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39 results on '"Steadman, Kenneth"'

1. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Author

Rotinen, Mirja, You, Sungyong, Yang, Julie, Coetzee, Simon G, Reis-Sobreiro, Mariana, Huang, Wen-Chin, Huang, Fangjin, Pan, Xinlei, Yáñez, Alberto, Hazelett, Dennis J, Chu, Chia-Yi, Steadman, Kenneth, Morrissey, Colm M, Nelson, Peter S, Corey, Eva, Chung, Leland WK, Freedland, Stephen J, Di Vizio, Dolores, Garraway, Isla P, Murali, Ramachandran, Knudsen, Beatrice S, and Freeman, Michael R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Genetics, Biotechnology, Cancer, Urologic Diseases, Adenocarcinoma, Androgens, Animals, Cell Line, Tumor, Disease Progression, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha, Homeodomain Proteins, Humans, Male, Mice, Neuroendocrine Tumors, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Signal Transduction, Transcription Factors, Xenograft Model Antitumor Assays, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

Published
2018

2. Technoeconomic Modeling of Plant-Based Griffithsin Manufacturing.

Author

Alam, Aatif, Jiang, Linda, Kittleson, Gregory A, Steadman, Kenneth D, Nandi, Somen, Fuqua, Joshua L, Palmer, Kenneth E, Tusé, Daniel, and McDonald, Karen A

Subjects
Griffithsin, antiviral, biomanufacturing, cost, economics, microbicide, modeling, Infectious Diseases, Prevention, Infection, Good Health and Well Being, Other Biological Sciences, Biomedical Engineering, Medical Biotechnology
Abstract

Griffithsin is a marine algal lectin that exhibits broad-spectrum antiviral activity by binding oligomannose glycans on viral envelope glycoproteins, including those found in HIV-1, HSV-2, SARS, HCV and other enveloped viruses. An efficient, scalable and cost-effective manufacturing process for Griffithsin is essential for the adoption of this drug in human antiviral prophylaxis and therapy, particularly in cost-sensitive indications such as topical microbicides for HIV-1 prevention. The production of certain classes of recombinant biologics in plants can offer scalability, cost and environmental impact advantages over traditional biomanufacturing platforms. Previously, we showed the technical viability of producing recombinant Griffithsin in plants. In this study, we conducted a technoeconomic analysis (TEA) of plant-produced Griffithsin manufactured at commercial launch volumes for use in HIV microbicides. Data derived from multiple non-sequential manufacturing batches conducted at pilot scale and existing facility designs were used to build a technoeconomic model using SuperPro Designer® modeling software. With an assumed commercial launch volume of 20 kg Griffithsin/year for 6.7 million doses of Griffithsin microbicide at 3 mg/dose, a transient vector expression yield of 0.52 g Griffithsin/kg leaf biomass, recovery efficiency of 70%, and purity of >99%, we calculated a manufacturing cost for the drug substance of $0.32/dose and estimated a bulk product cost of $0.38/dose assuming a 20% net fee for a contract manufacturing organization (CMO). This is the first report modeling the manufacturing economics of Griffithsin. The process analyzed is readily scalable and subject to efficiency improvements and could provide the needed market volumes of the lectin within an acceptable range of costs, even for cost-constrained products such as microbicides. The manufacturing process was also assessed for environmental, health and safety impact and found to have a highly favorable environmental output index with negligible risks to health and safety. The results of this study help validate the plant-based manufacturing platform and should assist in selecting preferred indications for Griffithsin as a novel drug.

Published
2018

4. Movie S2 from Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential

Author

Reis-Sobreiro, Mariana, primary, Chen, Jie-Fu, primary, Novitskaya, Tatiana, primary, You, Sungyong, primary, Morley, Samantha, primary, Steadman, Kenneth, primary, Gill, Navjot Kaur, primary, Eskaros, Adel, primary, Rotinen, Mirja, primary, Chu, Chia-Yi, primary, Chung, Leland W.K., primary, Tanaka, Hisashi, primary, Yang, Wei, primary, Knudsen, Beatrice S., primary, Tseng, Hsian-Rong, primary, Rowat, Amy C., primary, Posadas, Edwin M., primary, Zijlstra, Andries, primary, Di Vizio, Dolores, primary, and Freeman, Michael R., primary

Published
2023
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5. Supplementary Figure legends from Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential

Author

Reis-Sobreiro, Mariana, primary, Chen, Jie-Fu, primary, Novitskaya, Tatiana, primary, You, Sungyong, primary, Morley, Samantha, primary, Steadman, Kenneth, primary, Gill, Navjot Kaur, primary, Eskaros, Adel, primary, Rotinen, Mirja, primary, Chu, Chia-Yi, primary, Chung, Leland W.K., primary, Tanaka, Hisashi, primary, Yang, Wei, primary, Knudsen, Beatrice S., primary, Tseng, Hsian-Rong, primary, Rowat, Amy C., primary, Posadas, Edwin M., primary, Zijlstra, Andries, primary, Di Vizio, Dolores, primary, and Freeman, Michael R., primary

Published
2023
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6. Data from Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential

Author

Reis-Sobreiro, Mariana, primary, Chen, Jie-Fu, primary, Novitskaya, Tatiana, primary, You, Sungyong, primary, Morley, Samantha, primary, Steadman, Kenneth, primary, Gill, Navjot Kaur, primary, Eskaros, Adel, primary, Rotinen, Mirja, primary, Chu, Chia-Yi, primary, Chung, Leland W.K., primary, Tanaka, Hisashi, primary, Yang, Wei, primary, Knudsen, Beatrice S., primary, Tseng, Hsian-Rong, primary, Rowat, Amy C., primary, Posadas, Edwin M., primary, Zijlstra, Andries, primary, Di Vizio, Dolores, primary, and Freeman, Michael R., primary

Published
2023
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7. Abstract 421: PLX-3618, a potent, selective monovalent BRD4 degrader demonstrates activity in models of prostate cancer

Author

Steadman, Kenneth, primary, Parker, Gregory S., additional, Leriche, Geoffray, additional, Fish, Sarah, additional, Toth, Julia, additional, Spalding, Mary E., additional, Daniele, Elizabeth, additional, Jamborcic, Aleksandar, additional, Li, Xiaoming, additional, Kallel, E Adam, additional, Barmare, Farhana, additional, Chng, Kenneth, additional, Green, Erika, additional, Hocker, Michael, additional, Imler, Elliot, additional, Zhang, Yi, additional, Thompson, Peggy A., additional, and Bailey, Simon, additional

Published
2022
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12. Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential

Author

Reis-Sobreiro, Mariana, primary, Chen, Jie-Fu, additional, Novitskaya, Tatiana, additional, You, Sungyong, additional, Morley, Samantha, additional, Steadman, Kenneth, additional, Gill, Navjot Kaur, additional, Eskaros, Adel, additional, Rotinen, Mirja, additional, Chu, Chia-Yi, additional, Chung, Leland W.K., additional, Tanaka, Hisashi, additional, Yang, Wei, additional, Knudsen, Beatrice S., additional, Tseng, Hsian-Rong, additional, Rowat, Amy C., additional, Posadas, Edwin M., additional, Zijlstra, Andries, additional, Di Vizio, Dolores, additional, and Freeman, Michael R., additional

Published
2018
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15. A Phase I Study of Cetuximab and Lapatinib In Patients with Advanced Solid Tumor Malignancies

Author

Deeken, John F., Wang, Hongkun, Subramaniam, Deepa, He, Aiwu Ruth, Hwang, Jimmy, Marshall, John L., Urso, Christina E., Wang, Yiru, Ramos, Corinne, Steadman, Kenneth, and Pishvaian, Michael J.

Subjects
Adult, Diarrhea, Male, Lung Neoplasms, Genotype, Maximum Tolerated Dose, Receptor, ErbB-2, Biopsy, Cetuximab, Antibodies, Monoclonal, Humanized, Article, Drug Administration Schedule, Carcinoma, Non-Small-Cell Lung, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Humans, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Genetic Variation, Lapatinib, Middle Aged, Anus Neoplasms, ErbB Receptors, Treatment Outcome, Head and Neck Neoplasms, Pharmacogenetics, Carcinoma, Squamous Cell, Quinazolines, Female, Drug Eruptions, Colorectal Neoplasms, Signal Transduction
Abstract

Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors.Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies.Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders.The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.

Published
2015

16. Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes

Author

Morley, Samantha, primary, You, Sungyong, additional, Pollan, Sara, additional, Choi, Jiyoung, additional, Zhou, Bo, additional, Hager, Martin H., additional, Steadman, Kenneth, additional, Spinelli, Cristiana, additional, Rajendran, Kavitha, additional, Gertych, Arkadiusz, additional, Kim, Jayoung, additional, Adam, Rosalyn M., additional, Yang, Wei, additional, Krishnan, Ramaswamy, additional, Knudsen, Beatrice S., additional, Di Vizio, Dolores, additional, and Freeman, Michael R., additional

Published
2015
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18. Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

Author

Harris, Michael, primary, Bhuvaneshwar, Krithika, additional, Natarajan, Thanemozhi, additional, Sheahan, Laura, additional, Wang, Difei, additional, Tadesse, Mahlet G., additional, Shoulson, Ira, additional, Filice, Ross, additional, Steadman, Kenneth, additional, Pishvaian, Michael J., additional, Madhavan, Subha, additional, and Deeken, John, additional

Published
2014
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19. A phase I study of the BCR-ABL tyrosine kinase inhibitor nilotinib and cetuximab in patients with solid tumors that can be treated with cetuximab.

Author

Smaglo, Brandon George, primary, Wang, Hongkun, additional, Steadman, Kenneth, additional, Murray, Joseph, additional, Pishvaian, Michael, additional, He, Aiwu Ruth, additional, Hwang, Jimmy J., additional, Subramaniam, Deepa Suresh, additional, Deeken, John F., additional, and Weiner, Louis M., additional

Published
2013
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20. Final results of a phase I study of lapatinib (LAP) and cetuximab (CET) in patients with CET-sensitive solid tumors.

Author

Deeken, John F., primary, Wang, Hongkun, additional, Marshall, John, additional, Subramaniam, Deepa Suresh, additional, Hwang, Jimmy J., additional, He, Aiwu Ruth, additional, Ramos, Corinne, additional, Hardesty, Rosemarie A., additional, Steadman, Kenneth, additional, Weiner, Louis M., additional, and Pishvaian, Michael J., additional

Published
2013
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36. An army for the 21st century.

Author

Steadman, Kenneth

Subjects
OPERATIONAL readiness (Military science)
Abstract

Discusses the development by the US Army of full divisional operations for the early 21st century. Focus on power projection and advances in technology; Capability of deploying forces from the United States to regional conflicts; Transformation of the battlefield due to advances in technology.

Published
1996

37. Russia's army is steadily diminishing, but remains a viable force.

Author

Steadman, Kenneth

Subjects
RUSSIAN armed forces
Abstract

Assesses the capability and readiness of Russia's armed forces. Redeployment, reorganization and reductions of armed forces; Declaration of ownership of best military equipments by Ukraine and Belarus.

Published
1996

38. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas -deficient MRL/lpr−/− murine model of autoimmune lymphoproliferative syndrome (ALPS)

Author

Dowdell, Kennichi C., Pesnicak, Lesley, Hoffmann, Victoria, Steadman, Kenneth, Remaley, Alan T., Cohen, Jeffrey I., Straus, Stephen E., and Rao, V. Koneti

Subjects
*VALPROIC acid, *PHARMACODYNAMICS, *LYMPHOPROLIFERATIVE disorders, *ENZYME inhibitors, *HISTONE deacetylase, *APOPTOSIS, *T cells, *LABORATORY mice, *PATIENTS
Abstract

Objective: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis, often presenting in childhood. Similarly, MRL/lpr−/− mice homozygous for Fas mutations develop an ALPS-like disease with autoimmunity, lymphadenopathy, splenomegaly, and expansion of double-negative T cells. Currently, there are no proven therapies with adequate safety margins for sustained abolition of the lymphoproliferation associated with ALPS. We sought to test the ability of valproic acid (VPA), a histone deacetylase inhibitor, to induce apoptosis and inhibit lymphoproliferation. Materials and Methods: Human peripheral blood mononuclear cells from patients with ALPS and normal controls were tested in vitro to determine the efficacy of VPA at inducing cell death. VPA was used in vivo to control lymphoproliferation in MRL/lpr−/− mice, a model for ALPS. Results: VPA induced cell death in vitro, and was partially inhibited by the pan caspase inhibitor, Z-VAD-FMK. MRL/lpr−/− mice treated with VPA for 8 weeks showed significant reductions in spleen and lymph node weights and cellularity compared to controls. A concomitant decrease in double-negative T cells was observed in the spleen, lymph nodes, and peripheral blood. Serum levels of VPA peaked 1 hour after injection, and a 2.5-fold increase in histone acetylation was observed in the spleen at 4 hours after injection. Conclusion: Based on our data, VPA is effective at reducing lymphoproliferation in mice, and is currently being studied in a clinical trial as a lympholytic agent in patients with ALPS. [Copyright &y& Elsevier]

Published
2009
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39. Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11.

Author

Parker GS, Toth JI, Fish S, Blanco G, Kampert T, Li X, Yang L, Stumpf CR, Steadman K, Jamborcic A, Chien S, Daniele E, Dearie A, Leriche G, Bailey S, and Thompson PA

Abstract

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent "direct" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extraterminal protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent antitumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent antitumor activity in vivo., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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