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Gaillard, Stéphanie L.

Overview:

Dr. Stéphanie Gaillard is an Assistant Professor in Medical Oncology at the Duke Cancer Institute. Dr. Gaillard is board certified by the American Board of Internal Medicine in both Internal Medicine and Medical Oncology. At Duke, she focuses on treating patients with gynecologic malignancies and conducts basic science and clinical research. Dr. Gaillard’s laboratory research focuses on elucidating the biology of ovarian cancer, especially metabolic changes in the development of ovarian tumors, and mechanisms of resistance to chemotherapy. Her clinical research interests center on the development of novel therapeutic strategies for the treatment of ovarian cancer through early phase clinical trials. In addition to the Ovarian Cancer Research Fund Liz Tilberis Grant, Dr. Gaillard has received a Department of Defense Breast Cancer Research Program pre-doctoral research award and a Conquer Cancer Foundation Young Investigator Award.

Positions:

Adjunct Assistant Professor in the Department of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Internal Medicine Internship And Residency

Johns Hopkins University School of Medicine

Medical Oncology Fellowship

Johns Hopkins University School of Medicine

Publications:

Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival?

Women with advanced-stage, low-grade serous ovarian carcinoma (LGSC) have low chemotherapy response rates and poor overall survival. Most LGSC tumors overexpress hormone receptors, which represent a potential treatment target. Our study objective was to determine the outcomes of patients with advanced-stage LGSC treated with primary cytoreductive surgery (CRS) and hormone therapy (HT).A retrospective study was performed at two academic cancer centers. Patients with Stage II-IV LGSC underwent either primary or interval CRS followed by adjuvant HT between 2004 and 2016. Gynecologic pathologists reviewed all cases. Two-year progression-free (PFS) and overall survival (OS) were calculated.Twenty-seven patients were studied; primary CRS followed by HT were administered in 26, while 1 patient had neoadjuvant chemotherapy followed by CRS and HT. The median patient age was 47.5, and patients had Stage II (n=2), Stage IIIA (n=6), Stage IIIC (n=18), and Stage IV (n=1) disease. Optimal cytoreduction to no gross residual was achieved in 85.2%. Ninety six percent of tumors expressed estrogen receptors, while only 32% expressed progesterone receptors. Letrozole was administered post operatively in 55.5% cases, anastrozole in 37.1% and tamoxifen in 7.4%. After a median follow up of 41months, only 6 patients (22.2%) have developed a tumor recurrence and two patients have died of disease. Median PFS and OS have not yet been reached, but 2-year PFS and OS were 82.8% and 96.3%, respectively, and 3-year PFS and OS were 79.0% and 92.6%, respectively.Our series describes the initial experience with cytoreductive surgery and hormonal monotherapy for women with Stage II-IV primary ovarian LGSC. While surgery remains the mainstay of treatment, chemotherapy may not be necessary in patients with advanced-stage disease who receive adjuvant hormonal therapy. A cooperative group, Phase III trial is planned to define the optimal therapy for women with this ovarian carcinoma subtype.

Authors
Fader, AN; Bergstrom, J; Jernigan, A; Tanner, EJ; Roche, KL; Stone, RL; Levinson, KL; Ricci, S; Wethingon, S; Wang, T-L; Shih, I-M; Yang, B; Zhang, G; Armstrong, DK; Gaillard, S; Michener, C; DeBernardo, R; Rose, PG
MLA Citation
Fader, AN, Bergstrom, J, Jernigan, A, Tanner, EJ, Roche, KL, Stone, RL, Levinson, KL, Ricci, S, Wethingon, S, Wang, T-L, Shih, I-M, Yang, B, Zhang, G, Armstrong, DK, Gaillard, S, Michener, C, DeBernardo, R, and Rose, PG. "Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival?." Gynecologic oncology 147.1 (October 2017): 85-91.
PMID
28768570
Source
epmc
Published In
Gynecologic Oncology
Volume
147
Issue
1
Publish Date
2017
Start Page
85
End Page
91
DOI
10.1016/j.ygyno.2017.07.127

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study.

Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients.Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response.Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension.Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.

Authors
Chan, JK; Deng, W; Higgins, RV; Tewari, KS; Bonebrake, AJ; Hicks, M; Gaillard, S; Ramirez, PT; Chafe, W; Monk, BJ; Aghajanian, C
MLA Citation
Chan, JK, Deng, W, Higgins, RV, Tewari, KS, Bonebrake, AJ, Hicks, M, Gaillard, S, Ramirez, PT, Chafe, W, Monk, BJ, and Aghajanian, C. "A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study." Gynecologic oncology 146.3 (September 2017): 554-559.
PMID
28728751
Source
epmc
Published In
Gynecologic Oncology
Volume
146
Issue
3
Publish Date
2017
Start Page
554
End Page
559
DOI
10.1016/j.ygyno.2017.05.033

Impact of Chemotherapy and Radiotherapy on Management of Early Stage Clear Cell and Papillary Serous Carcinoma of the Uterus.

The aim of the study was to assess interaction of lymph node dissection (LND), adjuvant chemotherapy (CT), and radiotherapy (RT) in stage I uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCC).The National Cancer Data Base was queried for women diagnosed with International Federation of Gynecology and Obstetrics stage I UPSC and UCC from 1998 to 2012. Overall survival (OS) was estimated for combinations of RT and CT by the Kaplan-Meier method stratified by histology and LND. Multivariate Cox proportional hazard models were generated.Uterine papillary serous carcinoma: 5432 women with UPSC were identified. Uterine papillary serous carcinoma had the highest 5-year OS with CT + RT with (83%) or without LND (76%). On multivariate analyses, CT [hazard ratio (HR), 0.77; P = 0.01] and vaginal cuff brachytherapy (HR, 0.68; P = 0.003) with LND were independently associated with OS. Without LND, vaginal cuff brachytherapy (HR, 0.53; P = 0.03), but not CT (HR, 1.21; P = 0.92), was associated with OS. Uterine clear cell carcinoma: 2516 women with UCC were identified. Uterine clear cell carcinoma with and without LND had comparable 5-year OS for all combinations of CT and RT on univariate and multivariate analyses.In stage I papillary serous uterine cancer, brachytherapy and CT were associated with increased survival; however, the benefit of chemotherapy was limited to those with surgical staging. In contrast, no adjuvant therapy was associated with survival in stage I uterine clear cell carcinoma, and further investigation to identify more effective therapies is warranted.

Authors
Hong, JC; Foote, J; Broadwater, G; Gaillard, S; Havrilesky, LJ; Chino, JP
MLA Citation
Hong, JC, Foote, J, Broadwater, G, Gaillard, S, Havrilesky, LJ, and Chino, JP. "Impact of Chemotherapy and Radiotherapy on Management of Early Stage Clear Cell and Papillary Serous Carcinoma of the Uterus." International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 27.4 (May 2017): 720-729.
PMID
28375927
Source
epmc
Published In
International Journal of Gynecological Cancer
Volume
27
Issue
4
Publish Date
2017
Start Page
720
End Page
729
DOI
10.1097/igc.0000000000000926

The role of immune checkpoint inhibition in the treatment of ovarian cancer.

The introduction of immune checkpoint inhibitors has revolutionized treatment of multiple cancers and has bolstered interest in this treatment approach. So far, emerging clinical data show limited clinical efficacy of these agents in ovarian cancer with objective response rates of 10-15% with some durable responses. In this review, we present emerging clinical data of completed trials of immune checkpoint inhibitors and review ongoing studies. In addition we examine the current knowledge of the tumor microenvironment of ovarian cancers with a focus on the significance of PD-L1 expression and tumor-infiltrating lymphocytes on predicting response to immune checkpoint blockade. We evaluate approaches to improve treatment outcomes through the use of predictive biomarkers and patient selection. Finally, we review management considerations including immune related adverse events and response criteria.

Authors
Gaillard, SL; Secord, AA; Monk, B
MLA Citation
Gaillard, SL, Secord, AA, and Monk, B. "The role of immune checkpoint inhibition in the treatment of ovarian cancer." Gynecologic oncology research and practice 3 (January 2016): 11-. (Review)
PMID
27904752
Source
epmc
Published In
Gynecologic Oncology Research and Practice
Volume
3
Publish Date
2016
Start Page
11

Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.

Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.

Authors
Yu, Y; Gaillard, S; Phillip, JM; Huang, T-C; Pinto, SM; Tessarollo, NG; Zhang, Z; Pandey, A; Wirtz, D; Ayhan, A; Davidson, B; Wang, T-L; Shih, I-M
MLA Citation
Yu, Y, Gaillard, S, Phillip, JM, Huang, T-C, Pinto, SM, Tessarollo, NG, Zhang, Z, Pandey, A, Wirtz, D, Ayhan, A, Davidson, B, Wang, T-L, and Shih, I-M. "Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules." Cancer cell 28.1 (July 2015): 82-96.
PMID
26096845
Source
epmc
Published In
Cancer Cell
Volume
28
Issue
1
Publish Date
2015
Start Page
82
End Page
96
DOI
10.1016/j.ccell.2015.05.009

Patient preferences in advanced or recurrent ovarian cancer.

The objective of this study was to elucidate relative preferences of women with ovarian cancer for symptoms, treatment-related side effects, and progression-free survival (PFS) relevant to choosing a treatment regimen.Women with advanced or recurrent ovarian cancer participated in a survey that included 3 methods to measure patient preferences (ratings, rankings, and a discrete-choice experiment) for 7 attributes: mode of administration, visit frequency, peripheral neuropathy, nausea and vomiting, fatigue, abdominal discomfort, and PFS. Participants were asked to choose between 2 unlabeled treatment scenarios that were characterized using the 7 attributes. Each participant completed 12 choice questions in which attribute levels were assigned according to an experimental design and a fixed-choice question representing 2 chemotherapy regimens for ovarian cancer.In total, 95 women completed the survey. Participants' ratings and rankings revealed greater concern and importance for PFS than for any other attribute (P < .0001 for all). The discrete-choice experiment revealed that the relative odds that a participant would choose a scenario with 18 months, 21 months, and 24 months of PFS versus 15 months of PFS were 1.5 (P = .01), 3.4 (P < .001), and 7.5 (P < .001), respectively. However, participants' choices indicated that they were willing to accept a shorter PFS to avoid severe side effects: 6.7 months to reduce nausea and vomiting from severe to mild, 5.0 months to reduce neuropathy from severe to mild, and 3.7 months to reduce abdominal symptoms from severe to moderate.PFS is the predominant driver of patient preferences for chemotherapy regimens. However, women in the current study were willing to trade significant PFS time for reductions in treatment-related toxicity.

Authors
Havrilesky, LJ; Alvarez Secord, A; Ehrisman, JA; Berchuck, A; Valea, FA; Lee, PS; Gaillard, SL; Samsa, GP; Cella, D; Weinfurt, KP; Abernethy, AP; Reed, SD
MLA Citation
Havrilesky, LJ, Alvarez Secord, A, Ehrisman, JA, Berchuck, A, Valea, FA, Lee, PS, Gaillard, SL, Samsa, GP, Cella, D, Weinfurt, KP, Abernethy, AP, and Reed, SD. "Patient preferences in advanced or recurrent ovarian cancer." Cancer 120.23 (December 2014): 3651-3659.
PMID
25091693
Source
epmc
Published In
Cancer
Volume
120
Issue
23
Publish Date
2014
Start Page
3651
End Page
3659
DOI
10.1002/cncr.28940

Biology and genetics

Authors
Gaillard, S; Maxwell, GL; Sood, AK; Berchuck, A
MLA Citation
Gaillard, S, Maxwell, GL, Sood, AK, and Berchuck, A. "Biology and genetics." Berek and Hacker's Gynecologic Oncology: Sixth Edition. November 11, 2014. 2-38.
Source
scopus
Publish Date
2014
Start Page
2
End Page
38

A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: This open-label, multi-institutional phase II trial evaluated activity and safety of rilotumumab (AMG 102), a monoclonal antibody that targets HGF (hepatocyte growth factor), the ligand for the MET receptor, in women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer. PATIENTS AND METHODS: Women were eligible for treatment with rilotumumab if they had measurable disease, a performance status of 0, 1 or 2, previously received platinum-based therapy with a progression-free interval of <12 months or a second recurrence, and adequate bone marrow and organ function. Patients received rilotumumab 20mg/kg IV every 14 days until evidence of unacceptable toxicity or disease progression. The study utilized co-dual primary endpoints of tumor response and six-month PFS to assess the efficacy of rilotumumab. Secondary endpoints included the frequency and severity of adverse events and the duration of progression-free and overall survival. RESULTS: Thirty-one women enrolled and received rilotumumab. All were eligible for analysis. One patient achieved a complete response (3.2%; 90% CI 0.2-14%), and two women had 6-month PFS (6.5%; 90% CI 1.1-19%). Most adverse events were grade 1 or 2, with no grade 4 adverse events. Grade 3 adverse events were gastrointestinal (4), metabolic (3) anemia (3), a thromboembolic event (1), ventricular tachycardia (1), hypotension during infusion (1) and fatigue (1). The study was stopped after the first stage of accrual. CONCLUSION: Rilotumumab was well-tolerated, but had limited activity. The level of activity does not warrant further evaluation of rilotumumab as a single agent in patients with ovarian cancer.

Authors
Martin, LP; Sill, M; Shahin, MS; Powell, M; DiSilvestro, P; Landrum, LM; Gaillard, SL; Goodheart, MJ; Hoffman, J; Schilder, RJ
MLA Citation
Martin, LP, Sill, M, Shahin, MS, Powell, M, DiSilvestro, P, Landrum, LM, Gaillard, SL, Goodheart, MJ, Hoffman, J, and Schilder, RJ. "A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study." Gynecol Oncol 132.3 (March 2014): 526-530.
PMID
24361733
Source
pubmed
Published In
Gynecologic Oncology
Volume
132
Issue
3
Publish Date
2014
Start Page
526
End Page
530
DOI
10.1016/j.ygyno.2013.12.018

A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study

Objective This open-label, multi-institutional phase II trial evaluated activity and safety of rilotumumab (AMG 102), a monoclonal antibody that targets HGF (hepatocyte growth factor), the ligand for the MET receptor, in women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer. Patients and methods Women were eligible for treatment with rilotumumab if they had measurable disease, a performance status of 0, 1 or 2, previously received platinum-based therapy with a progression-free interval of < 12 months or a second recurrence, and adequate bone marrow and organ function. Patients received rilotumumab 20 mg/kg IV every 14 days until evidence of unacceptable toxicity or disease progression. The study utilized co-dual primary endpoints of tumor response and six-month PFS to assess the efficacy of rilotumumab. Secondary endpoints included the frequency and severity of adverse events and the duration of progression-free and overall survival. Results Thirty-one women enrolled and received rilotumumab. All were eligible for analysis. One patient achieved a complete response (3.2%; 90% CI 0.2-14%), and two women had 6-month PFS (6.5%; 90% CI 1.1-19%). Most adverse events were grade 1 or 2, with no grade 4 adverse events. Grade 3 adverse events were gastrointestinal (4), metabolic (3) anemia (3), a thromboembolic event (1), ventricular tachycardia (1), hypotension during infusion (1) and fatigue (1). The study was stopped after the first stage of accrual. Conclusion Rilotumumab was well-tolerated, but had limited activity. The level of activity does not warrant further evaluation of rilotumumab as a single agent in patients with ovarian cancer.

Authors
Martin, LP; Sill, M; Shahin, MS; Powell, M; Disilvestro, P; Landrum, LM; Gaillard, SL; Goodheart, MJ; Hoffman, J; Schilder, RJ
MLA Citation
Martin, LP, Sill, M, Shahin, MS, Powell, M, Disilvestro, P, Landrum, LM, Gaillard, SL, Goodheart, MJ, Hoffman, J, and Schilder, RJ. "A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study." Gynecologic Oncology 132.3 (January 1, 2014): 526-530.
Source
scopus
Published In
Gynecologic Oncology
Volume
132
Issue
3
Publish Date
2014
Start Page
526
End Page
530
DOI
10.1016/j.ygyno.2013.12.018

Patient preferences in advanced or recurrent ovarian cancer

© 2014 American Cancer Society. BACKGROUND: The objective of this study was to elucidate relative preferences of women with ovarian cancer for symptoms, treatment-related side effects, and progression-free survival (PFS) relevant to choosing a treatment regimen. METHODS: Women with advanced or recurrent ovarian cancer participated in a survey that included 3 methods to measure patient preferences (ratings, rankings, and a discrete-choice experiment) for 7 attributes: mode of administration, visit frequency, peripheral neuropathy, nausea and vomiting, fatigue, abdominal discomfort, and PFS. Participants were asked to choose between 2 unlabeled treatment scenarios that were characterized using the 7 attributes. Each participant completed 12 choice questions in which attribute levels were assigned according to an experimental design and a fixed-choice question representing 2 chemotherapy regimens for ovarian cancer. RESULTS: In total, 95 women completed the survey. Participants' ratings and rankings revealed greater concern and importance for PFS than for any other attribute (P < .0001 for all). The discrete-choice experiment revealed that the relative odds that a participant would choose a scenario with 18 months, 21 months, a nd 24 months of PFS versus 15 months of PFS were 1.5 (P5.01), 3.4 (P < .001), and 7.5 (P < .001), respectively. However, participants' choices indicated that they were willing to accept a shorter PFS to avoid severe side effects: 6.7 months to reduce nausea and vomiting from severe to mild, 5.0 months to reduce neuropathy from severe to mild, and 3.7 months to reduce abdominal symptoms from severe to moderate. CONCLUSIONS: PFS is the predominant driver of patient preferences for chemotherapy regimens. However, women in the current study were willing to trade significant PFS time for reductions in treatment-related toxicity.

Authors
Havrilesky, LJ; Secord, AA; Ehrisman, JA; Berchuck, A; Valea, FA; Lee, PS; Gaillard, SL; Samsa, GP; Cella, D; Weinfurt, KP; Abernethy, AP; Reed, SD
MLA Citation
Havrilesky, LJ, Secord, AA, Ehrisman, JA, Berchuck, A, Valea, FA, Lee, PS, Gaillard, SL, Samsa, GP, Cella, D, Weinfurt, KP, Abernethy, AP, and Reed, SD. "Patient preferences in advanced or recurrent ovarian cancer." Cancer 120.23 (January 1, 2014): 3651-3659.
Source
scopus
Published In
Cancer
Volume
120
Issue
23
Publish Date
2014
Start Page
3651
End Page
3659
DOI
10.1002/cncr.28940

Sustained elite suppression of replication competent HIV-1 in a patient treated with rituximab based chemotherapy

The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication-competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients. © 2011 Elsevier B.V.

Authors
Gaillard, S; Dinoso, JB; Marsh, JA; DeZern, AE; O'Connell, KA; Spivak, AM; Alwood, K; Durand, CM; Ambinder, RF; Blankson, JN
MLA Citation
Gaillard, S, Dinoso, JB, Marsh, JA, DeZern, AE, O'Connell, KA, Spivak, AM, Alwood, K, Durand, CM, Ambinder, RF, and Blankson, JN. "Sustained elite suppression of replication competent HIV-1 in a patient treated with rituximab based chemotherapy." Journal of Clinical Virology 51.3 (2011): 195-198.
PMID
21550842
Source
scival
Published In
Journal of Clinical Virology
Volume
51
Issue
3
Publish Date
2011
Start Page
195
End Page
198
DOI
10.1016/j.jcv.2011.04.002

Intraperitoneal chemotherapy for advanced epithelial ovarian cancer: Many questions, much promise&

Authors
Gaillard, S; Armstrong, D
MLA Citation
Gaillard, S, and Armstrong, D. "Intraperitoneal chemotherapy for advanced epithelial ovarian cancer: Many questions, much promise&." Oncology 25.2 (2011).
Source
scival
Published In
Oncology
Volume
25
Issue
2
Publish Date
2011

Aromatase inhibitor-associated bone and musculoskeletal effects: New evidence defining etiology and strategies for management

Aromatase inhibitors are widely used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. While the agents are associated with slightly improved survival outcomes when compared to tamoxifen alone, bone and musculoskeletal side effects are substantial and often lead to discontinuation of therapy. Ideally, the symptoms should be prevented or adequately treated. This review will focus on bone and musculoskeletal side effects of aromatase inhibitors, including osteoporosis, fractures, and arthralgias. Recent advances have been made in identifying potential mechanisms underlying these effects. Adequate management of symptoms may enhance patient adherence to therapy, thereby improving breast cancer-related outcomes. © 2011 BioMed Central Ltd.

Authors
Gaillard, S; Stearns, V
MLA Citation
Gaillard, S, and Stearns, V. "Aromatase inhibitor-associated bone and musculoskeletal effects: New evidence defining etiology and strategies for management." Breast Cancer Research 13.2 (2011).
PMID
21457526
Source
scival
Published In
Breast Cancer Research
Volume
13
Issue
2
Publish Date
2011
DOI
10.1186/bcr2818

Fasting-induced hepatic production of DHEA is regulated by PGC-1alpha, ERRalpha, and HNF4alpha.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic state, environmental cues, and nutrient availability. In exploring the specific pathways under PGC-1alpha regulation in the liver, we have made the surprising observation that this coactivator can induce the expression of CYP11A1 and CYP17A1, key rate-limiting enzymes involved in the initial steps of steroidogenesis. Both of these enzymes function to produce C(19)-steroids, converting cholesterol into pregnenolone, and then to dehydroepiandrosterone (DHEA). Estrogen-related receptor (ERR)-alpha mediates PGC-1alpha's induction of CYP11A1 and binds within the first intron of the CYP11A1 gene. Both ERR-alpha and hepatocyte nuclear factor-4alpha are required for PGC-1alpha-mediated induction of CYP17A1, and specific binding sites for these receptors have been identified in the regulatory regions of this gene. The potential physiological significance of these observations was highlighted in rats where fasting induced hepatic expression of PGC-1alpha and CYP17A1 and was associated with an increase in hepatic levels of DHEA. These data suggest that DHEA could be playing a role as an intracellular signaling molecule involved in modulating hepatic activity in response to fasting conditions.

Authors
Grasfeder, LL; Gaillard, S; Hammes, SR; Ilkayeva, O; Newgard, CB; Hochberg, RB; Dwyer, MA; Chang, C-Y; McDonnell, DP
MLA Citation
Grasfeder, LL, Gaillard, S, Hammes, SR, Ilkayeva, O, Newgard, CB, Hochberg, RB, Dwyer, MA, Chang, C-Y, and McDonnell, DP. "Fasting-induced hepatic production of DHEA is regulated by PGC-1alpha, ERRalpha, and HNF4alpha." Mol Endocrinol 23.8 (August 2009): 1171-1182.
PMID
19389810
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
23
Issue
8
Publish Date
2009
Start Page
1171
End Page
1182
DOI
10.1210/me.2009-0024

Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells.

Estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor family of transcription factors. In addition to its function as a metabolic regulator, ERRalpha has been implicated in the growth and progression of several malignancies. In the setting of breast cancer, not only is ERRalpha a putative negative prognostic factor, but we have recently found that knock-down of its expression retards tumor growth in a xenograft model of this disease. The specific aspects of ERRalpha function that are responsible for its actions in breast cancer, however, remain unclear. Using the coactivator PGC-1alpha as a protein ligand to regulate ERRalpha activity, we analyzed the effects of this receptor on gene expression in the ERalpha-positive MCF-7 cell line. This analysis led to the identification of a large number of potential ERRalpha target genes, many of which were subsequently validated in other breast cancer cell lines. Importantly, we demonstrate in this study that activation of ERRalpha in several different breast cancer cell lines leads to a significant increase in VEGF mRNA expression, an activity that translates into an increase in VEGF protein secretion. The induction of VEGF results from the interaction of ERRalpha with specific ERR-responsive elements within the VEGF promoter. These findings suggest that ERRalpha-dependent induction of VEGF may contribute to the overall negative phenotype observed in tumors in which ERRalpha is expressed and provide validation for its use as a therapeutic target in cancer.

Authors
Stein, RA; Gaillard, S; McDonnell, DP
MLA Citation
Stein, RA, Gaillard, S, and McDonnell, DP. "Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells." J Steroid Biochem Mol Biol 114.1-2 (March 2009): 106-112.
PMID
19429439
Source
pubmed
Published In
The Journal of Steroid Biochemistry and Molecular Biology
Volume
114
Issue
1-2
Publish Date
2009
Start Page
106
End Page
112
DOI
10.1016/j.jsbmb.2009.02.010

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor

Authors
Gaillard, S; Wondisford, FE
MLA Citation
Gaillard, S, and Wondisford, FE. "Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor." Clinical Management of Thyroid Disease (2009): 81-101.
Source
scival
Published In
Clinical Management of Thyroid Disease
Publish Date
2009
Start Page
81
End Page
101
DOI
10.1016/B978-1-4160-4745-2.00007-9

Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions.

Estrogen receptor-related receptor-alpha (ERRalpha) is an orphan nuclear receptor that does not appear to require a classical small molecule ligand to facilitate its interaction with coactivators and/or hormone response elements within target genes. Instead, the apo-receptor is capable of interacting in a constitutive manner with coactivators that stimulate transcription by acting as protein ligands. We have screened combinatorial phage libraries for peptides that selectively interact with ERRalpha to probe the architecture of the ERRalpha-coactivator pocket. In this manner, we have uncovered a fundamental difference in the mechanism by which this receptor interacts with peroxisome proliferator-activated receptor-gamma coactivator-1alpha, as compared with members of the steroid receptor coactivator subfamily of coactivators. Our findings suggest that it may be possible to develop ERRalpha ligands that exhibit different pharmacological activities as a consequence of their ability to differentially regulate coactivator recruitment. In addition, these findings have implications beyond ERRalpha because they suggest that subtle alterations in the structure of the activation function-2 pocket within any nuclear receptor may enable differential recruitment of coactivators, an observation of notable pharmaceutical importance.

Authors
Gaillard, S; Dwyer, MA; McDonnell, DP
MLA Citation
Gaillard, S, Dwyer, MA, and McDonnell, DP. "Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions." Mol Endocrinol 21.1 (January 2007): 62-76.
PMID
17053040
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
21
Issue
1
Publish Date
2007
Start Page
62
End Page
76
DOI
10.1210/me.2006-0179

Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.

In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor superfamily are not regulated by classical small molecules but rather their activity is controlled by interacting cofactors. Motivated by this finding, we have developed an approach to genetically isolate specific receptor-cofactor pairs in cells, allowing us to define the biological responses attributable to each complex. This is accomplished by using combinatorial peptide phage display to engineer the receptor interacting domain of each cofactor such that it interacts selectively with one nuclear receptor. In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells.

Authors
Gaillard, S; Grasfeder, LL; Haeffele, CL; Lobenhofer, EK; Chu, T-M; Wolfinger, R; Kazmin, D; Koves, TR; Muoio, DM; Chang, C-Y; McDonnell, DP
MLA Citation
Gaillard, S, Grasfeder, LL, Haeffele, CL, Lobenhofer, EK, Chu, T-M, Wolfinger, R, Kazmin, D, Koves, TR, Muoio, DM, Chang, C-Y, and McDonnell, DP. "Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs." Mol Cell 24.5 (December 8, 2006): 797-803.
PMID
17157261
Source
pubmed
Published In
Molecular Cell
Volume
24
Issue
5
Publish Date
2006
Start Page
797
End Page
803
DOI
10.1016/j.molcel.2006.10.012

Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogen-related receptors (ERRα and ERRγ). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor γ coactivator (PGC-1α) stimulates the expression of PDK4. Here we report that ERRα and ERRγ stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1α to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERRα and ERRγ. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1α. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1α from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression.

Authors
Zhang, Y; Ma, K; Sadana, P; Chowdhury, F; Gaillard, S; Wang, F; McDonnell, DP; Unterman, TG; Elam, MB; Park, EA
MLA Citation
Zhang, Y, Ma, K, Sadana, P, Chowdhury, F, Gaillard, S, Wang, F, McDonnell, DP, Unterman, TG, Elam, MB, and Park, EA. "Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression." Journal of Biological Chemistry 281.52 (2006): 39897-39906.
PMID
17079227
Source
scival
Published In
The Journal of biological chemistry
Volume
281
Issue
52
Publish Date
2006
Start Page
39897
End Page
39906
DOI
10.1074/jbc.M608657200

Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor γ and the classical estrogen receptor α demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRγ LBD confirms the molecular basis of the selectivity. © 2005 Elsevier Ltd. All rights reserved.

Authors
Chao, EYH; Collins, JL; Gaillard, S; Miller, AB; Wang, L; Orband-Miller, LA; Nolte, RT; McDonnell, DP; Willson, TM; Zuercher, WJ
MLA Citation
Chao, EYH, Collins, JL, Gaillard, S, Miller, AB, Wang, L, Orband-Miller, LA, Nolte, RT, McDonnell, DP, Willson, TM, and Zuercher, WJ. "Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ." Bioorganic and Medicinal Chemistry Letters 16.4 (2006): 821-824.
PMID
16307879
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
16
Issue
4
Publish Date
2006
Start Page
821
End Page
824
DOI
10.1016/j.bmcl.2005.11.030

Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy.

Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1alpha recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor alpha (RXRalpha), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1alpha-induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1-dependent, PGC-1alpha-stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression.

Authors
Safi, R; Kovacic, A; Gaillard, S; Murata, Y; Simpson, ER; McDonnell, DP; Clyne, CD
MLA Citation
Safi, R, Kovacic, A, Gaillard, S, Murata, Y, Simpson, ER, McDonnell, DP, and Clyne, CD. "Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy." Cancer Res 65.24 (December 15, 2005): 11762-11770.
PMID
16357189
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
24
Publish Date
2005
Start Page
11762
End Page
11770
DOI
10.1158/0008-5472.CAN-05-2792

HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.

The molecular chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a critical modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.

Authors
Kovacs, JJ; Murphy, PJM; Gaillard, S; Zhao, X; Wu, J-T; Nicchitta, CV; Yoshida, M; Toft, DO; Pratt, WB; Yao, T-P
MLA Citation
Kovacs, JJ, Murphy, PJM, Gaillard, S, Zhao, X, Wu, J-T, Nicchitta, CV, Yoshida, M, Toft, DO, Pratt, WB, and Yao, T-P. "HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor." Mol Cell 18.5 (May 27, 2005): 601-607.
PMID
15916966
Source
pubmed
Published In
Molecular Cell
Volume
18
Issue
5
Publish Date
2005
Start Page
601
End Page
607
DOI
10.1016/j.molcel.2005.04.021

Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRβ and ERRγ

The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRγ with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1α in activation of human ERRβ and ERRγ. © 2005 American Chemical Society.

Authors
Zuercher, WJ; Gaillard, S; Orband-Miller, LA; Chao, EYH; Shearer, BG; Jones, DG; Miller, AB; Collins, JL; McDonnell, DP; Willson, TM
MLA Citation
Zuercher, WJ, Gaillard, S, Orband-Miller, LA, Chao, EYH, Shearer, BG, Jones, DG, Miller, AB, Collins, JL, McDonnell, DP, and Willson, TM. "Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRβ and ERRγ." Journal of Medicinal Chemistry 48.9 (2005): 3107-3109.
PMID
15857113
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
48
Issue
9
Publish Date
2005
Start Page
3107
End Page
3109
DOI
10.1021/jm050161j
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