1. Antiangiogenic Tyrosine Kinase Inhibitors have Differential Efficacy in Clear Cell Renal Cell Carcinoma in Bone.
- Author
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Maksimovic S, Boscolo NC, La Posta L, Barrios S, Moussa MJ, Gentile E, Pesquera PI, Li W, Chen J, Gomez JA, Basi A, Burks JK, Alvarez-Breckenridge C, Gao J, Campbell MT, and Dondossola E
- Subjects
- Animals, Humans, Mice, Neovascularization, Pathologic drug therapy, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms secondary, Tumor Microenvironment drug effects, Cell Line, Tumor, Xenograft Model Antitumor Assays, Female, Tyrosine Kinase Inhibitors, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Bone Neoplasms drug therapy, Bone Neoplasms secondary, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Angiogenesis Inhibitors therapeutic use, Angiogenesis Inhibitors pharmacology, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use
- Abstract
Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel-Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anticancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and nonimmune (blood vessels and osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies., Significance: TKIs showed different efficacy in synchronous bone and lung metastases and did not eradicate tumors as single agents but induced extensive reprogramming of the BM microenvironment. This resulted in a significant decrease in neoangiogenic blood vessels, bone remodeling, and immune cell infiltration (including CD8 T cells) with altered spatial distribution., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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