Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.

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Zeitschriftentitel:	Journal of Clinical Oncology
Personen und Körperschaften:	Speers, Corey Wayne, Chandler, Benjamin, Zhao, Shuang, Liu, Meilan, Wilder-Romans, Kari, Olsen, Eric, Nyati, Shyam, Rae, James M., Hayes, Daniel F., Spratt, Daniel Eidelberg, Wahl, Daniel Richard, Feng, Felix Yi-Chung, Pierce, Lori J.
In:	Journal of Clinical Oncology, 35, 2017, 15_suppl, S. e12102-e12102
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Society of Clinical Oncology (ASCO)
Schlagwörter:	Cancer Research Oncology

author_facet	Speers, Corey Wayne Chandler, Benjamin Zhao, Shuang Liu, Meilan Wilder-Romans, Kari Olsen, Eric Nyati, Shyam Rae, James M. Hayes, Daniel F. Spratt, Daniel Eidelberg Wahl, Daniel Richard Feng, Felix Yi-Chung Pierce, Lori J. Speers, Corey Wayne Chandler, Benjamin Zhao, Shuang Liu, Meilan Wilder-Romans, Kari Olsen, Eric Nyati, Shyam Rae, James M. Hayes, Daniel F. Spratt, Daniel Eidelberg Wahl, Daniel Richard Feng, Felix Yi-Chung Pierce, Lori J.
author	Speers, Corey Wayne Chandler, Benjamin Zhao, Shuang Liu, Meilan Wilder-Romans, Kari Olsen, Eric Nyati, Shyam Rae, James M. Hayes, Daniel F. Spratt, Daniel Eidelberg Wahl, Daniel Richard Feng, Felix Yi-Chung Pierce, Lori J.
spellingShingle	Speers, Corey Wayne Chandler, Benjamin Zhao, Shuang Liu, Meilan Wilder-Romans, Kari Olsen, Eric Nyati, Shyam Rae, James M. Hayes, Daniel F. Spratt, Daniel Eidelberg Wahl, Daniel Richard Feng, Felix Yi-Chung Pierce, Lori J. Journal of Clinical Oncology Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor. Cancer Research Oncology
author_sort	speers, corey wayne
spelling	Speers, Corey Wayne Chandler, Benjamin Zhao, Shuang Liu, Meilan Wilder-Romans, Kari Olsen, Eric Nyati, Shyam Rae, James M. Hayes, Daniel F. Spratt, Daniel Eidelberg Wahl, Daniel Richard Feng, Felix Yi-Chung Pierce, Lori J. 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12102 <jats:p> e12102 </jats:p><jats:p> Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value < 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value < 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC. </jats:p> Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor. Journal of Clinical Oncology
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title	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_unstemmed	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_full	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_fullStr	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_full_unstemmed	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_short	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_sort	radiosensitization of androgen receptor (ar)-positive triple-negative breast cancer (tnbc) cells using seviteronel (sevi), a selective cyp17 lyase and ar inhibitor.
topic	Cancer Research Oncology
url	http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12102
publishDate	2017
physical	e12102-e12102
description	<jats:p> e12102 </jats:p><jats:p> Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value < 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value < 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC. </jats:p>
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author	Speers, Corey Wayne, Chandler, Benjamin, Zhao, Shuang, Liu, Meilan, Wilder-Romans, Kari, Olsen, Eric, Nyati, Shyam, Rae, James M., Hayes, Daniel F., Spratt, Daniel Eidelberg, Wahl, Daniel Richard, Feng, Felix Yi-Chung, Pierce, Lori J.
author_facet	Speers, Corey Wayne, Chandler, Benjamin, Zhao, Shuang, Liu, Meilan, Wilder-Romans, Kari, Olsen, Eric, Nyati, Shyam, Rae, James M., Hayes, Daniel F., Spratt, Daniel Eidelberg, Wahl, Daniel Richard, Feng, Felix Yi-Chung, Pierce, Lori J., Speers, Corey Wayne, Chandler, Benjamin, Zhao, Shuang, Liu, Meilan, Wilder-Romans, Kari, Olsen, Eric, Nyati, Shyam, Rae, James M., Hayes, Daniel F., Spratt, Daniel Eidelberg, Wahl, Daniel Richard, Feng, Felix Yi-Chung, Pierce, Lori J.
author_sort	speers, corey wayne
container_issue	15_suppl
container_start_page	0
container_title	Journal of Clinical Oncology
container_volume	35
description	<jats:p> e12102 </jats:p><jats:p> Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value < 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value < 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC. </jats:p>
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spelling	Speers, Corey Wayne Chandler, Benjamin Zhao, Shuang Liu, Meilan Wilder-Romans, Kari Olsen, Eric Nyati, Shyam Rae, James M. Hayes, Daniel F. Spratt, Daniel Eidelberg Wahl, Daniel Richard Feng, Felix Yi-Chung Pierce, Lori J. 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12102 <jats:p> e12102 </jats:p><jats:p> Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value < 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value < 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC. </jats:p> Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor. Journal of Clinical Oncology
spellingShingle	Speers, Corey Wayne, Chandler, Benjamin, Zhao, Shuang, Liu, Meilan, Wilder-Romans, Kari, Olsen, Eric, Nyati, Shyam, Rae, James M., Hayes, Daniel F., Spratt, Daniel Eidelberg, Wahl, Daniel Richard, Feng, Felix Yi-Chung, Pierce, Lori J., Journal of Clinical Oncology, Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor., Cancer Research, Oncology
title	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_full	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_fullStr	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_full_unstemmed	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_short	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
title_sort	radiosensitization of androgen receptor (ar)-positive triple-negative breast cancer (tnbc) cells using seviteronel (sevi), a selective cyp17 lyase and ar inhibitor.
title_unstemmed	Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
topic	Cancer Research, Oncology
url	http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12102