Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma
Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C.
The American Association for Cancer Research (AACR)
Published 2018
The American Association for Cancer Research (AACR)
Published 2018
| Publication Date: |
2018-07-17
|
|---|---|
| Publisher: |
The American Association for Cancer Research (AACR)
|
| Print ISSN: |
1078-0432
|
| Electronic ISSN: |
1557-3265
|
| Topics: |
Medicine
|
| Published by: |
| _version_ | 1836399007096635392 |
|---|---|
| autor | Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. |
| beschreibung | Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD + metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ( SDHB )-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR . |
| citation_standardnr | 6304556 |
| datenlieferant | ipn_articles |
| feed_id | 9363 |
| feed_publisher | The American Association for Cancer Research (AACR) |
| feed_publisher_url | http://www.aacr.org/ |
| insertion_date | 2018-07-17 |
| journaleissn | 1557-3265 |
| journalissn | 1078-0432 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | The American Association for Cancer Research (AACR) |
| quelle | Clinical Cancer Research |
| relation | http://clincancerres.aacrjournals.org/cgi/content/short/24/14/3423?rss=1 |
| search_space | articles |
| shingle_author_1 | Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. |
| shingle_author_2 | Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. |
| shingle_author_3 | Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. |
| shingle_author_4 | Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. |
| shingle_catch_all_1 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD + metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ( SDHB )-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR . Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
| shingle_catch_all_2 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD + metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ( SDHB )-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR . Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
| shingle_catch_all_3 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD + metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ( SDHB )-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR . Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
| shingle_catch_all_4 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD + metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ( SDHB )-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR . Pang, Y., Lu, Y., Caisova, V., Liu, Y., Bullova, P., Huynh, T.-T., Zhou, Y., Yu, D., Frysak, Z., Hartmann, I., Taïeb, D., Pacak, K., Yang, C. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
| shingle_title_1 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma |
| shingle_title_2 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma |
| shingle_title_3 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma |
| shingle_title_4 | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma |
| timestamp | 2025-06-30T23:36:07.002Z |
| titel | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma |
| titel_suche | Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma |
| topic | WW-YZ |
| uid | ipn_articles_6304556 |