scholarly journals Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models

2021 ◽  
Vol 15 (1) ◽  
pp. 10
Author(s):  
Jaline Broqueza ◽  
Chandra B. Prabaharan ◽  
Kevin J. H. Allen ◽  
Rubin Jiao ◽  
Darrell R. Fisher ◽  
...  

Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted.

2019 ◽  
Vol 18 (7) ◽  
pp. 1289-1301 ◽  
Author(s):  
Jieheng Wu ◽  
Donghui Han ◽  
Shengjia Shi ◽  
Qiang Zhang ◽  
Guoxu Zheng ◽  
...  

Cell Reports ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Yongliang Wang ◽  
Ali R. Nasiri ◽  
William E. Damsky ◽  
Curtis J. Perry ◽  
Xian-Man Zhang ◽  
...  

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hui Yuan ◽  
Zelong Lin ◽  
Yingjun Liu ◽  
Yuchuan Jiang ◽  
Ke Liu ◽  
...  

Abstract Background M2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism. Methods Two progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system. Results We found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p < 0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial–mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC. Conclusion Our results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.


mAbs ◽  
2017 ◽  
Vol 9 (5) ◽  
pp. 831-843 ◽  
Author(s):  
Lisa C. Schmitt ◽  
Alexander Rau ◽  
Oliver Seifert ◽  
Jonas Honer ◽  
Meike Hutt ◽  
...  

Author(s):  
Tomoyuki Sasano ◽  
Ricardo Gonzalez‐Delgado ◽  
Nina M. Muñoz ◽  
Wendolyn Carlos‐Alcade ◽  
Min Soon Cho ◽  
...  

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Qiu Tang ◽  
Jian Li ◽  
Hongfei Zhu ◽  
Pan Li ◽  
Zhenwei Zou ◽  
...  

In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, IL-17 deficiency results in reduced melanoma tumor size, diminished numbers of proliferating cells and blood vessels, and decreased percentage of CD11b+Gr-1+MDSCs in tumor tissues. IL-17 promotes IL-6 induction and Stat3 activation. Treatment of Stat3 inhibitor WP1066 in B16-F10 tumor cells inoculated wild-type mice inhibits tumor growth. Additional administration of recombinant IL-6 into B16-F10 tumor-bearing IL-17−/−mice results in markedly increased tumor size and p-Stat3 expression, whereas additional recombinant IL-17 administration into B16-F10 tumor-bearing wild-type mice treated with anti-IL-6 mAb does not significantly alter the tumor growth and p-Stat3 expression. In our further study, blockade of Hmgb1-RAGE pathway inhibits melanoma tumor growth and reduces production of IL-23 and IL-17. All these data suggest that Hmgb1-IL-23-IL-17-IL-6-Stat3 axis plays a pivotal role in tumor development in murine models of melanoma, and blocking any portion of this axis will attenuate melanoma tumor growth.


2016 ◽  
Vol 35 (1) ◽  
Author(s):  
Edina Bugyik ◽  
Ferenc Renyi-Vamos ◽  
Vanessza Szabo ◽  
Katalin Dezso ◽  
Nora Ecker ◽  
...  

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3335
Author(s):  
Jason A. Somarelli ◽  
Gabrielle Rupprecht ◽  
Erdem Altunel ◽  
Etienne M. Flamant ◽  
Sneha Rao ◽  
...  

Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.


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