Preclinical Experimentation in Oncology
Molecular targeting is the foundation of current cancer therapies. Although much more progress is to be made, overall survival rates have improved in a variety of cancers. Imaging is central to the assessment of those therapies, and the clinical use of nuclear imaging technologies—specifically positron emission tomography (PET) and single photon emission computed tomography (SPECT)—continues to grow. The functional information provided by nuclear imaging enables us to diagnose, stage, and monitor tumor response to therapy. There also has been tremendous growth in radiosynthetic methods, the development of radiotracers, and the number of radiotracers evaluated in humans. The clinical utility of a radiopharmaceutical is ultimately determined by its ability to quantify target expression and provide high-contrast images with specificity and sensitivity. In light of this, the robust validation of radiotracers is essential and requires the use of both in vitro and in vivo model systems that can capture the heterogeneity and genetic complexity of tumors. Along these lines, some of the most important challenges include modeling the interactions between the tumor and the host immune system, faithfully representing human tumor genetic diversity, mimicking drug resistance, predicting the in vivo behavior of imaging agents, and appreciating interspecies differences. This chapter addresses these difficulties and the tools needed to evaluate radiotracers in the right model system.
KeywordsCancer Cell Line Encyclopedia The Cancer Genome Atlas Ligand affinity Positron emission tomography (PET) Single photon emission computed tomography (SPECT) Humanized mouse models Radiopharmaceuticals
We gratefully acknowledge support from Allegheny Health Network-Johns Hopkins Cancer Research Fund, NIH R01CA166131, NIH R01CA236616, DoD W81XWH-16-1-0323, NIH R01 CA134675, NIH P30 CA006973, and NIH P41EB024495.
- 6.Wustemann T, Haberkorn U, Babich J, Mier W. Targeting prostate cancer: prostate-specific membrane antigen based diagnosis and therapy. Med Res Rev. 2018 May 17. https://doi.org/10.1002/med.21508. [Epub ahead of print]
- 28.Pollastri MP. Overview on the rule of five. Curr Protoc Pharmacol. 2010;Chapter 9:Unit 9.12.Google Scholar
- 39.Pearson T, Greiner DL, Shultz LD. Creation of “humanized” mice to study human immunity. Curr Protoc Immunol. 2008;Chapter 15:Unit 15 21.Google Scholar
- 40.England CG, Ehlerding EB, Hernandez R, Rekoske BT, Graves SA, Sun H, et al. Preclinical pharmacokinetics and biodistribution studies of 89Zr-labeled pembrolizumab. J Nucl Med. 2017;58(1):162–68.Google Scholar
- 53.Bradbury MS, Hambardzumyan D, Zanzonico PB, Schwartz J, Cai S, Burnazi EM, et al. Dynamic small-animal PET imaging of tumor proliferation with 3′-deoxy-3′-18F-fluorothymidine in a genetically engineered mouse model of high-grade gliomas. J Nucl Med. 2008;49(3):422–9.PubMedPubMedCentralCrossRefGoogle Scholar