27 results on '"Courtney L. Andersen"'
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2. Data from Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens
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Steffi Oesterreich, Robert P. Edwards, Esther Elishaev, Adrian V. Lee, Karen McLean, Kunle Odunsi, Gina M. Mantia-Smaldone, Paul Haluska, Uma Chandran, Soumya Luthra, Yongseok Park, George Tseng, Alec Christie, Tianzhou Ma, Michelle M. Boisen, Matthew J. Sikora, and Courtney L. Andersen more...
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Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC.Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERα target genes. Expression of this panel and ERα H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response.Results: Proliferation is ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3.Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802–12. ©2017 AACR. more...
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- 2023
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3. Supplementary File 3 from Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens
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Steffi Oesterreich, Robert P. Edwards, Esther Elishaev, Adrian V. Lee, Karen McLean, Kunle Odunsi, Gina M. Mantia-Smaldone, Paul Haluska, Uma Chandran, Soumya Luthra, Yongseok Park, George Tseng, Alec Christie, Tianzhou Ma, Michelle M. Boisen, Matthew J. Sikora, and Courtney L. Andersen more...
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Supplementary File 3 contains the available pre- and post-treatment CA-125 data for our patient cohort.
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- 2023
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4. Supplementary File 1 from Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens
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Steffi Oesterreich, Robert P. Edwards, Esther Elishaev, Adrian V. Lee, Karen McLean, Kunle Odunsi, Gina M. Mantia-Smaldone, Paul Haluska, Uma Chandran, Soumya Luthra, Yongseok Park, George Tseng, Alec Christie, Tianzhou Ma, Michelle M. Boisen, Matthew J. Sikora, and Courtney L. Andersen more...
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Supplementary File 1 contains the genes included in the "EndoRx" NanoString code set.
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- 2023
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5. Supplementary Figures from Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens
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Steffi Oesterreich, Robert P. Edwards, Esther Elishaev, Adrian V. Lee, Karen McLean, Kunle Odunsi, Gina M. Mantia-Smaldone, Paul Haluska, Uma Chandran, Soumya Luthra, Yongseok Park, George Tseng, Alec Christie, Tianzhou Ma, Michelle M. Boisen, Matthew J. Sikora, and Courtney L. Andersen more...
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This document contains the supplementary figures for the manuscript.
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- 2023
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6. Abstract 6150: AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models
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Courtney L. Andersen, Giulia Fabbri, David Jenkins, Zumla Cader, Shringi Sharma, Areya Tabatabai, Srividya Balachander, Jordan Roebuck, Melanie Galvin, Kathryn Simpson, Caroline Dive, Jordi Rodon Ahnert, and Jamal Saeh more...
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Cancer Research ,Oncology - Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy with critical need for new therapies. While currently treated as a single disease, SCLC is heterogenous, comprised of several transcriptional subtypes. Each of these subtypes has distinct drivers and may warrant unique therapeutic targets. Two potential therapeutic targets for SCLC are the pro-survival proteins BCL-2 and BCL-XL. BCL-2 is overexpressed in ASCL1 (A) and POUF3 (P) subtypes of SCLC. We therefore sought to evaluate efficacy of the dual BCL-2/XL inhibitor AZD0466 in SCLC models and to determine whether transcriptional subtype would predict response. AZD0466 is a novel drug-dendrimer conjugate. The active moiety, AZD4320, is a potent dual inhibitor of BCL-2 and BCL-XL. AZD4320 is covalently conjugated to a 5th-generation PEGylated poly-lysine dendrimer through a hydrolytically labile linker to make AZD0466. AZD0466 has been optimized to deliver efficacy while mitigating potential Cmax-driven on-target toxicities of AZD4320. AZD4320 was active (IC50 ≤0.1 µM) in 9/27 SCLC cell lines. AZD4320 in vitro sensitivity was enriched in cell lines that represented A and P subtypes of SCLC compared to NEUROD1 and YAP1 subtypes. We next profiled AZD0466 in a panel of SCLC patient-derived models: 14 patient-derived xenografts and 10 circulating tumor cell-derived xenografts. AZD0466 monotherapy dosed weekly IV was active in 12/24 SCLC xenografts, driving regressions in 8 models. AZD0466 drove efficacy and cleaved caspase-3 induction in a dose-dependent manner. Similar to in vitro, AZD0466 in vivo efficacy was enriched in subtype-A, driving responses in 10/14 ASCL1 models (7 regression, 3 stable disease). AZD0466 response also correlated strongly with BCL-2 mRNA expression (P Citation Format: Courtney L. Andersen, Giulia Fabbri, David Jenkins, Zumla Cader, Shringi Sharma, Areya Tabatabai, Srividya Balachander, Jordan Roebuck, Melanie Galvin, Kathryn Simpson, Caroline Dive, Jordi Rodon Ahnert, Jamal Saeh. AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6150. more...
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- 2023
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7. Abstract 4024: Combining selumetinib with BH3 mimetics enhances activity in MAPK-activated acute myeloid leukemia
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Courtney L. Andersen, Azadeh Cheraghchi-Bashi, Patricia Jaaks, Elizabeth A. Coker, Kathleen Burke, Justin Cidado, Paul Smith, Corinne Reimer, Raoul Tibes, Mathew Garnett, and Jerome Mettetal
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Cancer Research ,Oncology - Abstract
Mitogen-activated protein kinase (MAPK) pathway alterations comprise some of the most frequent mutations in newly diagnosed acute myeloid leukemia (AML). Moreover, MAPK pathway alterations are also emerging as potential mechanisms of resistance to targeted therapy in AML including FLT3 inhibitors and venetoclax. In an ex vivo pharmacologic analysis of primary AML samples, sensitivity to the MEK inhibitor selumetinib (ARRY-142886) was enriched in patient samples resistant to venetoclax. Clinical activity of MAPK pathway inhibitors such as selumetinib has been explored in AML but monotherapy responses were modest. Another MEK inhibitor, cobimetinib, is currently being tested in combination with venetoclax in AML. We sought to understand whether combining selumetinib with BH3 mimetics such as venetoclax would improve efficacy in AML models. We evaluated combination activity of selumetinib plus venetoclax or the MCL1 inhibitor AZD5991 in a panel of AML cell lines. Cells were exposed to a 6x6 matrix of both agents for 72hrs and then viability assessed using CellTiter-Glo. Combination benefit was assessed using highest single agent (HSA) analysis. Selumetinib+AZD5991 demonstrated strong combination benefit (HSA score >0.1, Emax >0.5) in 4/19 AML cell lines. Selumetinib+venetoclax showed strong combination activity in 6/19 lines. Three lines showed benefit with both combinations. Many of these cell lines harbor MAPK pathway mutations including OCI-AML5 (SOS1N233Y, NF1K1385R), ML-2 (KRASA146T), HL-60 (NRASQ61L), and Nomo-1 (KRASG13D). Selumetinib treatment also led to robust BIM induction in vitro. Nomo-1 xenografts were evaluated for in vivo sensitivity to venetoclax (100 mg/kg qd PO), 5-azacytidine (1mg/kg BID q8h 3days on/4days off IP), AZD5991 (30mpk bid q2h qw IV), selumetinib (10 mg/kg bid q8h PO), as well as combinations of venetoclax+5-aza, AZD5991+selumetinib, and venetoclax+selumetinib. Venetoclax and venetoclax+5-aza treatment were ineffective. Selumetinib monotherapy led to 63% tumor growth inhibition (TGI) but tumors eventually grew out through treatment. The combination of selumetinib+venetoclax slightly improved efficacy (81% TGI) but markedly delayed tumor outgrowth (selumetinib monotherapy arm reached mean tumor volume >1000 mm3 on day 17, selumetinib+venetoclax reached average of ~966 mm3 on day 28). Reducing venetoclax dose (30mg/kg qd) or frequency (100mg/kg 3days on/4days off) maintained most of the combination efficacy. Selumetinb+AZD5991 also strongly improved efficacy compared to either monotherapy (88% TGI, mean tumor volume did not exceed ~400mm3 by day 28). Together these data suggest potential for combining MEK inhibitors with BH3 mimetics in AML. Work is ongoing to further understand how scheduling impacts combination efficacy, evaluate the triple combination of selumetinib+BH3 mimetic+azacytidine, and assess efficacy in disseminated models. Citation Format: Courtney L. Andersen, Azadeh Cheraghchi-Bashi, Patricia Jaaks, Elizabeth A. Coker, Kathleen Burke, Justin Cidado, Paul Smith, Corinne Reimer, Raoul Tibes, Mathew Garnett, Jerome Mettetal. Combining selumetinib with BH3 mimetics enhances activity in MAPK-activated acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4024. more...
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- 2022
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8. The Evolution of Estrogen Receptor Signaling in the Progression of Endometriosis to Endometriosis-Associated Ovarian Cancer
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Uma R. Chandran, Anda M. Vlad, Steffi Oesterreich, Robert P. Edwards, Courtney L. Andersen, George C. Tseng, Tianzhou Ma, Michelle M. Boisen, Esther Elishaev, and Matthew J. Sikora
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Adult ,0301 basic medicine ,Cancer Research ,Endocrinology, Diabetes and Metabolism ,Endometriosis ,Estrogen receptor ,Carcinoma, Ovarian Epithelial ,Biology ,Malignant transformation ,Transcriptome ,03 medical and health sciences ,Endocrinology ,Gene expression ,medicine ,Humans ,Aged ,Ovarian Neoplasms ,business.industry ,Endocrine and Autonomic Systems ,Estrogen Receptor alpha ,Obstetrics and Gynecology ,Cancer ,Middle Aged ,medicine.disease ,030104 developmental biology ,Oncology ,Disease Progression ,Cancer research ,Female ,business ,Ovarian cancer ,Estrogen receptor alpha ,Signal Transduction - Abstract
To investigate changes in estrogen receptor alpha (ERα) signaling during progression of endometriosis to endometriosis-associated ovarian cancer (EAOC) as a driver of malignant transformation. We procured tissue samples of normal endometrium, endometriosis (benign, atypical, concurrent with EAOC), and EAOC. We evaluated expression of a 236-gene signature of estrogen signaling. ANOVA and unsupervised clustering were used to identify gene expression profiles across disease states. These profiles were compared to profiles of estrogen regulation in cancer models from the Gene Expression Omnibus (GEO). Gene Set Enrichment Analysis (GSEA) was performed to determine whether gene expression in EAOC was consistent with ERα activity. ANOVA revealed 158 differentially expressed genes (q more...
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- 2018
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9. Combination Therapy of Bcl-2/X L dual Inhibitor AZD0466 with Acalabrutinib to Overcome Therapeutic Resistance in Aggressive R/R Mantle Cell Lymphoma
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Angela Leeming, Courtney L. Andersen, Vivian Changying Jiang, Justin Cidado, Yijing Li, Yang Liu, Michael Wang, Yuxuan Che, Jingling Jin, Alexa A Jordan, and Joseph McIntosh
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Combination therapy ,business.industry ,Immunology ,Dual inhibitor ,Cell Biology ,Hematology ,Therapeutic resistance ,medicine.disease ,Biochemistry ,Cancer research ,Medicine ,Acalabrutinib ,Mantle cell lymphoma ,business - Abstract
Introduction As a rare form of non-Hodgkin's lymphoma, mantle cell lymphoma (MCL) is an aggressive subtype. This is largely due to frequent relapses after therapies including paradigm shifting therapies BTK inhibitors (BTKi), such as ibrutinib and acalabrutinib, and Bcl-2 inhibitor (Bcl-2i) venetoclax after long-term treatment in the clinic. Dysregulation of Bcl-2 and Bcl-X L, contributes to therapeutic resistance in MCL. AZD0466 is a novel and highly potent Bcl-2/X L dual inhibitor with active moiety AZD4320. Our preliminary data showed AZD4320 is potent in inhibiting cell viability of MCL cells (IC 50 = 1.6-78 nM). In this study, we assessed the combination efficacy of AZD4320/AZD0466 and acalabrutinib on preclinical MCL models. Methods Cell viability assay was performed to assess the in vitro efficacy of AZD4320 and acalabrutinib alone or in combination in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines. Cell apoptosis assay was also performed to determine if AZD4320 and acalabrutinib enhanced cell death by cell apoptosis in MCL cell lines. Protein expression profiles of a panel of pro- and anti-apoptotic proteins and other relevant proteins were detected by immunoblotting. Since AZD4320 is limited in preclinical model due to physicochemical properties and dose limiting cardiovascular toxicity, AZD0466, the drug-dendrimer conjugate of AZD4320, was used for in vivo experiment. In vivo efficacy of AZD0466 (34 mg/kg, weekly, iv) and acalabrutinib (20 mg/kg, BID, oral) alone or in combination was evaluated using a Mino-venetoclax-R (Mino-R) cell xenograft model and a PDX model derived from an ibrutinib-CAR-T dual-resistant MCL patient. Results AZD4320 in combo with acalabrutinib inhibited cell proliferation synergistically in both ibrutinib/venetoclax-sensitive and -resistant cell lines (combination index = 0.17-0.93). Compared to vehicle or either single agent, the combination enhanced cell apoptosis by increasing pro-apoptotic markers cleaved caspase 3 and cleaved PARP. In the xenograft mouse model derived from venetoclax-resistant Mino-R cells, co-treatment of AZD0466 and acalabrutinib decreased tumor size significantly compared to vehicle (n = 5, p < 0.0001) or either single agent (n = 5, p = 0.0118 and 0.0070, respectively). Furthermore, in the PDX mouse model derived from a patient relapsed subsequently from ibrutinib and CAR T therapy, the combination of AZD0466 and acalabrutinib inhibited tumor growth compared to vehicle or either single agent. Acalabrutinib or AZD0466 improved survival compared with vehicle by 14 days or 32 days, respectively. Compared to Acalabrutinib or AZD0466, the combination therapy extended survival by 25 days and 7 days, respectively. All mice tolerated the treatment dose without any weight loss compared to the vehicle or either single agent group. Conclusion Compared to AZD4320/AZD0466 and acalabrutinib, combination therapy demonstrated anti-MCL synergy both in vitro and in vivo. These findings suggest that targeting Bcl-2/X L and BTK is promising to overcome multiple acquired resistance phenotypes, including CD19 CAR T-cell therapy. Disclosures Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Wang: DTRM Biopharma (Cayman) Limited: Consultancy; BeiGene: Consultancy, Honoraria, Research Funding; Physicians Education Resources (PER): Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Epizyme: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; BGICS: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Oncternal: Consultancy, Research Funding; OMI: Honoraria; Newbridge Pharmaceuticals: Honoraria; Scripps: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Chinese Medical Association: Honoraria; Pharmacyclics: Consultancy, Research Funding; Juno: Consultancy, Research Funding; CStone: Consultancy; Bayer Healthcare: Consultancy; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Moffit Cancer Center: Honoraria; Mumbai Hematology Group: Honoraria. more...
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- 2021
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10. NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies
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Marina Konopleva, Nitin Jain, Courtney L Andersen, Natalia Couto Francisco, Nairouz Elgeioushi, Rosalind Hobson, Martin Scott, John Stone, Shringi Sharma, Pablo Morentin Gutierrez, Raoul Tibes, Barry Davies, Thomas Winkler, Giulia Fabbri, Fathima Zumla Cader, and Nicole McNeer more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction: While BCL2 inhibition benefits many patients with acute myeloid leukemia (AML), resistance often occurs due to upregulation of other anti-apoptotic proteins such as MCL and BCLxL. Dual BCL2/xL inhibition with AZD4320 has potential for broader activity than BCL2-specific inhibition with venetoclax (Balachander et al, Clinical Cancer Research 2020). AZD0466 is a drug-dendrimer conjugate in which AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and where, following IV infusion, AZD4320 is gradually released by hydrolysis. The dendrimer construct allows for efficient delivery of the highly potent but poorly soluble active drug, and this release profile was designed to mitigate potential maximum concentration (Cmax)-dependent BCLxL mediated effects (Patterson et al, Nature Communications Biology 2021). AZD0466 has shown antitumor activity in a range of preclinical models of hematological malignancy, including cell-line derived and patient-derived xenograft models of acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and T-cell acute lymphoblastic leukemia (T-ALL - Kannan et al AACR 2020 Abstract 3075). AZD0466 has previously been administered to 9 patients with advanced solid malignancies at doses declared tolerable through 200 mg in the first-time-in-human study (NCT04214093), and a physiologically based PK model validated across nonclinical species was used to predict human doses and exposures expected to drive tumor regression in hematologic malignancy. These studies provide rationale for testing AZD0466 in refractory AML and ALL patients in this phase I/II dose escalation and monotherapy expansion and drug-drug interaction study (NCT04865419). Study Design and Methods: NIMBLE (drug deNdrIMer targeting BCL2/xL in acute LEukemias) is a modular, non-randomized phase I/II dose escalation and expansion study. Module 1 will evaluate safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD0466 as monotherapy in patients with relapsed/refractory AML or ALL. Patients are eligible if ≥ 18 years of age with any subtypes of relapsed/refractory AML or ALL without active CNS involvement and after at least one prior line of therapy. Treatment with hydroxyurea during screening and cycle 1 is permitted to control white blood cell count. Patients with extramedullary disease are also eligible. Primary endpoints are safety and tolerability of AZD0466 in patients with acute leukemia. In dose escalation, patients will be treated in each dose level according to an mTPI-2 design. Secondary endpoints are to determine pharmacokinetic parameters for total and released AZD4320. Exploratory endpoints include association of pharmacodynamic effects including changes to peripheral blasts and cleaved caspase activation, and initial evaluation of efficacy in relation to baseline leukemia characteristics. Planned dose expansion cohorts are AML patients with a prior history of MPN with ≤ 2 prior lines of therapy, AML patients with TP53 mutation treated with ≤ 3 prior lines of therapy, other AML treated with ≤ 3 prior lines (including venetoclax), and B- or T-ALL treated with ≤ 3 prior lines. Module 2 is a drug-drug interaction (DDI) study that will investigate the safety and establish the sensitivity of AZD0466 to voriconazole, a strong inhibitor of CYP3A4. There are no additional inclusion or exclusion criteria specific to Module 2. Further modules will be added via protocol amendment to investigate AZD0466 in combination with other antileukemia treatments, and may be triggered at the planned interim analyses during expansion. AZD0466 will be administered with a dose ramp-up in cycle 1 from a starting dose on day 1, with subsequent titration to an intermediate dose on day 4, and target dose on day 8, with weekly 1-hour IV administration thereafter at the target dose. The duration of cycle 1 is 35 days, and subsequent cycles are 28 days in which AZD0466 will be administered once weekly. Patients will continue until treatment failure, unacceptable toxicity, or withdrawal of consent. This study is actively enrolling patients at sites in the USA, and will be opening at multiple sites in Australia, Europe and South Korea. An update of preliminary safety and pharmacokinetics will be presented. Figure 1 Figure 1. Disclosures Konopleva: AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jain: Fate Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria; Beigene: Honoraria; TG Therapeutics: Honoraria. Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Couto Francisco: AstraZeneca: Current Employment, Other: may own stock or stock options. Elgeioushi: AstraZeneca: Current Employment, Other: may own stock or stock options. Hobson: AstraZeneca: Current Employment, Other: may own stock or stock options. Scott: AstraZeneca: Current Employment, Other: may own stock or stock options. Stone: AstraZeneca: Current Employment, Other: may own stock or stock options. Sharma: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Morentin Gutierrez: AstraZeneca: Current Employment, Other: may own stock or stock options. Tibes: AstraZeneca: Current Employment, Other: may own stock or stock options. Davies: AstraZeneca: Current Employment, Other: may own stock or stock options. Winkler: AstraZeneca: Current Employment, Other: may own stock or stock options. Fabbri: AstraZeneca: Current Employment, Other: may own stock or stock options. Zumla Cader: AstraZeneca: Current Employment, Other: may own stock or stock options. McNeer: AstraZeneca: Current Employment, Other: may own stock or stock options. more...
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- 2021
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11. AZD4573 Effectively Induces Apoptosis in r/r MCL As a Monotherapy or in Combination with Acalabrutinib
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Lisa Drew, Gregory Dowdell, Scott Boiko, Danielle M. Townsley, Justin Cidado, Huiling Liang, Justine Roderick, Corinne Reimer, and Courtney L. Andersen
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Apoptosis ,Chemistry ,Immunology ,Cancer research ,Acalabrutinib ,Cell Biology ,Hematology ,Biochemistry - Abstract
Mantle cell lymphoma (MCL) is an aggressive form of NHL where frequent relapse following standard therapies remains a serious concern, even for promising new treatments such as combinations of a BTK inhibitor with the selective Bcl2 inhibitor venetoclax. Previous studies have also shown that MCL cells develop resistance through tumor microenvironment interactions that increase levels of Mcl1, BclxL, and/or Bfl1. Given the ability of CDK9 inhibition to deplete Mcl1 and Bfl1 (Boiko et al 2021), we explored the potential of clinical-stage inhibitor AZD4573 to induce apoptosis in MCL cell lines and PDX models as a monotherapy or in combination with acalabrutinib. Currently, AZD4573 is being evaluated as a monotherapy in a first-in-human study for relapsed or refractory hematological malignancies (NCT03263637) as well as in combination with the BTK inhibitor, acalabrutinib, in patients with non-Hodgkin lymphoma (NHL) (NCT04630756). CDK9 is a serine/threonine kinase that mediates transcription elongation via phosphorylation of serine 2 of the RNA polymerase II carboxyl-terminal domain (pSer2-RNAP2). As previously shown, potent and selective inhibition of CDK9 by AZD4573 results in reduction of pSer2-RNAP2 levels leading to preferential depletion of labile proteins, including the Bcl2 family anti-apoptotic proteins Mcl1 and Bfl1 (as well as other known oncoproteins like Myc). This in turn drives rapid induction of apoptosis in a broad range of preclinical cancer models, particularly those derived from hematologic malignancies (Cidado et al 2020). Here, we used 7 MCL cell lines and 1 PDX organoid to assess the rapid apoptogenic potential of AZD4573 in vitro. Cleaved caspase-3 (CC3), a hallmark of apoptosis, was measured immediately following acute treatment (6h) using Caspase-Glo 3/7. Four models were sensitive to CDK9 inhibition (EC 50 < 100nM; max. CC3 > 50%) while 1 cell line exhibited intermediate sensitivity (EC 50 < 100nM; max. CC3 < 50%) and 3 others were resistant (EC 50 > 100nM; max. CC3 < 50%). Regardless of sensitivity, AZD4573 caused a dose- and time-dependent reduction of pSer2-RNAP2, Mcl1, and Myc, consistent with our prior reports. Most MCL cell lines are not responsive to BTK inhibition and, therefore, did not show combination benefit with AZD4573. We, therefore, chose to evaluate the in vivo activity of AZD4573 +/- acalabrutinib in 3 disseminated r/r MCL PDX models. In DFBL-44685, an acalabrutinib-unresponsive model harboring a CARD11 mutation, AZD4573 showed moderate activity, reducing MCL cells in all compartments analyzed (peripheral blood, bone marrow, and spleen) by >40% two weeks into treatment and increasing overall survival benefit (P80% and significantly increased survival over vehicle as well as monotherapy treatments (P50% and significantly increased survival over vehicle (P Our findings show that targeting CDK9 with AZD4573 can effectively induce apoptosis in a range of MCL cell lines and PDX models, including acalabrutinib-sensitive and -insensitive models as well as those expressing high levels of Bfl1. In 3 r/r MCL PDX models, single agent AZD4573 significantly reduced the tumor burden in the peripheral blood, bone marrow, and spleen of the affected mice, resulting in increased survival. Combination of AZD4573 with acalabrutinib resulted in greater anti-tumor activity than either monotherapy. Altogether, these data suggest that AZD4573, alone or in combination with acalabrutinib, could be an effective therapy for patients with r/r MCL. Figure 1 Figure 1. Disclosures Boiko: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Liang: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Dowdell: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Reimer: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Drew: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Townsley: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. more...
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- 2021
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12. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
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Emma Minihane, Jonathan R. Dry, Simon J. Cook, Mario Aladren Vicente, Matthew J. Sale, Noel R. Monks, Paul D Smith, Aleksandra Markovets, Lisa Drew, Duncan I. Jodrell, Frances M. Richards, Theresa Proia, Courtney L. Andersen, Emma J. Davies, Vikki Flemington, Eiko Ozono, Rebecca Gilley, Kevin Schifferli, Richards, Frances M. [0000-0001-7947-7853], Andersen, Courtney L. [0000-0003-2064-2273], Jodrell, Duncan I. [0000-0001-9360-1670], Smith, Paul D. [0000-0002-2812-5978], Cook, Simon J. [0000-0001-9087-1616], Apollo - University of Cambridge Repository, Richards, Frances M [0000-0001-7947-7853], Andersen, Courtney L [0000-0003-2064-2273], Jodrell, Duncan I [0000-0001-9360-1670], Smith, Paul D [0000-0002-2812-5978], and Cook, Simon J [0000-0001-9087-1616] more...
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0301 basic medicine ,45/41 ,General Physics and Astronomy ,Apoptosis ,Drug resistance ,13/2 ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,MCL1 ,Molecular Targeted Therapy ,lcsh:Science ,Melanoma ,Multidisciplinary ,3. Good health ,13/31 ,Cancer therapeutic resistance ,631/67/1059/602 ,030220 oncology & carcinogenesis ,38/39 ,Growth inhibition ,biological phenomena, cell phenomena, and immunity ,Cell signalling ,Proto-Oncogene Proteins B-raf ,Cell death ,Programmed cell death ,Macrocyclic Compounds ,631/80/82 ,Cell Survival ,MAP Kinase Signaling System ,Science ,bcl-X Protein ,631/80/86 ,13/106 ,13/109 ,General Biochemistry, Genetics and Molecular Biology ,Article ,38 ,96/95 ,03 medical and health sciences ,Therapeutic index ,14/34 ,Targeted therapies ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,neoplasms ,42 ,45 ,business.industry ,Comment ,General Chemistry ,medicine.disease ,digestive system diseases ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,lcsh:Q ,business - Abstract
BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-XL inhibitors is stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-XL inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes., BRAF or MEK1/2 inhibitors are cytostatic in melanoma and the surviving cells develop drug resistance. This study shows that the pro-survival pool is biased towards MCL1 in melanoma so that BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, improving tumour growth inhibition. more...
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- 2019
13. Author response: The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells
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Matthew A. Belmonte, Seung Hyun Baik, Hong Ma, Courtney L. Andersen, Lisa Drew, Therese Mitros, Justin Cidado, Pei-Chun Lin, Jacob E. Corn, Cortni Dick, and Shaheen Kabir
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Chemistry ,Ubiquitin ligase complex ,medicine ,Cancer research ,MCL1 ,Cyclin-dependent kinase 9 ,Lung cancer ,medicine.disease ,CUL5 - Published
- 2019
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14. Abstract 2957: A novel circulating tumor DNA (ctDNA) assay enables monitoring of disease progression and treatment response in disseminated preclinical hematologic cancer models
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Andrew Bloecher, Brian Dougherty, Deborah Lawson, Daniel Stetson, Courtney L. Andersen, Amanda L. Christie, Justine Roderick, Jacob Gordon, Corinne Reimer, Denise Hughes, Brandon Willis, Kimberly Maratea, and Paul Labrousse more...
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Cancer Research ,Treatment response ,Hematologic cancer ,Oncology ,Circulating tumor DNA ,business.industry ,Disease progression ,Cancer research ,Medicine ,business - Abstract
We have established a novel assay to assess circulating tumor DNA (ctDNA) in mice engrafted with disseminated cell line and patient-derived xenografts (PDX) of hematologic malignancies. Disseminated models recapitulate many features of human disease, but engraftment in multiple tissues makes monitoring of disease and treatment response difficult. Existing assays also lack the sensitivity required to assess minimal residual disease (MRD). This novel ddPCR assay targets highly conserved human-specific regions of LINE-1 and HERV-K repeat elements resulting in exceptionally sensitive detection of shed human ctDNA. Initial data shows sensitivity of 0.8 haploid genome equivalents (one haploid genome is ~3.3pg of human DNA), whereas ctDNA monitoring assays currently on the market require 1,000 times more input DNA to reach a sensitivity of just 2-9 genome equivalents. Serial dilution experiments confirm this assay is suitable to detect increases in ctDNA over several orders of magnitude, while also establishing a minimum plasma input of 40uL. To validate the assay we assessed the ability of ctDNA to detect disease alongside traditional histology, bioluminescence imaging, and flow cytometry assays in 10 leukemia and lymphoma models. Levels of ctDNA correlated well with disease progression across models engrafting in bone marrow, spleen, liver, blood and other tissues. In all cases where early stage disease was analyzed, the ctDNA assay was able to detect disease earlier relative to other methods due to its increased sensitivity, and these data can be effectively used for randomization into treatment groups. We also assessed the utility of ctDNA for determining drug treatment response in mice engrafted with a disseminated mantle cell lymphoma PDX. Baseline ctDNA assessment was completed on day 11 post-engraftment confirming ctDNA levels above baseline, at which point mice were divided into 7 treatment groups: Vehicle, Acalabrutinib, and 5 combination arms of Acalabrutinib plus clinically used agents. After 4 weeks of treatment disease burden was assessed by flow cytometry of the bone marrow (femur) compared to ctDNA detected in plasma. Efficacy readouts from both assays agreed for all groups, while the ctDNA assay was able to identify a significant difference between the two best responding arms which appeared to have near complete responses when assessed by flow cytometry alone. The fold difference between the two best responding arms was 1.1 fold by flow cytometry and 3.6 fold by ctDNA, illuminating a greater disparity in MRD and relapse potential between these 2 groups. This novel ctDNA assay allows for robust experimental designs to answer questions about the depth and durability of treatment responses, as well as to identify early stage disease. Work is ongoing to explore extended monitoring for relapse and application to solid tumor models. Citation Format: Amanda L. Christie, Paul Labrousse, Courtney L. Andersen, Justine E. Roderick, Jacob Gordon, Deborah Lawson, Denise Hughes, Kimberly Maratea, Daniel Stetson, Brandon Willis, Andrew Bloecher, Corinne Reimer, Brian Dougherty. A novel circulating tumor DNA (ctDNA) assay enables monitoring of disease progression and treatment response in disseminated preclinical hematologic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2957. more...
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- 2021
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15. AZD4320 Is a Novel and Potent BCL-2/XL Dual Inhibitor in Targeting Aggressive Mantle Cell Lymphoma
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Angela Leeming, Justin Cidado, Michael Wang, Courtney L. Andersen, Alexa A Jordan, Yijing Li, Yang Liu, Joseph McIntosh, and Vivian Changying Jiang
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Oncology ,medicine.medical_specialty ,Cell growth ,business.industry ,Venetoclax ,Immunology ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,chemistry.chemical_compound ,Kite Pharma ,chemistry ,Internal medicine ,Ibrutinib ,medicine ,Mantle cell lymphoma ,business ,Ex vivo - Abstract
Introduction: Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma. It is an incurable disease with frequent relapse from chemotherapies, targeted therapies, and cell therapies. Dysregulated expression of BCL-2 family members resulting in enhanced cell survival frequently occurs in many cancer types and often contributes to the development of therapeutic resistance. The BCL-2 inhibitor venetoclax has been shown to be effective in treating refractory/relapsed MCL patients. However, resistance often occurs and one of the underlying mechanisms of this resistance is the increased expression of other anti-apoptotic BCL-2 family members, such as BCL-XL and MCL-1. In this study, we assessed the in vitro and in vivo efficacy of a novel and highly potent BCL-2/XL dual inhibitor AZD4320 in preclinical models. Methods: Cell viability assay was tested after 72-hour treatment with AZD4320 in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines by CellTiter-Glo (Promega). The assay was also done after a 24-hour treatment in primary PDX cells. Cell apoptosis assay was performed to determine if AZD4320 induces cell apoptosis in MCL cell lines. Furthermore, the in vivo efficacy of AZD4320 was assessed in a CAR-T resistant MCL patient-derived xenograft (PDX) model. Results: AZD4320 significantly inhibited cell proliferation in all tested MCL cell lines, including both ibrutinib/venetoclax-sensitive and -resistant cell lines. It had an IC50 value at a low nanomolar range between 0.59 nM to 18 nM. Consistently, AZD4320 was effective in targeting primary PDX cells ex vivo. AZD4320 induced cell apoptosis in a dose-dependent manner. AZD0466, the nanomedicine formulation of AZD4320 (30mg/kg, weekly, IV), dramatically inhibited tumor growth and prolonged mouse survival in an ibrutinib-CAR-T dual-resistant PDX mouse model. All mice tolerated the treatment dose without any body weight loss. Conclusion: The novel BCL-2/XL dual inhibitor AZD4320 demonstrated excellent anti-MCL activity in both ibrutinib/venetoclax-sensitive and -resistant MCL cells in vitro. This was further validated in vivo in a ibrutinib-CAR-T dual-resistant PDX model. These findings provide evidence that dual targeting of BCL-2 and BCL-XL by AZD4320 is promising as it may overcome therapeutic resistance in relapsed/refractory MCL. Disclosures Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Wang:OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Loxo Oncology: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Lu Daopei Medical Group: Honoraria; Acerta Pharma: Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Oncternal: Consultancy, Research Funding; Pulse Biosciences: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Guidepoint Global: Consultancy; Targeted Oncology: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy. more...
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- 2020
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16. The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells
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Matthew A. Belmonte, Hong Ma, Lisa Drew, Seung Hyun Baik, Pei-Chun Lin, Justin Cidado, Courtney L. Andersen, Cortni Dick, Shaheen Kabir, Therese Mitros, and Jacob E. Corn
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0301 basic medicine ,Lung Neoplasms ,Drug Resistance ,Apoptosis ,MCL1 inhibitor ,genome-wide CRISPRi screens ,0302 clinical medicine ,cell biology ,CRISPR ,MCL1 ,Biology (General) ,Lung ,Cancer Biology ,cancer biology ,Cancer ,0303 health sciences ,Tumor ,Bcl-2-Like Protein 11 ,Chemistry ,General Neuroscience ,Ubiquitin-Protein Ligase Complexes ,General Medicine ,Cullin Proteins ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-bcl-2 ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Ubiquitin ligase complex ,Medicine ,Development of treatments and therapeutic interventions ,CUL5 ,Research Article ,Human ,QH301-705.5 ,Science ,Ubiquitin-Protein Ligases ,Antineoplastic Agents ,CDK9 inhibitor ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,human ,Lung cancer ,030304 developmental biology ,Neoplastic ,General Immunology and Microbiology ,CUL5-RNF7-UBE2F ubiquitin ligase complex ,Cell Biology ,medicine.disease ,Cyclin-Dependent Kinase 9 ,030104 developmental biology ,Gene Expression Regulation ,Drug Resistance, Neoplasm ,noxa ,Neoplasm ,Myeloid Cell Leukemia Sequence 1 Protein ,bim ,Cyclin-dependent kinase 9 ,Biochemistry and Cell Biology - Abstract
Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL are frequently observed in many cancers. Inhibitors targeting MCL1 are in clinical development, however numerous cancer models are intrinsically resistant to this approach. To discover mechanisms underlying resistance to MCL1 inhibition, we performed multiple flow-cytometry based genome-wide CRISPR screens interrogating two drugs that directly (MCL1i) or indirectly (CDK9i) target MCL1. Remarkably, both screens identified three components (CUL5, RNF7 and UBE2F) of a cullin-RING ubiquitin ligase complex (CRL5) that resensitized cells to MCL1 inhibition. We find that levels of the BH3-only pro-apoptotic proteins Bim and Noxa are proteasomally regulated by the CRL5 complex. Accumulation of Noxa caused by depletion of CRL5 components was responsible for re-sensitization to CDK9 inhibitor, but not MCL1 inhibitor. Discovery of a novel role of CRL5 in apoptosis and resistance to multiple types of anticancer agents suggests the potential to improve combination treatments., eLife digest Organisms keep their tissues healthy by instructing damaged or unwanted cells to kill themselves via a controlled process known as apoptosis. Cancer cells, however, are able to evade death by increasing the level of proteins that block apoptosis, such as MCL1. Researchers have recently developed new drugs that can inhibit the action of the MCL1 protein. But a number of cancers have become resistant to these inhibitors. So, one important question is whether other proteins in cancer cells could be drugged, together with MCL1, to overcome or even avoid this resistance. Now, Kabir et al. have addressed this question by searching the genome of human lung cancer cells, which were resistant to treatment, for targets that could improve the performance of two MCL1 inhibitors. This involved reducing the level of every protein in these cells one by one using a genetic technique known as CRISPR-Cas9, and looking for cells that lost their resistance to the MCL1 inhibitor. From these genetic screens, Kabir et al. identified three proteins that are part of complex called CRL5. Inactivating this protein complex caused cancer cells to become more sensitive to the MCL1 inhibitor. Further biochemical experiments showed that CRL5 may contribute to drug resistance by reducing the levels of two proteins that promote apoptosis. These findings suggest that inhibiting CRL5 in combination with MCL1 could combat drug resistance. Although there are currently no drugs against CRL5, future experiments determining how CRL5 and MCL1 are linked could identify new drug targets and improve existing cancer treatments. more...
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- 2019
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17. Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges
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Andrew M. Stern, Michelle M. Boisen, Courtney L. Andersen, Sreeja Sreekumar, and Steffi Oesterreich
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Selective Estrogen Receptor Modulators ,medicine.medical_specialty ,Estrogen receptor ,Context (language use) ,Biochemistry ,Endocrinology ,Internal medicine ,Ovarian carcinoma ,medicine ,Humans ,Molecular Biology ,Predictive biomarker ,Ovarian Neoplasms ,Clinical Trials as Topic ,business.industry ,medicine.disease ,Endometrial Neoplasms ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,Drug Resistance, Neoplasm ,Selective estrogen receptor modulator ,Cancer research ,Female ,Signal transduction ,Ovarian cancer ,business ,Tamoxifen ,Signal Transduction ,medicine.drug - Abstract
Endometrial and ovarian cancers are estrogen-dependent gynecologic malignancies. Although many are estrogen receptor (ER) positive, treatment with the selective estrogen receptor modulator (SERM) tamoxifen, a tissue selective partial-agonist, has demonstrated only modest clinical benefit. Selective estrogen receptor downregulators (SERDs) are pure ER antagonists showing a benefit for advanced ER positive breast cancer, which has bolstered their potential use for ER positive gynecologic malignancies. We summarize these preclinical and clinical data, suggesting that a subpopulation of patients with endometrial or ovarian cancer exists in which treatment with SERDs results in improved outcome. However, the full potential of SERDs for a gynecologic malignancies will be realized only when the appropriate predictive biomarkers are identified. Additionally, a further understanding ER signaling in the context of ovarian and endometrial tissues that appear to involve c-Src and other kinase pathways is needed to successfully address the emergence of resistance with rationally designed combination therapies. more...
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- 2015
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18. Identification of Novel Combination Therapies Active in BCL2 Inhibitor-Resistant Patient-Derived AML Models
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Amanda L. Christie, Courtney L. Andersen, Alan Rosen, Kim Maratea, Edwin Clark, Maureen Hattersley, Corinne Reimer, Jerome T. Mettetal, Sai Pulukuri, Jon Travers, Jamal Carlos Saeh, and Justin Cidado
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Venetoclax ,medicine.medical_treatment ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Hypomethylating agent ,In vivo ,Internal medicine ,medicine ,Bone marrow ,business ,Ex vivo ,medicine.drug - Abstract
Acute myeloid leukemia (AML) is an aggressive, heterogeneous malignancy. AML patients whose disease relapses on chemotherapy or are unfit for aggressive induction regimens have limited therapeutic options. Many patients benefit from the combination of venetoclax (BCL2i) and a hypomethylating agent (HMA) but this regimen is rarely curative. The addition of novel agents could provide improved benefit for relapsed/refractory patients. To identify such regimens, we screened a panel of 10 AML cell lines with combinations of venetoclax and novel targeted agents. The agents used spanned multiple mechanisms of action (e.g. DNA damage response, kinase signaling, pro-apoptotic agents) and are all in early clinical development. Cells were treated for 72hrs and viability was assessed by CellTiter-Glo. In several of the cell lines that were insensitive or partially sensitive to venetoclax (OCI-AML3, KG1a, MonoMac6, THP1), combinations with inhibitors of MCL1 (AZD5991), AURKB (AZD2811), and BRD4 (AZD5153) showed synergistic activity (Loewe synergy score >5, growth inhibition > 180%) (Table 1). We next asked if these combinations were active in patient-derived xenograft (PDX) models of AML. We established an ex vivo co-culture assay using the HS-5 bone marrow stromal cell line. AML PDX cells were isolated from mouse spleens and plated in 96-well format in direct co-culture with HS-5 cells or in HS-5-derived conditioned media. Cells were treated with three doses of each monotherapy and three doses of fixed ratio combination. Replicate screens using cells from individual mice on different days confirmed data were reproducible (r2=0.687) across animals engrafted with the same PDX. Drug response was similar between conditioned media and direct co-culture assays (r2=0.81). Venetoclax sensitivity varied across PDX models ex vivo. Notably, 2/5 PDX models screened (DFAM-68555 and DFAM-10360) were insensitive to both venetoclax and the combination of venetoclax + 5-azacytidine (HMA) ex vivo. Both models were established from untreated/1L patients and harbor TP53 mutations. Combination treatments did not add additional benefit over venetoclax monotherapy in the DFAM-10360 model. However, in DFAM-68555, AZD5153, AZD5991, and AZD2811 showed improved activity over venetoclax alone (67%, 54%, and 67% vs. 26% decrease in viability for venetoclax alone, respectively). Since combination strategies will likely be most impactful in patients refractory to or relapsed after venetoclax, we chose this venetoclax insensitive model to prioritize in vivo. To confirm the translatability of these findings, we designed a pilot in vivo study using DFAM-68555. Mice were randomized to receive vehicle, venetoclax + HMA, or venetoclax + AZD5153 when peripheral blood disease reached ~5% (hCD45+hCD33+ cells by flow cytometry). After two weeks of dosing, animals were sacrificed to evaluate disease burden in bone marrow (sternum), spleen, and peripheral blood. The model remained insensitive to venetoclax + HMA in vivo. The combination of AZD5153 with venetoclax decreased disease burden in blood and spleen compared to vehicle (30% and 42% hCD45+CD33+ cells by flow cytometry vs 70% and 95%, respectively) with similar efficacy seen by immunohistochemistry in the bone. Finally, we screened these venetoclax combinations in additional aggressive AML PDX models which were resistant or only partially responsive to venetoclax in vivo. Addition of AZD2811NP and AZD5991 to venetoclax was more effective than venetoclax alone and venetoclax + HMA in the bone marrow. The most active combination varied from model to model. Efficacy screening in additional models is ongoing to further build ex vivo to in vivo translation and prioritize development of specific combinations. Also ongoing is genomic and transcriptomic profiling of these PDXs to identify potential predictive biomarkers of combination activity. In summary, we developed an ex vivo screening platform to test clinically actionable combinations for activity in clinically relevant models. Using this platform and subsequent in vivo efficacy, we identified venetoclax combinations across multiple mechanisms (pro-apoptotic, cell cycle regulation, transcriptional regulation, DNA damage response) with activity in venetoclax-insensitive models. These results suggest potential therapeutic options to explore clinically for AML patients. Disclosures Andersen: AstraZeneca: Employment. Christie:AstraZeneca: Employment. Rosen:Astrazeneca: Employment. Maratea:AstraZeneca: Employment. Hattersley:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Cidado:AstraZeneca: Employment. Pulukuri:AstraZeneca: Employment. Saeh:AstraZeneca: Employment. Clark:AstraZeneca: Employment, Equity Ownership. Reimer:AstraZeneca: Employment. Mettetal:AstraZeneca: Employment. more...
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- 2019
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19. Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens
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Tianzhou Ma, Alec Christie, Courtney L. Andersen, Esther Elishaev, Karen McLean, Matthew J. Sikora, Uma R. Chandran, Steffi Oesterreich, Soumya Luthra, Kunle Odunsi, Yongseok Park, Michelle M. Boisen, Gina Mantia-Smaldone, Paul Haluska, Robert P. Edwards, Adrian V. Lee, and George C. Tseng more...
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0301 basic medicine ,Cancer Research ,medicine.drug_class ,Context (language use) ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Endocrine system ,Animals ,Humans ,Fulvestrant ,Cell Proliferation ,Ovarian Neoplasms ,Estradiol ,Estrogen Receptor alpha ,Cancer ,Estrogens ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Insulin-Like Growth Factor Binding Protein 3 ,Oncology ,Estrogen ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,MCF-7 Cells ,Female ,Ovarian cancer ,Estrogen receptor alpha ,Tamoxifen ,medicine.drug - Abstract
Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC. Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERα target genes. Expression of this panel and ERα H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response. Results: Proliferation is ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3. Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802–12. ©2017 AACR. more...
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- 2017
20. Abstract B23: The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer
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Tianzhou Ma, Matthew J. Sikora, Courtney L. Andersen, Esther Elishaev, Uma R. Chandran, George C. Tseng, Anda M. Vlad, Robert Edwards, Michelle M. Boisen, and Steffi Oesterreich
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Cancer Research ,business.industry ,medicine.drug_class ,Endometriosis ,Cancer ,Estrogen receptor ,FGF18 ,medicine.disease ,Malignant transformation ,Oncology ,Estrogen ,Gene expression ,Cancer research ,Medicine ,business ,Ovarian cancer - Abstract
Objectives: To investigate changes in estrogen receptor–alpha (ERα) signaling during the progression of endometriosis to endometriosis-associated ovarian cancer (EAOC) as a putative driver of malignant transformation. Methods: We procured tissue samples of normal endometrium (n=23), endometriosis (benign, n=19; atypical, n=11; concurrent with EAOC, n=9), and EAOC (n=21). In this cohort, we evaluated expression of a 236-gene signature of estrogen signaling. ANOVA and unsupervised clustering were used to identify distinct gene expression profiles across disease states. These profiles were compared to public profiles of estrogen regulation in preclinical cancer models from the Gene Expression Omnibus (GEO). Gene set enrichment analysis (GSEA) was performed to determine whether gene expression in EAOC was consistent with ERα activity. Results: ANOVA revealed 158 differentially expressed genes (q Conclusions: Gene expression data suggest that classical ERα signaling becomes inactivated throughout the progression of endometriosis to EAOC. Rather, the gene expression pattern in EAOC is more consistent with profiles of endocrine resistance. De-repression of ERα target genes such as FGF18 may contribute to evolution of endometriosis into EAOC. Citation Format: Michelle Boisen, Courtney Andersen, Matt Sikora, Tianzhou Ma, George Tseng, Anda Vlad, Esther Elishaev, Uma Chandran, Robert Edwards, Steffi Oesterreich. The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B23. more...
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- 2018
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21. Abstract B25: Hormone receptor expression and response in ovarian tumors of low malignant potential
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Robert P. Edwards, Sarah Taylor, Steffi Oesterreich, Rohit Bhargava, Courtney L. Andersen, George C. Tseng, and Adrian V. Lee
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Cancer Research ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Targeted therapy ,Serous fluid ,Oncology ,Hormone receptor ,medicine ,Cancer research ,Immunohistochemistry ,Ovarian cancer ,business ,Estrogen receptor alpha ,Hormone - Abstract
Objective: Primary treatment for ovarian low malignant potential (LMP) tumors is surgical resection with little proven effect of cytotoxic chemotherapy. New therapeutic strategies are needed to prevent and treat recurrence. The objective of this study is to investigate the role of hormone receptors in ovarian low malignant potential tumors. Methods: We obtained formalin-fixed, paraffin embedded (FFPE) tissue samples from patients with ovarian LMP tumors. Clinicopathologic data were collected for all available specimens. Immunohistochemistry (IHC) was performed to determine protein expression. Gene expression was measured using the NanoString nCounter platform. Differences in expression between histologic subtypes were by t-test, followed by a Bonferroni adjustment for multiple comparisons (p Results: Thirty-eight patients were included in this study. The histologic subtypes were divided between 20 serous and 18 mucinous tumors. All serous tumors were ERα and PR positive by IHC and 6 of 20 (30%) were ERβ positive. Only one of the 18 mucinous tumors (5.6%) was positive for both ERα and PR, and all the samples were negative for ERβ. ERβ mRNA levels were elevated in the mucinous LMP tumors and ERα mRNA was higher in the serous samples. ERα and PR protein expression correlated with mRNA expression of ESR1 (r2=0.5606) and PR (r2=0.42), respectively. ERβ expression did not correlate with mRNA expression of ESR2 (r2=0.038). Measurement of estrogen-regulated genes and genes involved in ER signaling (n=236) revealed a clear separation of serous from mucinous subtypes, with 44 genes showing a statistically significant difference (p Conclusion: High levels of ERα, PR, and downstream ERα targets in serous LMP tumors suggest hormone responsiveness and that these tumors are potentially treatable with endocrine therapy. Mucinous tumors largely did not express hormone receptors. In light of this, differences in gene expression observed are more likely attributable to underlying lineage differences than differences in estrogen signaling. Additional large-scale analyses are warranted to better understand the differences between subtypes and to identify avenues for targeted therapy in mucinous LMPs. Citation Format: Sarah E. Taylor, Courtney L. Andersen, Rohit Bhargava, George Tseng, Steffi Oesterreich, Robert P. Edwards, Adrian V. Lee. Hormone receptor expression and response in ovarian tumors of low malignant potential. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B25. more...
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- 2018
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22. High expression of orphan nuclear receptor NR4A1 in a subset of ovarian tumors with worse outcome
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Adrian V. Lee, Stephen Safe, George C. Tseng, Chi Song, Matthew J. Sikora, Rui Chen, Jad Sallit, Paul Haluska, Robert P. Edwards, Mark E. Schurdak, Zachary A. Yochum, R. Laskey, Esther Elishaev, Evan R. Delgado, Steffi Oesterreich, Courtney L. Andersen, Jacob Wagner, and Michelle M. Boisen more...
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Ovary ,Mice, SCID ,Carcinoma, Ovarian Epithelial ,Article ,03 medical and health sciences ,Mice ,Prostate ,Cell Line, Tumor ,medicine ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Animals ,Humans ,Progression-free survival ,Neoplasms, Glandular and Epithelial ,RNA, Messenger ,Orphan receptor ,Ovarian Neoplasms ,Genome ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Prognosis ,Immunohistochemistry ,Serous fluid ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Nuclear receptor ,Cancer research ,Heterografts ,Female ,business ,Ovarian cancer - Abstract
Objective Nuclear receptors (NRs) play a vital role in the development and progression of several cancers including breast and prostate. Using TCGA data, we sought to identify critical nuclear receptors in high grade serous ovarian cancers (HGSOC) and to confirm these findings using in vitro approaches. Methods In silico analysis of TCGA data was performed to identify relevant NRs in HGSOC. Ovarian cancer cell lines were screened for NR expression and functional studies were performed to determine the significance of these NRs in ovarian cancers. NR expression was analyzed in ovarian cancer tissue samples using immunohistochemistry to identify correlations with histology and stage of disease. Results The NR4A family of NRs was identified as a potential driver of ovarian cancer pathogenesis. Overexpression of NR4A1 in particular correlated with worse progression free survival. Endogenous expression of NR4A1 in normal ovarian samples was relatively high compared to that of other tissue types, suggesting a unique role for this orphan receptor in the ovary. Expression of NR4A1 in HGSOC cell lines as well as in patient samples was variable. NR4A1 primarily localized to the nucleus in normal ovarian tissue while co-localization within the cytoplasm and nucleus was noted in ovarian cancer cell lines and patient tissues. Conclusions NR4A1 is highly expressed in a subset of HGSOC samples from patients that have a worse progression free survival. Studies to target NR4A1 for therapeutic intervention should include HGSOC. more...
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- 2015
23. Abstract 862: WNT4 mediates endocrine response and resistance in invasive lobular carcinoma cell lines and patient tumor explants
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Courtney L. Andersen, Priscilla M. McAuliffe, Steffi Oesterreich, Matthew J. Sikora, and Caroline M. Alexander
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Cancer Research ,medicine.medical_specialty ,animal structures ,Fulvestrant ,Cell growth ,Wnt signaling pathway ,Estrogen receptor ,Biology ,medicine.disease ,body regions ,Endocrinology ,Oncology ,Internal medicine ,Invasive lobular carcinoma ,WNT4 ,medicine ,Cancer research ,Endocrine system ,skin and connective tissue diseases ,Tamoxifen ,medicine.drug - Abstract
Invasive lobular carcinoma (ILC) is a breast cancer subtype affecting ∼30,000 U.S. women annually. Over 90% of ILC are estrogen receptor (ER)-positive; however, endocrine therapy may have poorer efficacy in a subset of ILC patients versus invasive ductal carcinoma (IDC) patients. This prompted us to assess global ER activity in ILC cell lines MDA MB 134VI (MM134) and SUM44PE (44PE) to identify novel mediators of ER signaling. These analyses identified the Wnt ligand WNT4 as an ILC-specific ER target gene, with an ILC-specific ER binding site (ERBS) at the WNT4 locus. Considering the critical role of WNT4 in normal mammary gland expansion, we hypothesize that ILC cells utilize WNT4 signaling to drive endocrine response and resistance. We assessed whether WNT4 is necessary for ILC cell growth using siRNA. WNT4 knockdown completely blocked estrogen-induced growth in ILC cells but not IDC cells. In parallel, the WNT4 ERBS was only occupied in ILC cells in response to estrogen, but progesterone-induced WNT4 in IDC was not associated with this ERBS. This suggests that, via the ILC-specific WNT4 ERBS, ILC cells drive estrogen-regulated proliferation by hijacking a developmental Wnt pathway. Wnt pathways typically activate â-catenin; however, we observed â-catenin dysfunction in ILC cells and that WNT4 cannot activate â-catenin. Thus, WNT4 signals in ILC cells via a novel non-canonical pathway. Using long-term estrogen-deprived (LTED) variants of MM134 and 44PE (4 and 2 lines, respectively), we assessed WNT4 in ILC endocrine resistance. WNT4 is over-expressed, but uncoupled from ER, in all MM134-LTED. Conversely, WNT4 is reduced in 44PE-LTED but remains ER-regulated; ER occupies the WNT4 ERBS only in 44PE-LTED cells and not MM134-LTED. Using siRNA, MM134-LTED (high WNT4) are growth-inhibited by WNT4 knockdown, while 44PE-LTED (low WNT4) are insensitive. However, WNT4 knockdown sensitizes 44PE-LTED to endocrine therapy. Taken together, uncoupling and upregulating WNT4 or WNT4/ER cross-talk may represent convergent endocrine resistance mechanisms in ILC. To assess the role of WNT4 in patient ILC, we examined WNT4 protein in archival breast tumors and observed that WNT4 is frequently expressed in ILC and IDC tumors. We also examined WNT4 regulation and endocrine response in patient tumor explants. We observed ER regulation of WNT4 directly in ILC tissues that correlated with sensitivity to fulvestrant but resistance to tamoxifen; this may mimic clinical endocrine resistance. Ongoing studies are assessing WNT4 as a biomarker and mediator of endocrine resistance in ILC. Clinical observations suggest that ER regulates unique pathways in ILC. We identified WNT4 as a downstream effector of endocrine signaling in ILC, with critical roles in both estrogen-induced growth and endocrine resistance. WNT4 signaling may represent a novel target to modulate endocrine response specifically for ILC patients. Citation Format: Matthew J. Sikora, Courtney L. Andersen, Caroline M. Alexander, Priscilla M. McAuliffe, Steffi Oesterreich. WNT4 mediates endocrine response and resistance in invasive lobular carcinoma cell lines and patient tumor explants. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 862. more...
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- 2016
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24. Hormone response in ovarian cancer: time to reconsider as a clinical target?
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Francesmary Modugno, R. Laskey, Courtney L. Andersen, Steffi Oesterreich, Ashlee L. Smith, and Paul Haluska
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Oncology ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Receptors, Cell Surface ,Biology ,Carcinoma, Ovarian Epithelial ,medicine.disease_cause ,Article ,Endocrinology ,Internal medicine ,medicine ,Animals ,Humans ,Hormone metabolism ,Neoplasms, Glandular and Epithelial ,Ovarian Neoplasms ,Cancer ,medicine.disease ,Hormones ,Clinical trial ,Estrogen ,Immunology ,Female ,Carcinogenesis ,Ovarian cancer ,Progestin ,Hormone - Abstract
Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence fromin vitrostudies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response. more...
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- 2012
25. Abstract 2103: Utilizing ER target genes as biomarkers of endocrine response in serous ovarian carcinoma
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Steffi Oesterreich, Uma R. Chandran, Soumya Luthra, Paul Haluska, Courtney L. Andersen, and Matthew J. Sikora
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Cancer Research ,Fulvestrant ,Serous carcinoma ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Targeted therapy ,GREB1 ,Serous fluid ,Oncology ,Ovarian carcinoma ,Immunology ,medicine ,Cancer research ,Ovarian cancer ,business ,medicine.drug - Abstract
Ovarian cancer is the most common and most lethal gynecologic malignancy. Despite clear histologic and molecular differences between disease subtypes, all patients receive cytotoxic chemotherapy and survival has not improved significantly for several decades. Identifying avenues for targeted therapy is critical to improving clinical outcomes. Given the vast heterogeneity of ovarian cancer, therapeutic strategies will vary based on subtype and specific biomarkers. Estrogen receptor-alpha (ER) is expressed in ∼70% of serous ovarian tumors and epidemiologic evidence indicates estrogen contributes to the disease etiology. Further, clinical data suggest that a subset of patients with serous carcinoma benefit from endocrine therapy. However, the full potential of endocrine therapy in ovarian cancer has been understudied. We hypothesize that a subset of serous ovarian tumors are dependent upon estrogen and that expression of ER target genes will identify patients who can be successfully treated with endocrine therapy. We characterized response to estradiol (E2) in four ER+ serous ovarian cancer cell lines, focusing on cell proliferation, survival, and gene expression. Proliferation was evaluated in 2-D and in a 3-D matrigel system. Survival was assayed in low-attachment conditions. We also evaluated response to anti-estrogens 4-hydroxytamoxifen (4OHT) and fulvestrant (ICI). Expression of canonical ER targets (e.g. GREB1, IGFBP3) was measured by qPCR. Gene expression microarrays after E2 treatment were used to identify genome-wide effects of ER. Studies of endocrine response in vivo are ongoing in patient-derived xenograft models. E2 promotes growth of PEO1 and PEO4 cells in 2-D and 3-D culture, with PEO4 cells exhibiting greater E2 dependence. Preliminary results indicate that E2 also promotes survival in low-attachment conditions. Growth and survival are both decreased by treatment with fulvestrant or 4-hydroxytamoxifen. Conversely, OVCA432 and OVSAHO cells do not respond to treatment with ER ligands. Microarrays identified E2-regulated genes in PEO1 and PEO4 cells that may be utilized as biomarkers of ER activity. Several of these ER targets are differentially expressed between E2-responsive and E2-independent cell lines including DEPTOR, GREB1, GFRA2, and EPHB3. We are currently overlapping our array results with publicly available datasets to develop a gene signature of E2 response, which we will use to profile ER signaling in clinical specimens and patient derived xenografts. Our results suggest that a subset of serous ovarian cancers are endocrine responsive. These studies will determine if expression of specific ER targets correlates with endocrine response and thus if they can be harnessed to predict clinical response to endocrine therapy. Citation Format: Courtney L. Andersen, Matthew J. Sikora, Soumya Luthra, Uma Chandran, Paul Haluska, Steffi Oesterreich. Utilizing ER target genes as biomarkers of endocrine response in serous ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2103. doi:10.1158/1538-7445.AM2014-2103 more...
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- 2014
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26. Abstract 94: Identifying biomarkers of estrogen response in models of serous ovarian cancer
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Matthew J. Sikora, Paul Haluska, Courtney L. Andersen, and Steffi Oesterreich
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Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Fulvestrant ,business.industry ,Cancer ,medicine.disease ,Primary tumor ,GREB1 ,Serous fluid ,Breast cancer ,Tumor progression ,Internal medicine ,medicine ,business ,Ovarian cancer ,medicine.drug - Abstract
Ovarian cancer is the fifth leading cause of cancer death among women in the United States. Despite advances in treatment for other cancers, ovarian cancer patient prognosis has not improved significantly since the advent of platinum-based chemotherapy. It is a highly heterogeneous disease with at least four distinct histological subtypes: serous, mucinous, endometrioid, and clear cell. However, no subtype- or biomarker-specific therapies are approved for ovarian cancer. Identifying targeted therapies is crucial to improving clinical outcomes. Specific therapies will likely vary based on tumor histology and biomarkers. Expression of estrogen receptor alpha (ER) is a well established biomarker of response to endocrine therapies in breast cancer. Despite the success of anti-estrogen therapies in treating breast cancer, little attention has been given to their potential in ovarian cancer. However, epidemiologic studies show that approximately 70% of epithelial ovarian tumors express ER, particularly serous and endometrioid subtypes, and that estrogen plays a role in ovarian cancer etiology. Further, clinical data suggest that a subset of ovarian cancer patients can be successfully treated with endocrine therapy. We hypothesize that some ovarian tumors require estrogen for growth and that predictive biomarkers will identify patients who will benefit from endocrine therapy. Using cell line models, we examined the response of ovarian cancer cells to estrogen (E2) and anti-estrogens with regard to gene expression and cell proliferation. E2 induces expression of canonical ER target genes (e.g. GREB1) in these cells, suggesting that they are estrogen-responsive. We observe that 4-hydroxytamoxifen and fulvestrant inhibit growth of ovarian cancer cells including the chemo-resistant line PEO4. Gene expression microarray studies identified additional E2-regulated genes in ovarian cancer cells that may be utilized as biomarkers of ER activity. We are expanding our studies to in vivo models (human primary tumor xenografts) to evaluate the role of E2 in driving tumor progression and determine the efficacy of anti-estrogens in treating serous ovarian cancer. There is a critical need for targeted therapies in ovarian cancer. Our studies will determine if endocrine responsiveness correlates with gene expression of specific biomarkers, which may lead to the identification of predictive clinical markers of response to endocrine therapy. Citation Format: Courtney L. Andersen, Matthew J. Sikora, Paul Haluska, Steffi Oesterreich. Identifying biomarkers of estrogen response in models of serous ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 94. doi:10.1158/1538-7445.AM2013-94 more...
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- 2013
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27. Non-coding single nucleotide variants affecting estrogen receptor binding and activity
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Courtney L. Andersen, Steffi Oesterreich, Lucas Santana-Santos, Panayiotis V. Benos, Peilu Wang, Adrian V. Lee, Kevin M. Levine, and Amir Bahreini
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0301 basic medicine ,Estrogen receptor ,Breast Neoplasms ,Biology ,Polymorphism, Single Nucleotide ,Transcriptome ,03 medical and health sciences ,Breast cancer ,Non-coding SNVs ,IGF1R ,Gene expression ,medicine ,Genetics ,Humans ,Genetics(clinical) ,DNA binding ,Gene ,Molecular Biology ,Alleles ,Genetics (clinical) ,Insulin-like growth factor 1 receptor ,Binding Sites ,Estrogen receptor binding ,Research ,Estrogen Receptor alpha ,medicine.disease ,Neoplasm Proteins ,3. Good health ,030104 developmental biology ,Cistrome ,MCF-7 Cells ,Cancer research ,Molecular Medicine ,Female - Abstract
Background Estrogen receptor (ER) activity is critical for the development and progression of the majority of breast cancers. It is known that ER is differentially bound to DNA leading to transcriptomic and phenotypic changes in different breast cancer models. We investigated whether single nucleotide variants (SNVs) in ER binding sites (regSNVs) contribute to ER action through changes in the ER cistrome, thereby affecting disease progression. Here we developed a computational pipeline to identify SNVs in ER binding sites using chromatin immunoprecipitation sequencing (ChIP-seq) data from ER+ breast cancer models. Methods ER ChIP-seq data were downloaded from the Gene Expression Omnibus (GEO). GATK pipeline was used to identify SNVs and the MACS algorithm was employed to call DNA-binding sites. Determination of the potential effect of a given SNV in a binding site was inferred using reimplementation of the is-rSNP algorithm. The Cancer Genome Atlas (TCGA) data were integrated to correlate the regSNVs and gene expression in breast tumors. ChIP and luciferase assays were used to assess the allele-specific binding. Results Analysis of ER ChIP-seq data from MCF7 cells identified an intronic SNV in the IGF1R gene, rs62022087, predicted to increase ER binding. Functional studies confirmed that ER binds preferentially to rs62022087 versus the wild-type allele. By integrating 43 ER ChIP-seq datasets, multi-omics, and clinical data, we identified 17 regSNVs associated with altered expression of adjacent genes in ER+ disease. Of these, the top candidate was in the promoter of the GSTM1 gene and was associated with higher expression of GSTM1 in breast tumors. Survival analysis of patients with ER+ tumors revealed that higher expression of GSTM1, responsible for detoxifying carcinogens, was correlated with better outcome. Conclusions In conclusion, we have developed a computational approach that is capable of identifying putative regSNVs in ER ChIP-binding sites. These non-coding variants could potentially regulate target genes and may contribute to clinical prognosis in breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0382-0) contains supplementary material, which is available to authorized users. more...
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