Imaging of Growth Factor Receptors Background The recognition of the role of growth factor receptors in the growth and progression of tumors has had widespread implications for cancer treatment. Not only have blocking antibodies been developed , but downstream small molecule inhibitors have also been developed. Both drug types have already had impact on the management of several major cancers. Regardless of the receptor imaged, imaging represents a potentially important avenue of research. Potential uses of imaging agents targeting receptors include more accurate sampling of tissue, patient selection for drug trials, monitoring of therapies directed at the receptor or its downstream clients which impact receptor expression, developing immuno-conjugates for delivering specific drug therapy and radioimmunotherapy/photoimmunotherapy in which therapeutic isotopes or photosensitizers are attached to the antibody. We are conducting a variety of pre-clinical and clinical studies to investigate the potential roles of this class of imaging agents. Pre-Clinical Research Individual antibodies have limitations because a tumor may express polyclonal distribution of receptors. For instance, part of the tumor may express HER2 but another part may express MET, HER1 or Mesothelin. We have explored the idea of a labeled cocktail of antibodies for tumor diagnosis and characterization. The potential use of optically labeled monoclonal antibodies for diagnosis is being explored by mixing combinations of antibodies and injecting the cocktail. Cocktails of optically labeled antibodies (Trastuzumab-anti HER2, Cetuximab, anti-HER2, and Declizimab anti-IL2) are injected into mice growing tumors expressing different antigens. The optically labeled antibodies, each labeled with a fluorophore of a unique wavelenth, attach to their respective cancer cells opening the possibility of performing in vivo immunohistochemistry. This may find particular application in improving the sampling of tumors during surgery or during endoscopy. However, another potential use is to use various pro-drug strategies to deliver each part of the pro-drug via different monoclonal antibody vectors. Proof of this concept is provided by optical imaging that can demonstrate the co-localization and internalization of two or more monoclonal antibodies in vivo. An advantage of optical imaging over radionuclide imaging is that optical imaging is inherently polychromatic allowing each agent to be tagged individually. This allows real time pharmacodynamic analysis of drug effects of tumors (visible superficially at least) and is of potential importance to drug discovery and drug testing(2). Recently, we have discovered that when the antibody is attached to a unique photofluor, near infrared light at one intensity could be used for diagnosis but by increasing the intensity the tumor can actually be treated. This process is known as photoimmunotherapy and holds great promise for the treatment of some forms of cancer that can be approached with near infrared light. In collaboration with Dr. Brechbiels lab we are testing PET and SPECT labeled monoclonal antibodies and have performed this with both trastuzumab and cetuximab and panitumimab(3). It is still unclear whether SPECT or PET imaging is preferred and a comparison trial using the Small Animal Imaging Programs PET-SPECT-CT device will be conducted. Recently, this work has been enabled in Bethesda using microSPECT and microPET cameras in the Molecular Imaging Program. We have also explored theuse of radiolabeled affibodies which are considerably smaller than antibodies. HER2 binding affibodies have proven to be more sensitive than FDG PET for detecting metastases in mouse models of lung metastases. Extensive work has been done on MET receptor where we have labeled both the external and internal domains of this receptor. We are developing an F18 labeled version of this agent for human use. Anti-Mesothelin antibody (Raffit Hassan, Ira Pastan, Laboratory of Molecular Biology) has also been developed. This receptor is associated with an aggressive phenotype. We have performed preclinical studies in mice with this labeled antibody and will shortly initiate a clinical trial. Clinical Studies We are conducting several studies involving growth factor receptors. The original clinical study used 111Indium trastuzumab in breast cancer patients. This protocols tests the uptake of trastuzumab (Herceptin) in patients with breast cancer who either overexpress or do not overexpress HER2/neu. Preliminary JDC approval was also received for 111Indium-panitumimab to be used in patients with colon and lung cancer. The preliminary pre-clinical work has been submitted to the Cancer Imaging Program for incorporation into an xIND submission and SOPs are being written for a GMP product. Indium labeled mesothelin (MORAb009) will begin clinical trials shortly. Cell proliferation is a direct result of activation of the growth factor receptors. We have investigated the ability to measure proliferation with a novel PET agent for human use, 18 F-L-thymidine, a proliferation marker for cancer. We have been using this agent in a variety of tumors and have demonstrated its utility. This work is ongoing in a trial of lymphoma and pediatric medulloblastoma, neurofibromatosis and leukemia post transplant. 1. Koyama, Y., Hama, Y., Urano, Y., Nguyen, D. M., Choyke, P. L., and Kobayashi, H. Spectral fluorescence molecular imaging of lung metastases targeting HER2/neu. Clin Cancer Res, 13: 2936-2945, 2007. 2. Hama, Y., Koyama, Y., Choyke, P. L., and Kobayashi, H. Two-color in vivo dynamic contrast-enhanced pharmacokinetic imaging. J Biomed Opt, 12: 034016, 2007. 3. Xu, H., Baidoo, K., Gunn, A. J., Boswell, C. A., Milenic, D. E., Choyke, P. L., and Brechbiel, M. W. Design, Synthesis, and Characterization of a Dual Modality Positron Emission Tomography and Fluorescence Imaging Agent for Monoclonal Antibody Tumor-Targeted Imaging. J Med Chem, 2007.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Nakajima, Takahito; Sato, Kazuhide; Hanaoka, Hirofumi et al. (2014) The effects of conjugate and light dose on photo-immunotherapy induced cytotoxicity. BMC Cancer 14:389
Wulfert, Sarah; Kratochwil, Clemens; Choyke, Peter L et al. (2014) Multimodal imaging for early functional response assessment of (90)Y-/ (177)Lu-DOTATOC peptide receptor targeted radiotherapy with DW-MRI and (68)Ga-DOTATOC-PET/CT. Mol Imaging Biol 16:586-94
Sano, Kohei; Mitsunaga, Makoto; Nakajima, Takahito et al. (2013) Acute cytotoxic effects of photoimmunotherapy assessed by 18F-FDG PET. J Nucl Med 54:770-5
Azad, Nilofer; Yu, Minshu; Davidson, Ben et al. (2013) Translational predictive biomarker analysis of the phase 1b sorafenib and bevacizumab study expansion cohort. Mol Cell Proteomics 12:1621-31
Sano, Kohei; Nakajima, Takahito; Choyke, Peter L et al. (2013) Markedly enhanced permeability and retention effects induced by photo-immunotherapy of tumors. ACS Nano 7:717-24
Xu, Heng; Eck, Peter K; Baidoo, Kwamena E et al. (2009) Toward preparation of antibody-based imaging probe libraries for dual-modality positron emission tomography and fluorescence imaging. Bioorg Med Chem 17:5176-81
Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L et al. (2009) Tumor-specific detection of an optically targeted antibody combined with a quencher-conjugated neutravidin "quencher-chaser": a dual "quench and chase" strategy to improve target to nontarget ratios for molecular imaging of cancer. Bioconjug Chem 20:147-54
Kosaka, Nobuyuki; Ogawa, Mikako; Longmire, Michelle R et al. (2009) Multi-targeted multi-color in vivo optical imaging in a model of disseminated peritoneal ovarian cancer. J Biomed Opt 14:014023
Longmire, Michelle; Kosaka, Nobuyuki; Ogawa, Mikako et al. (2009) Multicolor in vivo targeted imaging to guide real-time surgery of HER2-positive micrometastases in a two-tumor coincident model of ovarian cancer. Cancer Sci 100:1099-104
Ogawa, Mikako; Regino, Celeste A S; Choyke, Peter L et al. (2009) In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies. Mol Cancer Ther 8:232-9

Showing the most recent 10 out of 14 publications