Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
| العنوان: | Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models |
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| المؤلفون: | Joshua M. Dempster, D. Allen Annis, Neekesh V. Dharia, William C. Hahn, Xintao Qiu, Brian J. Haas, Julie Jang, Kay Shigemori, Giorgio Inghirami, Ahmet Dogan, Sara N. Morrow, Eric D. Jacobsen, Andrew D. Cherniack, Aviad Tsherniak, Jian-Guo Ren, Noriaki Yoshida, Mark A. Murakami, Aaron R. Thorner, David M. Weinstock, Manuel Aivado, Amanda L. Christie, Nicolas A. Cordero, Vincent Guerlavais, Abner Louissaint, Robin M. Meyers, Raphael Koch, Alan L. Epstein, Yanming Zhang, Maneka Puligandla, Mahmoud Ghandi, David E. Root, Elizabeth A. Morgan, Mansoor N. Saleh, Samuel Y. Ng, Danilo Fiore, Jon C. Aster, Alexandria Van Scoyk, Valentina Nardi, Henry W. Long, David M. Dorfman, Amitkumar Mehta, Steven M. Horwitz, Solimar Santiago, Kristen E. Stevenson, Francisca Vazquez, Galen F. Gao, Christopher Lo |
| المساهمون: | Ng, S. Y., Yoshida, N., Christie, A. L., Ghandi, M., Dharia, N. V., Dempster, J., Murakami, M., Shigemori, K., Morrow, S. N., Van Scoyk, A., Cordero, N. A., Stevenson, K. E., Puligandla, M., Haas, B., Lo, C., Meyers, R., Gao, G., Cherniack, A., Louissaint, A., Nardi, V., Thorner, A. R., Long, H., Qiu, X., Morgan, E. A., Dorfman, D. M., Fiore, D., Jang, J., Epstein, A. L., Dogan, A., Zhang, Y., Horwitz, S. M., Jacobsen, E. D., Santiago, S., Ren, J. -G., Guerlavais, V., Annis, D. A., Aivado, M., Saleh, M. N., Mehta, A., Tsherniak, A., Root, D., Vazquez, F., Hahn, W. C., Inghirami, G., Aster, J. C., Weinstock, D. M., Koch, R. |
| المصدر: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Myeloid, MDMX, Cell, Drug Evaluation, Preclinical, General Physics and Astronomy, Cell Cycle Proteins, Whole Exome Sequencing, Romidepsin, Antineoplastic Agent, Mice, Depsipeptides, Cell Cycle Protein, Imidazoline, Medicine, lcsh:Science, Depsipeptide, Nuclear Protein, Proto-Oncogene Protein, Multidisciplinary, biology, Remission Induction, Nuclear Proteins, Proto-Oncogene Proteins c-mdm2, 3. Good health, Gene Expression Regulation, Neoplastic, Lymphoma, Extranodal NK-T-Cell, medicine.anatomical_structure, Peptide, Mdm2, Human, medicine.drug, Protein Binding, Signal Transduction, Xenograft Model Antitumor Assay, Science, Antineoplastic Agents, Lymphoma, T-Cell, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Ikaros Transcription Factor, In vivo, Proto-Oncogene Proteins, Exome Sequencing, Animals, Humans, Imidazolines, Animal, business.industry, Complete remission, General Chemistry, Janus Kinase 2, medicine.disease, Xenograft Model Antitumor Assays, Lymphoma, 030104 developmental biology, biology.protein, Cancer research, lcsh:Q, Tumor Suppressor Protein p53, business, Peptides |
| الوصف: | T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models. T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1f547fda85fead85c157861340e629f0Test https://doaj.org/article/ecc83cf960564bd2938fc055d45d8a01Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1f547fda85fead85c157861340e629f0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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