Metastasis is the major cause of morbidity and mortality in cancer. Approximately 30-40% of all diagnosed breast cancers eventually develop lesions in lymph nodes, lung, liver and bone. The stromal-derived factor SDF-1 (or CXCL12) is secreted by stroma in potential metastatic sites and attracts circulating chemokine receptor 4 (CXCR4) expressing cells. CXCR4 is often overexpressed in breast cancer cells and CXCR4- CXCL12 signaling is central not only for the migration of cancer cells but also for the survival and growth of micrometastatic and primary tumors. Inhibitors targeting CXCR4 reduce the incidence of metastasis. Of the known molecular phenotypes, triple negative (TN) [estrogen receptor (ER), progestin receptor (PR) and HER-2 negative] breast cancer patients have the worst prognosis, with most patients likely to experience distant recurrence and refractory disease. Nearly 75% of TN breast cancers have high levels of activated CXCR4 and this overexpression in TN breast cancers results in poor clinical outcome. Because of its critical role in cancer cell survival, invasion, recruitment of myeloid bone marrow-derived cells and angiogenesis, noninvasive imaging of CXCR4 receptor in TN breast cancer is important to evaluate elevated CXCR4 expression in primary and metastatic tumors. CXCR4 based imaging probes can be used i) to evaluate primary tumors for elevated CXCR4 expression and therapeutic intervention; ii) to screen for secondary metastatic spread to both local and distant sites; and, iii) for therapeutic monitoring. We previously developed and evaluated the positron emission tomography (PET) imaging agent [64Cu]AMD3100 in orthotopic and experimental lung metastatic models of breast cancer to detect CXCR4 expression. More recently, we developed the positron-emitting monocyclam analog [64Cu]AMD3465, which has nearly 16-fold higher binding affinity to CXCR4 when compared to [64Cu]AMD3100, and has provided the clearest images with very high target selectivity. Our purpose here is to develop an 18F-labeled AMD3465 analog for rapid clinical translational imaging of breast cancer. Also, TN breast cancers particularly lack the benefit of targeted therapy and show higher recurrence rates and shorter survival than other phenotypes. Targeting and selective depletion of lethal CXCR4 positive cancer cell populations within the tumors and metastases would likely to result in reduced metastatic burden. Because CXCR4 is highly expressed in TN breast cancers, we will develop therapeutic agents decorated with clinically available CXCR4 binding motifs and multimodality imaging reporters for targeting CXCR4 positive TN breast cancers. Relevance CXCR4 based imaging probes and CXCR4 targeted therapeutic agents that selectively eliminate CXCR4 positive cells within the primary tumors and metastases will be developed for imaging and targeting of triple negative breast cancer.

Public Health Relevance

Metastasis is the major cause of mortality and triple negative (TN) breast cancers has the worst prognosis and survival. Chemokine Receptor 4(CXCR4) is expressed in majority of TN breast cancers. With an ultimate goal of clinical translation, we intend to synthesize CXCR4 binding PET imaging and therapeutic agents for identifying and targeting metastatic disease, respectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA166131-05
Application #
9079449
Study Section
Special Emphasis Panel (ZRG1)
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Nimmagadda, Sridhar; Pullambhatla, Mrudula; Chen, Ying et al. (2018) Low-Level Endogenous PSMA Expression in Nonprostatic Tumor Xenografts Is Sufficient for In Vivo Tumor Targeting and Imaging. J Nucl Med 59:486-493
Lesniak, Wojciech G; Aboye, Teshome; Chatterjee, Samit et al. (2017) In vivo Evaluation of an Engineered Cyclotide as Specific CXCR4 Imaging Reagent. Chemistry 23:14469-14475
Chatterjee, Samit; Lesniak, Wojciech G; Miller, Michelle S et al. (2017) Corrigendum to ""Rapid PD-L1 detection in tumors with PET using a highly specific peptide"" [Biochemical and Biophysical Research Communications 483/1 (2017) 258-263]. Biochem Biophys Res Commun 491:1125
Chatterjee, Samit; Lesniak, Wojciech G; Nimmagadda, Sridhar (2017) Noninvasive Imaging of Immune Checkpoint Ligand PD-L1 in Tumors and Metastases for Guiding Immunotherapy. Mol Imaging 16:1536012117718459
Chatterjee, Samit; Lesniak, Wojciech G; Miller, Michelle S et al. (2017) Rapid PD-L1 detection in tumors with PET using a highly specific peptide. Biochem Biophys Res Commun 483:258-263
Azad, Babak Behnam; Chatterjee, Samit; Lesniak, Wojciech G et al. (2016) A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts. Oncotarget 7:12344-58
Lesniak, Wojciech G; Chatterjee, Samit; Gabrielson, Matthew et al. (2016) PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET. Bioconjug Chem 27:2103-10
Behnam Azad, Babak; Lisok, Ala; Chatterjee, Samit et al. (2016) Targeted Imaging of the Atypical Chemokine Receptor 3 (ACKR3/CXCR7) in Human Cancer Xenografts. J Nucl Med 57:981-8
Lesniak, Wojciech G; Oskolkov, Nikita; Song, Xiaolei et al. (2016) Salicylic Acid Conjugated Dendrimers Are a Tunable, High Performance CEST MRI NanoPlatform. Nano Lett 16:2248-53
Chatterjee, Samit; Lesniak, Wojciech G; Gabrielson, Matthew et al. (2016) A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors. Oncotarget 7:10215-27

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