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Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target
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| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , , , , , |
| In: | Clinical Cancer Research, 25, 2019, 1, S. 210-221 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Koshkin, Vadim S. Garcia, Jorge A. Reynolds, Jordan Elson, Paul Magi-Galluzzi, Cristina McKenney, Jesse K. Isse, Kumiko Bishop, Evan Saunders, Laura R. Balyimez, Aysegul Rashid, Summya Hu, Ming Stephenson, Andrew J. Fergany, Amr F. Lee, Byron H. Haber, Georges-Pascal Dowlati, Afshin Gilligan, Timothy Ornstein, Moshe C. Rini, Brian I. Abazeed, Mohamed E. Mian, Omar Y. Grivas, Petros Koshkin, Vadim S. Garcia, Jorge A. Reynolds, Jordan Elson, Paul Magi-Galluzzi, Cristina McKenney, Jesse K. Isse, Kumiko Bishop, Evan Saunders, Laura R. Balyimez, Aysegul Rashid, Summya Hu, Ming Stephenson, Andrew J. Fergany, Amr F. Lee, Byron H. Haber, Georges-Pascal Dowlati, Afshin Gilligan, Timothy Ornstein, Moshe C. Rini, Brian I. Abazeed, Mohamed E. Mian, Omar Y. Grivas, Petros |
|---|---|
| author |
Koshkin, Vadim S. Garcia, Jorge A. Reynolds, Jordan Elson, Paul Magi-Galluzzi, Cristina McKenney, Jesse K. Isse, Kumiko Bishop, Evan Saunders, Laura R. Balyimez, Aysegul Rashid, Summya Hu, Ming Stephenson, Andrew J. Fergany, Amr F. Lee, Byron H. Haber, Georges-Pascal Dowlati, Afshin Gilligan, Timothy Ornstein, Moshe C. Rini, Brian I. Abazeed, Mohamed E. Mian, Omar Y. Grivas, Petros |
| spellingShingle |
Koshkin, Vadim S. Garcia, Jorge A. Reynolds, Jordan Elson, Paul Magi-Galluzzi, Cristina McKenney, Jesse K. Isse, Kumiko Bishop, Evan Saunders, Laura R. Balyimez, Aysegul Rashid, Summya Hu, Ming Stephenson, Andrew J. Fergany, Amr F. Lee, Byron H. Haber, Georges-Pascal Dowlati, Afshin Gilligan, Timothy Ornstein, Moshe C. Rini, Brian I. Abazeed, Mohamed E. Mian, Omar Y. Grivas, Petros Clinical Cancer Research Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target Cancer Research Oncology |
| author_sort |
koshkin, vadim s. |
| spelling |
Koshkin, Vadim S. Garcia, Jorge A. Reynolds, Jordan Elson, Paul Magi-Galluzzi, Cristina McKenney, Jesse K. Isse, Kumiko Bishop, Evan Saunders, Laura R. Balyimez, Aysegul Rashid, Summya Hu, Ming Stephenson, Andrew J. Fergany, Amr F. Lee, Byron H. Haber, Georges-Pascal Dowlati, Afshin Gilligan, Timothy Ornstein, Moshe C. Rini, Brian I. Abazeed, Mohamed E. Mian, Omar Y. Grivas, Petros 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-18-1278 <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC).</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on &gt;10% and CD56 expression on &gt;30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.</jats:p> </jats:sec> Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target Clinical Cancer Research |
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10.1158/1078-0432.ccr-18-1278 |
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American Association for Cancer Research (AACR), 2019 |
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American Association for Cancer Research (AACR), 2019 |
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1078-0432 1557-3265 |
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Clinical Cancer Research |
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| title |
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_unstemmed |
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_full |
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_fullStr |
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_full_unstemmed |
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_short |
Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_sort |
transcriptomic and protein analysis of small-cell bladder cancer (scbc) identifies prognostic biomarkers and dll3 as a relevant therapeutic target |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-18-1278 |
| publishDate |
2019 |
| physical |
210-221 |
| description |
<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Purpose:</jats:title>
<jats:p>Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Experimental Design:</jats:title>
<jats:p>Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC).</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results:</jats:title>
<jats:p>Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on &gt;10% and CD56 expression on &gt;30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions:</jats:title>
<jats:p>Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.</jats:p>
</jats:sec> |
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| author | Koshkin, Vadim S., Garcia, Jorge A., Reynolds, Jordan, Elson, Paul, Magi-Galluzzi, Cristina, McKenney, Jesse K., Isse, Kumiko, Bishop, Evan, Saunders, Laura R., Balyimez, Aysegul, Rashid, Summya, Hu, Ming, Stephenson, Andrew J., Fergany, Amr F., Lee, Byron H., Haber, Georges-Pascal, Dowlati, Afshin, Gilligan, Timothy, Ornstein, Moshe C., Rini, Brian I., Abazeed, Mohamed E., Mian, Omar Y., Grivas, Petros |
| author_facet | Koshkin, Vadim S., Garcia, Jorge A., Reynolds, Jordan, Elson, Paul, Magi-Galluzzi, Cristina, McKenney, Jesse K., Isse, Kumiko, Bishop, Evan, Saunders, Laura R., Balyimez, Aysegul, Rashid, Summya, Hu, Ming, Stephenson, Andrew J., Fergany, Amr F., Lee, Byron H., Haber, Georges-Pascal, Dowlati, Afshin, Gilligan, Timothy, Ornstein, Moshe C., Rini, Brian I., Abazeed, Mohamed E., Mian, Omar Y., Grivas, Petros, Koshkin, Vadim S., Garcia, Jorge A., Reynolds, Jordan, Elson, Paul, Magi-Galluzzi, Cristina, McKenney, Jesse K., Isse, Kumiko, Bishop, Evan, Saunders, Laura R., Balyimez, Aysegul, Rashid, Summya, Hu, Ming, Stephenson, Andrew J., Fergany, Amr F., Lee, Byron H., Haber, Georges-Pascal, Dowlati, Afshin, Gilligan, Timothy, Ornstein, Moshe C., Rini, Brian I., Abazeed, Mohamed E., Mian, Omar Y., Grivas, Petros |
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| description | <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC).</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on &gt;10% and CD56 expression on &gt;30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.</jats:p> </jats:sec> |
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| spelling | Koshkin, Vadim S. Garcia, Jorge A. Reynolds, Jordan Elson, Paul Magi-Galluzzi, Cristina McKenney, Jesse K. Isse, Kumiko Bishop, Evan Saunders, Laura R. Balyimez, Aysegul Rashid, Summya Hu, Ming Stephenson, Andrew J. Fergany, Amr F. Lee, Byron H. Haber, Georges-Pascal Dowlati, Afshin Gilligan, Timothy Ornstein, Moshe C. Rini, Brian I. Abazeed, Mohamed E. Mian, Omar Y. Grivas, Petros 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-18-1278 <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC).</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on &gt;10% and CD56 expression on &gt;30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.</jats:p> </jats:sec> Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target Clinical Cancer Research |
| spellingShingle | Koshkin, Vadim S., Garcia, Jorge A., Reynolds, Jordan, Elson, Paul, Magi-Galluzzi, Cristina, McKenney, Jesse K., Isse, Kumiko, Bishop, Evan, Saunders, Laura R., Balyimez, Aysegul, Rashid, Summya, Hu, Ming, Stephenson, Andrew J., Fergany, Amr F., Lee, Byron H., Haber, Georges-Pascal, Dowlati, Afshin, Gilligan, Timothy, Ornstein, Moshe C., Rini, Brian I., Abazeed, Mohamed E., Mian, Omar Y., Grivas, Petros, Clinical Cancer Research, Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target, Cancer Research, Oncology |
| title | Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_full | Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_fullStr | Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_full_unstemmed | Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_short | Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| title_sort | transcriptomic and protein analysis of small-cell bladder cancer (scbc) identifies prognostic biomarkers and dll3 as a relevant therapeutic target |
| title_unstemmed | Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-18-1278 |