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3. Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC

Author

Hayhow, Thomas G., Williamson, Beth, Lawson, Mandy, Cureton, Natalie, Braybrooke, Erin L., Campbell, Andrew, Carbajo, Rodrigo J., Cheraghchi-Bashi, Azadeh, Chiarparin, Elisabetta, Diène, Coura R., Fallan, Charlene, Fisher, David I., Goldberg, Frederick W., Hopcroft, Lorna, Hopcroft, Philip, Jackson, Anne, Kettle, Jason G., Klinowska, Teresa, Künzel, Ulrike, Lamont, Gillian, Lewis, Hilary J., Maglennon, Gareth, Martin, Scott, Gutierrez, Pablo Morentin, Morrow, Christopher J., Nikolaou, Myria, Nissink, J. Willem M., O’Shea, Patrick, Polanski, Radoslaw, Schade, Markus, Scott, James S., Smith, Aaron, Weber, Judith, Wilson, Joanne, Yang, Bin, and Crafter, Claire

Published
2024
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6. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial

Author

Oliveira, Mafalda, Pominchuk, Denys, Nowecki, Zbigniew, Hamilton, Erika, Kulyaba, Yaroslav, Andabekov, Timur, Hotko, Yevhen, Melkadze, Tamar, Nemsadze, Gia, Neven, Patrick, Vladimirov, Vladimir, Zamagni, Claudio, Denys, Hannelore, Forget, Frédéric, Horvath, Zsolt, Nesterova, Alfiya, Ajimi, Maxine, Kirova, Bistra, Klinowska, Teresa, Lindemann, Justin P O, Lissa, Delphine, Mathewson, Alastair, Morrow, Christopher J, Traugottova, Zuzana, van Zyl, Ruaan, and Arkania, Ekaterine

Published
2024
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13. Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer

Author

Harrod, Alison, Lai, Chun-Fui, Goldsbrough, Isabella, Simmons, Georgia M., Oppermans, Natasha, Santos, Daniela B., Győrffy, Balazs, Allsopp, Rebecca C., Toghill, Bradley J., Balachandran, Kirsty, Lawson, Mandy, Morrow, Christopher J., Surakala, Manasa, Carnevalli, Larissa S., Zhang, Pei, Guttery, David S., Shaw, Jacqueline A., Coombes, R. Charles, Buluwela, Lakjaya, and Ali, Simak

Published
2022
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15. Author Correction: Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids

Author

Papsdorf, Katharina, Miklas, Jason W., Hosseini, Amir, Cabruja, Matias, Morrow, Christopher S., Savini, Marzia, Yu, Yong, Silva-García, Carlos G., Haseley, Nicole R., Murphy, Luke Meraz, Yao, Pallas, de Launoit, Elisa, Dixon, Scott J., Snyder, Michael P., Wang, Meng C., Mair, William B., and Brunet, Anne

Published
2023
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18. The Effect of Dysautonomia on Motor, Behavioral, and Cognitive Fluctuations in Parkinson's Disease.

Author

Mahajan, Abhimanyu, Morrow, Christopher B., Seemiller, Joseph, Mills, Kelly A., and Pontone, Gregory M.

Subjects
*PARKINSON'S disease, *MOVEMENT disorders, *DYSAUTONOMIA, *ODDS ratio, *LOGISTIC regression analysis
Abstract

Background Objective Methods Results Conclusions Motor and nonmotor fluctuations adversely impact the quality of life in Parkinson's disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations.We sought to evaluate the effect of dysautonomia on motor and nonmotor fluctuations in PD.Two hundred subjects with PD were evaluated in both on and off dopamine states to assess changes in symptoms related to dopaminergic fluctuations. Multivariable logistic regression was performed to assess the association of dysautonomia with motor, cognitive, and psychiatric worsening from on to off states with adjustment for disease duration, levodopa equivalent daily dosage (LEDD), and dopamine‐agonist LEDD.Subjects with dysautonomia had greater odds of clinically meaningful change in motor features (odds ratio [OR]: 3.0), cognition (OR: 3.4), and anxiety (OR: 4.3) compared to those without dysautonomia.Dysautonomia may be a contributory mechanism behind fluctuations in PD. The exact nature of this relationship deserves further evaluation. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49th Annual Meeting of the American Aging Association

Author

Murphy, Michaela E., Narasimhan, Akilavalli, Adrian, Alexis, Kumar, Ankur, Green, Cara L., Soto-Palma, Carolina, Henpita, Chathurika, Camell, Christina, Morrow, Christopher S., Yeh, Chung-Yang, Richardson, Claire E., Hill, Cristal M., Moore, Darcie L., Lamming, Dudley W., McGregor, Eric R., Simmons, Heather A., Pak, Heidi H., Bai, Hua, Denu, John M., Clark, Josef, Simcox, Judith, Chittimalli, Kishore, Dahlquist, Korbyn, Lee, Kyoo-a, Calubag, Mariah, Bouska, Mark, Yousefzadeh, Matthew J., Sonsalla, Michelle, Babygirija, Reji, Yuan, Rong, Tsuji, Tadataka, Rhoads, Timothy, Menon, Vinal, Jarajapu, Yagna PR., and Zhu, Yun

Published
2022
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25. Long-term, home-based transcranial direct current stimulation coupled with computerized cognitive training in frontotemporal dementia: A case report.

Author

Tippett, Donna C., Neophytou, Kyriaki, Tao, Yuan, Gallegos, Jessica, Morrow, Christopher, Onyike, Chiadi U., and Tsapkini, Kyrana

Abstract

We present the case of a 62-year-old woman with probable behavioral variant of frontotemporal dementia (bvFTD) with cognitive/language deficits who demonstrated improved performance on cognitive/language testing and in functional tasks following long-term, home-based transcranial direct current stimulation (tDCS) coupled with computerized cognitive training (CCT). The patient underwent home-based tDCS (anode on the left prefrontal cortex and cathode on the right homologue) for 46 sessions over 10 weeks along with CCT. On post-treatment testing, the patient improved by 3 points on the Mini-Mental State Exam (MMSE) (23 to 26). She also showed improvement on several cognitive/language tasks, such as immediate recall of single words and word pairs, total accurate words in sentence repetition, delayed recall, semantic processing, and sentence level comprehension. There was no decline in several other cognitive and language tasks. Family members reported subjective improvements in expressiveness, communication, and interaction with others as well as increased attention to grooming and style which contrasted with her pre-treatment condition. This report suggests that home-based tDCS combined with CCT for an extended period may slow decline, and improve cognitive/language performance and everyday function in FTD. Plain Language Summary: Long-term, Home-based Transcranial Direct Current Stimulation Coupled with Computerized Cognitive Training in Frontotemporal Dementia: A Case Report: A 62-year-old woman with probable behavioral variant of frontotemporal dementia (bvFTD) improved on cognitive/language testing and in functional tasks following long-term, home-based transcranial direct current stimulation (tDCS) coupled with computerized cognitive training (CCT). The patient underwent home-based tDCS for 46 sessions over 10 weeks along with CCT. On post-treatment testing, the patient improved by three points on the Mini-Mental State Exam (MMSE) (23 to 26). She also improved immediate recall of single words and word pairs, total accurate words in sentence repetition, delayed recall, semantic processing, and sentence level comprehension. There was no decline in several other cognitive and language tasks. Family members described improvements in expressiveness, communication, and interaction with others and increased attention to grooming and style which was different from her pre-treatment condition. This case report suggests that home-based tDCS combined with CCT for an extended period may slow decline and improve cognitive/language performance and everyday function in FTD. [ABSTRACT FROM AUTHOR]

Published
2024
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29. The next-generation oral selective estrogen receptor degrader camizestrant (AZD9833) suppresses ER+ breast cancer growth and overcomes endocrine and CDK4/6 inhibitor resistance

Author

Lawson, Mandy, primary, Cureton, Natalie, additional, Ros, Susana, additional, Cheraghchi-Bashi-Astaneh, Azadeh, additional, Urosevic, Jelena, additional, D'Arcy, Sophie, additional, Delpuech, Oona, additional, DuPont, Michelle, additional, Fisher, David I., additional, Gangl, Eric T., additional, Lewis, Hilary, additional, Trueman, Dawn, additional, Wali, Neha, additional, Williamson, Stuart Charles., additional, Moss, Jennifer, additional, Montaudon, Elodie, additional, Derrien, Héloïse, additional, Marangoni, Elisabetta, additional, Miragaia, Ricardo J., additional, Gagrica, Sladjana, additional, Morentin Gutierrez, Pablo, additional, Moss, Thomas, additional, Maglennon, Gareth A., additional, Sutton, Daniel, additional, Polanski, Radoslaw, additional, Rosen, Alan, additional, Cairns, Jonathan, additional, Zhang, Pei, additional, Sánchez-Guixé, Mònica, additional, Serra, Violeta, additional, Critchlow, Susan E., additional, Scott, James S., additional, Lindemann, Justin P.O., additional, Barry, Simon T., additional, Klinowska, Teresa, additional, Morrow, Christopher J., additional, and Carnevalli, Larissa S., additional

Published
2023
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31. Abstract P3-07-13: The next generation oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833) is active against wild type and mutant estrogen receptor α

Author

Morrow, Christopher, Carnevalli, Larissa, Baird, Richard D, Brier, Tim, Ciardullo, Carmela, Cureton, Natalie, Lawson, Mandy, McEwen, Robert, Nikolaou, Myria, Armstrong, Anne, Bermejo, Begoña, Calvo, Emiliano, Ciruelos, Eva, Garcia-Corbacho, Javier, Hamilton, Erika, Incorvati, Jason, Kabos, Peter, Oliveira, Mafalda, Patel, Manish R, Ruiz-Borregó, Manuel, Turner, Nicholas, Twelves, Chris, Vaklavas, Christos, Carroll, Danielle, Ching, Steven, Cvetesic, Nevena, DuPont, Michelle, Gibbons, Lisa, Mathewson, Alastair, Maudsley, Rhiannon, Gutierrez, Pablo Morentin, Reddy, Avinash, Rodriguez-Canales, Jaime, Ros, Susana, Sudhan, Dhivya, Sykes, Andy, Whitson, David, Klinowska, Teresa, Lindemann, Justin, Baird, Richard [0000-0001-7071-6483], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, Oncology, Clinical Research, Breast Cancer, Clinical Trials and Supportive Activities, Genetics, 32 Biomedical and Clinical Sciences, 3211 Oncology and Carcinogenesis, 3202 Clinical Sciences, Estrogen, Cancer
Abstract

Endocrine therapy forms the backbone treatment for patients with estrogen receptor (ER) positive tumors in both the adjuvant and metastatic setting. Aromatase inhibitors (AI) are the most common endocrine treatment option. Mutation of ESR1, the gene encoding ERα, is a common mechanism of resistance to AIs which leads to ligand independent activity of ERα. Camizestrant (AZD9833) is a next generation SERD and pure ER antagonist that is in Phase 3 trials (SERENA-4: NCT04711252; SERENA-6: NCT04964934). Here we report the preclinical and clinical activity of camizestrant in patients with ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors. The binding affinities of camizestrant, fulvestrant, and estradiol to wt ERα and ERα variants with mutations in the ligand binding domain were assessed. All three compounds exhibited reduced binding to mutant forms of ERα compared with wt ERα; the Y537S mutation had the greatest impact on binding. This was reflected in requirement for greater concentrations of camizestrant and fulvestrant to degrade and antagonize mutated ERα and to impact cellular proliferation in MCF-7 cells that expressed Y537S ESR1m compared to ESR1wt MCF-7 cells. Furthermore, while a 3 mg/kg dose of camizestrant achieved a maximal anti-tumor effect in a ESR1wt patient derived xenograft model, a 10 mg/kg was required for maximal effect in a D538G ESR1m model. Considering this difference between ESR1m and ESR1wt, pharmacokinetic/pharmacodynamic modelling of preclinical data predicted that a camizestrant dose of 75 mg would be maximally efficacious in patients with ESR1m tumors. Indeed, analysis of ESR1m circulating tumor DNA levels in patients from the SERENA-1 (NCT03616587) Phase 1 trial showed a clear effect of 14 days treatment with 75 mg camizestrant resulting in a >2-fold reduction in ESR1m variant allele frequency in 12/13 (92%) cases with complete clearance of ESR1m ctDNA in 7/13 (54%) cases. Interestingly, the clinical activity of camizestrant was higher in heavily pretreated patients with metastatic breast cancer with ESR1m tumors compared to those with no detectable mutation (ESR1m not detected). At a camizestrant dose of 75 mg, median progression-free survival was 8.3 months (maturity 12/15) in patients with ESR1m tumors compared to 5.6 months (8/9) in those with ESR1m not detected (data cut-off 6 October 2021). Camizestrant-induced ERα degradation was seen in both groups (mean reduction in H-score 42% in ESR1m tumors (n= 12 evaluable pairs) and 46% in tumors with ESR1m not detected (n=7)). Whole transcriptome analysis revealed a trend towards higher ERα activity at baseline in ESR1m tumors compared to ESR1m not detected; ERα activity reduced on treatment in both groups. Consistent with the clinical activity data, camizestrant induced more profound reductions in cell proliferation in ESR1m tumors compared to ESR1m not detected tumors (as seen by greater reductions in Ki67-positive tumor cells). These data demonstrate the activity of camizestrant in patients with ESR1m tumors. Clinical activity along with degradation and antagonism of the ERα is also seen in patients with tumors in which ESR1 mutations are not detected. In this heavily pre-treated Phase 1 patient population from SERENA-1, ESR1m may be a predictive biomarker to enrich for patients with maintained endocrine sensitivity. The SERENA-6 trial is investigating the efficacy and safety of camizestrant plus a CDK4/6 inhibitor in patients with metastatic breast cancer and detectable ESR1m. We acknowledge Helen Heffron, PhD, from InterComm International who provided medical writing support funded by AstraZeneca. Citation Format: Christopher Morrow, Larissa Carnevalli, Richard D. Baird, Tim Brier, Carmela Ciardullo, Natalie Cureton, Mandy Lawson, Robert McEwen, Myria Nikolaou, Anne Armstrong, Begoña Bermejo, Emiliano Calvo, Eva Ciruelos, Javier Garcia-Corbacho, Erika Hamilton, Jason Incorvati, Peter Kabos, Mafalda Oliveira, Manish R Patel, Manuel Ruiz-Borregó, Nicholas Turner, Chris Twelves, Christos Vaklavas, Danielle Carroll, Steven Ching, Nevena Cvetesic, Michelle DuPont, Lisa Gibbons, Alastair Mathewson, Rhiannon Maudsley, Pablo Morentin Gutierrez, Avinash Reddy, Jaime Rodriguez-Canales, Susana Ros, Dhivya Sudhan, Andy Sykes, David Whitson, Teresa Klinowska, Justin Lindemann. The next generation oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833) is active against wild type and mutant estrogen receptor α [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-13.

Published
2023

37. Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

Author

Lear, Bo P., primary, Thompson, Elizabeth A.N., additional, Rodriguez, Kendra, additional, Arndt, Zachary P., additional, Khullar, Saniya, additional, Klosa, Payton C., additional, Lu, Ryan J., additional, Morrow, Christopher S., additional, Risgaard, Ryan, additional, Peterson, Ella R., additional, Teefy, Brian B., additional, Bhattacharyya, Anita, additional, Sousa, Andre M.M., additional, Wang, Daifeng, additional, Benayoun, Bérénice A., additional, and Moore, Darcie L., additional

Published
2023
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39. Supplementary Figure 3 from [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Author

Cawthorne, Christopher, primary, Burrows, Natalie, primary, Gieling, Roben G., primary, Morrow, Christopher J., primary, Forster, Duncan, primary, Gregory, Jamil, primary, Radigois, Marc, primary, Smigova, Alison, primary, Babur, Muhammad, primary, Simpson, Kathryn, primary, Hodgkinson, Cassandra, primary, Brown, Gavin, primary, McMahon, Adam, primary, Dive, Caroline, primary, Hiscock, Duncan, primary, Wilson, Ian, primary, and Williams, Kaye J., primary

Published
2023
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40. Supplementary Figure 4 from [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Author

Cawthorne, Christopher, primary, Burrows, Natalie, primary, Gieling, Roben G., primary, Morrow, Christopher J., primary, Forster, Duncan, primary, Gregory, Jamil, primary, Radigois, Marc, primary, Smigova, Alison, primary, Babur, Muhammad, primary, Simpson, Kathryn, primary, Hodgkinson, Cassandra, primary, Brown, Gavin, primary, McMahon, Adam, primary, Dive, Caroline, primary, Hiscock, Duncan, primary, Wilson, Ian, primary, and Williams, Kaye J., primary

Published
2023
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43. Supplementary Figure 1 from [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Author

Cawthorne, Christopher, primary, Burrows, Natalie, primary, Gieling, Roben G., primary, Morrow, Christopher J., primary, Forster, Duncan, primary, Gregory, Jamil, primary, Radigois, Marc, primary, Smigova, Alison, primary, Babur, Muhammad, primary, Simpson, Kathryn, primary, Hodgkinson, Cassandra, primary, Brown, Gavin, primary, McMahon, Adam, primary, Dive, Caroline, primary, Hiscock, Duncan, primary, Wilson, Ian, primary, and Williams, Kaye J., primary

Published
2023
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45. Data from Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists

Author

Toy, Weiyi, primary, Weir, Hazel, primary, Razavi, Pedram, primary, Lawson, Mandy, primary, Goeppert, Anne U., primary, Mazzola, Anne Marie, primary, Smith, Aaron, primary, Wilson, Joanne, primary, Morrow, Christopher, primary, Wong, Wai Lin, primary, De Stanchina, Elisa, primary, Carlson, Kathryn E., primary, Martin, Teresa S., primary, Uddin, Sharmeen, primary, Li, Zhiqiang, primary, Fanning, Sean, primary, Katzenellenbogen, John A., primary, Greene, Geoffrey, primary, Baselga, José, primary, and Chandarlapaty, Sarat, primary

Published
2023
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46. Data from [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Author

Cawthorne, Christopher, primary, Burrows, Natalie, primary, Gieling, Roben G., primary, Morrow, Christopher J., primary, Forster, Duncan, primary, Gregory, Jamil, primary, Radigois, Marc, primary, Smigova, Alison, primary, Babur, Muhammad, primary, Simpson, Kathryn, primary, Hodgkinson, Cassandra, primary, Brown, Gavin, primary, McMahon, Adam, primary, Dive, Caroline, primary, Hiscock, Duncan, primary, Wilson, Ian, primary, and Williams, Kaye J., primary

Published
2023
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47. Supplementary Figure 2 from [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Author

Cawthorne, Christopher, primary, Burrows, Natalie, primary, Gieling, Roben G., primary, Morrow, Christopher J., primary, Forster, Duncan, primary, Gregory, Jamil, primary, Radigois, Marc, primary, Smigova, Alison, primary, Babur, Muhammad, primary, Simpson, Kathryn, primary, Hodgkinson, Cassandra, primary, Brown, Gavin, primary, McMahon, Adam, primary, Dive, Caroline, primary, Hiscock, Duncan, primary, Wilson, Ian, primary, and Williams, Kaye J., primary

Published
2023
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49. Supplementary Figure Legends from [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Author

Cawthorne, Christopher, primary, Burrows, Natalie, primary, Gieling, Roben G., primary, Morrow, Christopher J., primary, Forster, Duncan, primary, Gregory, Jamil, primary, Radigois, Marc, primary, Smigova, Alison, primary, Babur, Muhammad, primary, Simpson, Kathryn, primary, Hodgkinson, Cassandra, primary, Brown, Gavin, primary, McMahon, Adam, primary, Dive, Caroline, primary, Hiscock, Duncan, primary, Wilson, Ian, primary, and Williams, Kaye J., primary

Published
2023
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50. Supplementary Figures 1 - 8, Tables 1 - 3 from Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists

Author

Toy, Weiyi, primary, Weir, Hazel, primary, Razavi, Pedram, primary, Lawson, Mandy, primary, Goeppert, Anne U., primary, Mazzola, Anne Marie, primary, Smith, Aaron, primary, Wilson, Joanne, primary, Morrow, Christopher, primary, Wong, Wai Lin, primary, De Stanchina, Elisa, primary, Carlson, Kathryn E., primary, Martin, Teresa S., primary, Uddin, Sharmeen, primary, Li, Zhiqiang, primary, Fanning, Sean, primary, Katzenellenbogen, John A., primary, Greene, Geoffrey, primary, Baselga, José, primary, and Chandarlapaty, Sarat, primary

Published
2023
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