| Autor: |
Martin Lang, Laura S. Schmidt, Kelli M. Wilson, Christopher J. Ricketts, Carole Sourbier, Cathy D. Vocke, Darmood Wei, Daniel R. Crooks, Youfeng Yang, Benjamin K. Gibbs, Xiaohu Zhang, Carleen Klumpp-Thomas, Lu Chen, Rajarshi Guha, Marc Ferrer, Crystal McKnight, Zina Itkin, Darawalee Wangsa, Danny Wangsa, Amy James, Simone Difilippantonio, Baktir Karim, Francisco Morís, Thomas Ried, Maria J. Merino, Ramaprasad Srinivasan, Craig J. Thomas, W. Marston Linehan |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Journal of Experimental & Clinical Cancer Research. 42 |
| ISSN: |
1756-9966 |
| Popis: |
Background MiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3, TFEB, or MITF. MiT-RCC represents a specific subtype of sporadic RCC that is predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology of this aggressive cancer is poorly understood and there is no accepted standard of care therapy for patients with advanced disease. Tumor-derived cell lines have been established from human TFE3-RCC providing useful models for preclinical studies. Methods TFE3-RCC tumor derived cell lines and their tissues of origin were characterized by IHC and gene expression analyses. An unbiased high-throughput drug screen was performed to identify novel therapeutic agents for treatment of MiT-RCC. Potential therapeutic candidates were validated in in vitro and in vivo preclinical studies. Mechanistic assays were conducted to confirm the on-target effects of drugs. Results The results of a high-throughput small molecule drug screen utilizing three TFE3-RCC tumor-derived cell lines identified five classes of agents with potential pharmacological efficacy, including inhibitors of phosphoinositide-3-kinase (PI3K) and mechanistic target of rapamycin (mTOR), and several additional agents, including the transcription inhibitor Mithramycin A. Upregulation of the cell surface marker GPNMB, a specific MiT transcriptional target, was confirmed in TFE3-RCC and evaluated as a therapeutic target using the GPNMB-targeted antibody-drug conjugate CDX-011. In vitro and in vivo preclinical studies demonstrated efficacy of the PI3K/mTOR inhibitor NVP-BGT226, Mithramycin A, and CDX-011 as potential therapeutic options for treating advanced MiT-RCC as single agents or in combination. Conclusions The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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