl Acad Sci USA 101: 12288–12293

    Article  CAS  Google Scholar 

  47. Weber WA (2006) Positron emission tomography as an imaging biomarker. J Clin Oncol 24: 3282–3292

    Article  CAS  Google Scholar 

  48. Shankar LK et al. (2006) Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med 47: 1059–1066

    CAS  PubMed  Google Scholar 

  49. Juweid ME et al. (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25: 571–578

    Article  Google Scholar 

  50. Van den Abbeele AD and Badawi RD (2002) Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer 38 (Suppl 5): S60–S65

    Article  Google Scholar 

  51. Su H et al. (2006) Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 12: 5659–5667

    Article  CAS  Google Scholar 

  52. Vesselle H et al. (2002) In vivo validation of 3′deoxy-3′-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 8: 3315–3323

    CAS  PubMed  Google Scholar 

  53. Chen W et al. (2005) Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med 46: 945–952

    CAS  PubMed  Google Scholar 

  54. Chen W et al. (2006) Predicting response of malignant brain tumors to bevacizumab and irinotecan therapy with FLT and FDOPA PET [abstract #78P]. J Nucl Med 47

Download references

Acknowledgements

We thank the members of the Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, Crump Institute for Molecular Imaging, and Ahmanson Biological Imaging Division for their helpful conversations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Harvey R Herschman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weber, W., Czernin, J., Phelps, M. et al. Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs. Nat Rev Clin Oncol 5, 44–54 (2008). https://doi.org/10.1038/ncponc0982

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncponc0982

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing