124 results on '"Jeffrey Ecsedy"'
Search Results
2. Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines
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Ningbo Liu, Yong Antican Wang, Yunguang Sun, Jeffrey Ecsedy, Jifeng Sun, Xue Li, and Ping Wang
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AURKA ,MLN8237 ,Alisertib ,Radiosensitivity ,Lung cancer ,P53 ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC). Methods Here, we first analyzed AURKA expression in 63 NSCLC tumor samples by immunohistochemistry (IHC) and used an MTS assay to compare cell survival by targeting AURKA with MLN8237 (Alisertib) in H460 and HCC2429 (P53-competent), and H1299 (P53-deficient) cell lines. The radiosensitivity of MLN8237 was further evaluated by clonogenic assay. Finally, we examined the effect of combining radiation and AURKA inhibition in vivo with a xenograft model and explored the potential mechanism. Results We found that increased AURKA expression correlated with decreased time to progression and overall survival (p = 0.0447 and 0.0096, respectively). AURKA inhibition using 100 nM MLN8237 for 48 h decreases cell growth in a partially P53-dependent manner, and the survival rates of H460, HCC2429, and H1299 cells were 56, 50, and 77%, respectively. In addition, the survival of H1299 cells decreased 27% after ectopic restoration of P53 expression, and the radiotherapy enhancement was also influenced by P53 expression (DER H460 = 1.33; HCC2429 = 1.35; H1299 = 1.02). Furthermore, tumor growth of H460 was delayed significantly in a subcutaneous mouse model exposed to both MLN8237 and radiation. Conclusions Taken together, our results confirmed that the expression of AURKA correlated with decreased NSCLC patient survival, and it might be a promising inhibition target when combined with radiotherapy, especially for P53-competent lung cancer cells. Modulation of P53 function could provide a new option for reversing cell resistance to the AURKA inhibitor MLN8237, which deserves further investigation.
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- 2019
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3. Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor
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Huifeng Niu, Hyunjin Shin, Feng Gao, Jacob Zhang, Brittany Bahamon, Hadi Danaee, Bohuslav Melichar, Russell J. Schilder, Robert L. Coleman, Gerald Falchook, Antoine Adenis, Kian Behbakht, Angela DeMichele, Elizabeth Claire Dees, Kimberly Perez, Ursula Matulonis, Piotr Sawrycki, Dirk Huebner, and Jeffrey Ecsedy
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Aurora A kinase inhibitor ,Alisertib ,SNP ,Prognosis ,Predictive biomarker ,Correlative analysis ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. Methods: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n = 62) or paclitaxel alone (n = 60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. Findings: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p
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- 2017
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4. Supplementary Table from Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
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Jeffrey Ecsedy, Xiaoyan M. Zhang, Mark Manfredi, Prabitha Natarajan, Sakeena Syed, Jeremy Tchaicha, Meghan Walsh, Silvia Coma, Jill Cavanaugh, Alfredo C. Castro, and Karen McGovern
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Supplementary Table from Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
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- 2023
5. Supplementary Figure 2 from The Aurora Kinase A Inhibitor MLN8237 Enhances Cisplatin-Induced Cell Death in Esophageal Adenocarcinoma Cells
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Wael El-Rifai, Abbes Belkhiri, Regine Schneider-Stock, Tilman T. Rau, Alexander Zaika, Jeffrey Ecsedy, Frank Revetta, M. Kay Washington, Mohammed Soutto, DunFa Peng, and Vikas Sehdev
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PDF file - 155K, Effects of MLN8237 and CDDP on cell cycle progression.
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- 2023
6. Supplementary Figure 3 from The Aurora Kinase A Inhibitor MLN8237 Enhances Cisplatin-Induced Cell Death in Esophageal Adenocarcinoma Cells
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Wael El-Rifai, Abbes Belkhiri, Regine Schneider-Stock, Tilman T. Rau, Alexander Zaika, Jeffrey Ecsedy, Frank Revetta, M. Kay Washington, Mohammed Soutto, DunFa Peng, and Vikas Sehdev
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PDF file - 1.8MB, Effects of MLN8238 and CDDP on proliferation and apoptosis in vivo.
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- 2023
7. Data from The Aurora Kinase A Inhibitor MLN8237 Enhances Cisplatin-Induced Cell Death in Esophageal Adenocarcinoma Cells
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Wael El-Rifai, Abbes Belkhiri, Regine Schneider-Stock, Tilman T. Rau, Alexander Zaika, Jeffrey Ecsedy, Frank Revetta, M. Kay Washington, Mohammed Soutto, DunFa Peng, and Vikas Sehdev
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Esophageal adenocarcinomas are poorly responsive to chemotherapeutics. This study aimed to determine the levels of Aurora kinase A (AURKA) and the therapeutic potential of MLN8237, an investigational AURKA inhibitor, alone and in combination with cisplatin. Using quantitative real-time PCR, we detected frequent AURKA gene amplification (15 of 34, 44%) and mRNA overexpression (37 of 44, 84%) in esophageal adenocarcinomas (P < 0.01). Immunohistochemical analysis showed overexpression of AURKA in more than two-thirds of esophageal adenocarcinoma tissue samples (92 of 132, 70%; P < 0.001). Using FLO-1, OE19, and OE33 esophageal adenocarinoma cell lines, with constitutive AURKA overexpression and mutant p53, we observed inhibition of colony formation with a single treatment of 0.5 μmol/L MLN8237 (P < 0.05). This effect was further enhanced in combination with 2.5 μmol/L cisplatin (P < 0.001). Twenty-four hours after treatment with the MLN8237 or MLN8237 and cisplatin, cell-cycle analyses showed a sharp increase in the percentage of polyploid cells (P < 0.001). This was followed by an increase in the percentage of cells in the sub-G1 phase at 72 hours, concordant with the occurrence of cell death (P < 0.001). Western blot analysis showed higher induction of TAp73β, PUMA, NOXA, cleaved caspase-3, and cleaved PARP with the combined treatment, as compared with a single-agent treatment. Using xenograft models, we showed an enhanced antitumor role for the MLN8237 and cisplatin combination, as compared with single-agent treatments (P < 0.001). In conclusion, this study shows frequent overexpression of AURKA and suggests that MLN8237 could be an effective antitumor agent, which can be combined with cisplatin for a better therapeutic outcome in esophageal adenocarcinomas. Mol Cancer Ther; 11(3); 763–74. ©2012 AACR.
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- 2023
8. Supplementary Figure from Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
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Jeffrey Ecsedy, Xiaoyan M. Zhang, Mark Manfredi, Prabitha Natarajan, Sakeena Syed, Jeremy Tchaicha, Meghan Walsh, Silvia Coma, Jill Cavanaugh, Alfredo C. Castro, and Karen McGovern
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Supplementary Figure from Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
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- 2023
9. Supplementary Figure Legends 1-3, Table Legend 1 from The Aurora Kinase A Inhibitor MLN8237 Enhances Cisplatin-Induced Cell Death in Esophageal Adenocarcinoma Cells
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Wael El-Rifai, Abbes Belkhiri, Regine Schneider-Stock, Tilman T. Rau, Alexander Zaika, Jeffrey Ecsedy, Frank Revetta, M. Kay Washington, Mohammed Soutto, DunFa Peng, and Vikas Sehdev
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PDF file - 45K
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- 2023
10. Supplementary Table 1 from The Aurora Kinase A Inhibitor MLN8237 Enhances Cisplatin-Induced Cell Death in Esophageal Adenocarcinoma Cells
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Wael El-Rifai, Abbes Belkhiri, Regine Schneider-Stock, Tilman T. Rau, Alexander Zaika, Jeffrey Ecsedy, Frank Revetta, M. Kay Washington, Mohammed Soutto, DunFa Peng, and Vikas Sehdev
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PDF file - 229K, Details of cell cycle analysis following MLN8237 and CDDPand CDDP.
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- 2023
11. Supplementary Figure 1 from The Aurora Kinase A Inhibitor MLN8237 Enhances Cisplatin-Induced Cell Death in Esophageal Adenocarcinoma Cells
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Wael El-Rifai, Abbes Belkhiri, Regine Schneider-Stock, Tilman T. Rau, Alexander Zaika, Jeffrey Ecsedy, Frank Revetta, M. Kay Washington, Mohammed Soutto, DunFa Peng, and Vikas Sehdev
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PDF file - 149K, AURKA expression levels in esophageal cell lines.
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- 2023
12. Data from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.
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- 2023
13. Supplementary Figure S1 from Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells
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Wael El-Rifai, Abbes Belkhiri, Jeffrey Ecsedy, Omar M. Omar, Janet Arras, Lihong Wang, and Ahmed Katsha
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Supp Fig 1
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- 2023
14. Data from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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Purpose: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer.Experimental Design: Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated.Results: Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co-immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P < 0.05).Conclusion: Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76–86. ©2013 AACR.
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- 2023
15. Supplementary Tables 1 - 4 from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 92K, Supplementary Table S1. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 7-day schedule. Supplementary Table S2. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 14-day schedule. Supplementary Table S3. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 21-day schedule. Supplementary Table S4. Summary of pharmacokinetic parameters for MLN8237 twice-daily dosing on the 7-day schedule.
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- 2023
16. Supplementary Figure 2 from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 2004K, Figure S2. Changes in skin mitotic index on days 7, 14 and 21.
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- 2023
17. Data from Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells
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Wael El-Rifai, Abbes Belkhiri, Jeffrey Ecsedy, Omar M. Omar, Janet Arras, Lihong Wang, and Ahmed Katsha
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Purpose: Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus).Experimental Design: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo.Results: Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib.Conclusions: Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA–EIF4E–c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC. Clin Cancer Res; 23(14); 3756–68. ©2017 AACR.
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- 2023
18. Supplementary Figure 2 from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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PDF file 1423K, AURKA regulates HDM2 through an AKT-independent mechanism
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- 2023
19. Supplementary Methods from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 55K.
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- 2023
20. Supplementary Materials and Methods from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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Supplementary Materials and Methods PDF file 37K, Supplementary Materials and Methods
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- 2023
21. Supplementary Figure 5 from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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PDF file 1254K, AURKA is present in an immunocomplex with HDM2
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- 2023
22. Supplementary Figure 4 from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 1749K, Figure S4. Changes in tumor mitotic index on days 1, 7, and 21.
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- 2023
23. Supplementary Figure 5 from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 2119K, Figure S5. Changes in chromosome alignment and spindle bipolarity on days 1 and 21.
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- 2023
24. Supplementary Figure 3 from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 2001K, Figure S3. Changes in skin apoptotic index on days 7, 14 and 21.
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- 2023
25. Supplementary Figure 3 from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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PDF file 260K, AURKA-mediated regulation of HDM2 attenuates CDDP-induced p53 expression in GC cells
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- 2023
26. Supplementary Figure 4 from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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PDF file 167K, AURKA overexpression counteracts CDDP-induced cell death in AGS cells
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- 2023
27. Supplementary Figure 1 from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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PDF file 1884K, AURKA and HDM2 are frequently overexpressed in esophageal adenocarcinoma cells
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- 2023
28. Supplementary Table S1 from Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells
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Wael El-Rifai, Abbes Belkhiri, Jeffrey Ecsedy, Omar M. Omar, Janet Arras, Lihong Wang, and Ahmed Katsha
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Supp Table 1
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- 2023
29. Supplementary Figure 6 from HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
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Wael El-Rifai, Abbes Belkhiri, Alexander Zaika, Jeffrey Ecsedy, Mohammed Soutto, Dunfa Peng, Janet Arras, Ahmed Katsha, and Vikas Sehdev
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PDF file 179K, Frequent overexpression and direct correlation between AURKA and HDM2 in human esophageal adenocarcinoma tissues
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- 2023
30. Supplementary Figure 1 from Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
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Josep Tabernero, Jose Baselga, Howard Fingert, José-Alejandro Pérez-Fidalgo, Laura Maños, Inma Blasco, Adelaida Piera, Juan Manuel Sanchis-Garcia, JungAh Jung, Jordi Andreu, Susana Roselló, Karthik Venkatakrishnan, Teresa Macarulla, Jeffrey Ecsedy, Desamparados Roda, Elena Elez, and Andres Cervantes
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PDF file, 1635K, Figure S1. MLN8237 dose-escalation and schedule extension schema.
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- 2023
31. Abstract 1646: IK-930, a paralog-selective TEAD inhibitor for treating YAP/TAZ-TEAD dependent cancers
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Nathan Young, George Punkosdy, Jill Cavanaugh, Collin Bantle, Alex Constan, Bin Li, James Conley, Marta Sanchez-Martin, Lan Xu, Karen McGovern, Alfredo Castro, Michelle Zhang, and Jeffrey Ecsedy
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Cancer Research ,Oncology - Abstract
The Hippo signaling cascade regulates cell proliferation and survival, as well as overall tissue homeostasis. These functions are mediated by the TEAD family of transcription factors which, when bound to the co-activators YAP or TAZ, induce expression of pro-growth and anti-apoptotic genes. This pathway is frequently dysregulated across tumor types, with genetic alterations along with other mechanisms driving hyper-active YAP/TAZ-TEAD. In addition, Hippo signaling mediates resistance to therapies targeting key oncogenic pathways such as EGFR and RAS. As a result, TEAD transcription factors are promising therapeutic targets. The TEAD family comprises four paralogs (TEAD1-4) that have both over-lapping and non-redundant functions. Given the essential roles of the Hippo pathway in normal physiology, it may be beneficial to target a subset of TEADs to minimize potential on-target toxicity while maintaining anti-tumor efficacy. Although highly homologous, the lipid-binding pocket of TEADs harbor some sequence divergence, highlighting an opportunity to design paralog-specific compounds. We developed IK-930 as a novel, selective inhibitor that potently blocks TEAD transcriptional activity by disrupting the auto-palmitoylation required for its interaction with YAP/TAZ. To demonstrate the selectivity profile of IK-930, a suite of biochemical assays was employed, all of which showed preferential compound binding to an individual paralog. A novel NanoBRETTM system that enabled quantitative, high-throughput measurements of cellular TEAD engagement also documented selective inhibitor interaction with the same family member. To assess how differences in selectivity affect therapeutic index, the in vivo efficacy and toxicity of IK-930 was compared to a pan-TEAD inhibitor. In several Hippo-mutated xenograft models, both compounds displayed potent anti-tumor activity. Moreover, IK-930 exhibited synergy with targeted agents, including EGFR inhibitors, indicating that its selectivity profile could drive robust efficacy in diverse tumor types. Previous studies in genetically engineered mouse models reported that perturbation of YAP/TAZ results in kidney toxicity. Treatment with a pan-TEAD inhibitor in rats and non-human primates led to substantial proteinuria and kidney pathology at exposures similar to those needed for antitumor activity in mouse models. In contrast, IK-930 demonstrated limited kidney toxicity in rats above efficacious doses and no signs of renal problems in non-human primates. Collectively, these results suggest that paralog selectivity with IK-930 broadens the therapeutic window of this novel compound class. With its distinct TEAD inhibitory profile, IK-930 offers unique therapeutic index advantages, further supporting its development as a first-in-class paralog-selective TEAD inhibitor. Citation Format: Nathan Young, George Punkosdy, Jill Cavanaugh, Collin Bantle, Alex Constan, Bin Li, James Conley, Marta Sanchez-Martin, Lan Xu, Karen McGovern, Alfredo Castro, Michelle Zhang, Jeffrey Ecsedy. IK-930, a paralog-selective TEAD inhibitor for treating YAP/TAZ-TEAD dependent cancers [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 1646.
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- 2023
32. Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
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Karen McGovern, Alfredo C. Castro, Jill Cavanaugh, Silvia Coma, Meghan Walsh, Jeremy Tchaicha, Sakeena Syed, Prabitha Natarajan, Mark Manfredi, Xiaoyan M. Zhang, and Jeffrey Ecsedy
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Immunosuppression Therapy ,Cancer Research ,Mice ,Oncology ,Receptors, Aryl Hydrocarbon ,Neoplasms ,Cytochrome P-450 CYP1A1 ,Tumor Microenvironment ,Animals ,Cytokines ,Humans ,Kynurenine ,Rats - Abstract
Aryl hydrocarbon receptor (AHR) is a transcription factor that regulates the activity of multiple innate and adaptive immune cells subsequent to binding to numerous endogenous and exogenous ligands. For example, AHR is activated by the metabolite kynurenine, which is secreted into the tumor microenvironment by cancer cells leading to broad immunosuppression. Therefore, AHR inhibition provides a novel and ideal approach to stimulate immune-mediated recognition and subsequent eradication of tumor cells. We report here the discovery and characterization of IK-175, a novel, potent and selective AHR antagonist with favorable ADME and pharmacokinetic profiles in preclinical species. IK-175 inhibits AHR activity in experimental systems derived from multiple species including mouse, rat, monkey, and humans. In human primary immune cells, IK-175 decreased AHR target gene expression and anti-inflammatory cytokine release and increased proinflammatory cytokine release. Moreover, IK-175 led to a decrease in suppressive IL17A–, IL-22+ expressing T cells in a Th17 differentiation assay. IK-175 dose dependently blocks ligand-stimulated AHR activation of Cyp1a1 transcription in mouse liver and spleen, demonstrating on-target in vivo activity. IK-175 increases proinflammatory phenotype of the tumor microenvironment in mouse syngeneic tumors and in adjacent tumor-draining lymph nodes. As a monotherapy and combined with an anti-PD-1 antibody, IK-175 demonstrates antitumor activity in syngeneic mouse models of colorectal cancer and melanoma. IK-175 also demonstrates antitumor activity combined with liposomal doxorubicin in syngeneic mouse tumors. These studies provide rationale for targeting AHR in patients with cancer. IK-175 is being evaluated in a phase I clinical trial in patients with advanced solid tumors.
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- 2021
33. 93 Computational biology and tissue-based approaches to inform indication selection for a novel AHR inhibitor
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Jeffrey Ecsedy, Lei Wang, Karen McGovern, Michelle Zhang, and Marta Sanchez-Martin
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Pharmacology ,Cancer Research ,Oncology ,Computer science ,Immunology ,Molecular Medicine ,Immunology and Allergy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Computational biology ,Selection (genetic algorithm) ,RC254-282 - Abstract
BackgroundAryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activities of multiple innate and adaptive immune cell types. Multiple ligands such as kynurenine bind to AHR driving its nuclear translocation and transcriptional activation, leading to an immunosuppressive tumor microenvironment.1 2 AHR activation is implicated in tumor development in multiple cancer types. In addition, high levels of serum kynurenine are associated with resistance to checkpoint inhibitors.3 To overcome AHR-mediated immunosuppression in cancers, we developed a selective oral AHR inhibitor IK-175 and took a combined computational and tissue-based approach to select cancer indications for its clinical development.MethodsThe aim of this work is to identify tumor indications dependent on AHR signaling and design patient selection strategies based on a proprietary transcriptional signature, mRNA and protein detection assays to evaluate AHR pathway activation in tumors.ResultsGenomic profiling of solid and hematological cancers from TCGA and Project GENIE databases identified bladder and esophageal tumors among others, as frequently harboring AHR gene amplifications.A proprietary gene signature of AHR activation was developed integrating literature, pathway analysis, RNAseq and nanostring data from PBMC, T-cells and cell lines upon AHR inhibition. Transcriptional analysis of the TCGA data using this signature demonstrated bladder cancer has the highest expressions of AHR and AHR signature genes, suggesting increased pathway activity in bladder cancer relative to other cancer types. Increased AHR signature gene expression was associated with worse overall survival in the TCGA bladder cancer cohort. Furthermore, RNAscope analysis of a tissue microarray containing 10 different tumor types revealed bladder cancer had one of the highest AHR transcript expression in the tumor compartment.Finally, nuclear localization of AHR protein was assessed as an indicator of pathway activation through the development of a novel IHC method. Extensive TMA screening of AHR protein in 15 different indications demonstrated bladder cancer as the tumor type with the highest prevalence of AHR nuclear expression.ConclusionsIn summary, we demonstrated high prevalence of nuclear AHR protein expression, AHR gene amplification and target gene expression in bladder cancer, suggesting aberrant AHR activation may play an important role in the progression of this tumor type. This study provides rationale for therapeutic targeting of AHR in bladder cancer patients. Ikena is currently evaluating the anti-tumor activity of IK-175 as a single agent and in combination with nivolumab in bladder cancer in a Phase 1a/1b clinical study (NCT04200963).ReferencesQuintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013 Aug 1;65(4):1148–61.Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014 Dec;14(12):801–14.Li, Haoxin et al. ‘Metabolomic adaptations and correlates of survival to immune checkpoint blockade.’ Nature Communications 2019 Sep 25;10:1–4346.
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- 2021
34. Abstract 2156: IK-930 is a novel TEAD inhibitor for the treatment of cancers harboring mutations in the Hippo signal transduction pathway
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Benjamin S. Amidon, Marta Sanchez-Martin, Wilmin Bartolini, Sakeena Syed, Karen McGovern, Lan Xu, Jeffrey Ecsedy, X. Michelle Zhang, Alex Constan, and Alfredo C. Castro
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Cancer Research ,Oncology - Abstract
The Hippo pathway is critical to cancer progression, biogenesis, metastasis, and therapeutic resistance. Many cancer indications have a high frequency of mutations in the Hippo pathway. These pro-tumor mutations lead to constitutive TEAD transcription factor activation, which drives gene expression involved in cell growth and pro-survival signaling. To target cancers harboring mutations in the Hippo pathway, we have discovered and are developing IK-930, a novel small molecule that selectively inhibits TEAD-dependent transcription by directly blocking autopalmitoylation. IK-930 prevents this critical post-translational modification that is required for the functional interaction of TEAD with two transcriptional activators, YAP1 and TAZ (WWTR1). IK-930 inhibits in vitro proliferation of Hippo pathway-deficient cancer cell lines, but not Hippo pathway wild type cells. In human mesothelioma xenografts, IK-930 downregulates TEAD-dependent genes. Daily oral administration of IK-930 resulted in antitumor activity in Hippo-dysregulated mesothelioma xenograft models. In EGFR or KRAS mutated tumors, IK-930 enhanced apoptosis and in vivo antitumor activity in combination with EGFR and MEK inhibitors, respectively. IK-930 is inactive in a broad panel of kinases, receptors, and transporters, furthering evidence of selectivity. Multispecies pharmacokinetic analysis and additional in vitro ADME properties imply favorable pharmacokinetic properties, with a low potential for clinically significant drug-drug interactions. To identify indications that may be dependent on TEAD we evaluated tumor types for the incidence of gene alterations in the Hippo pathway, as well as for YAP1 and TAZ activation. YAP1 and TAZ activation was assessed by evaluating nuclear protein expression in tumor tissue microarrays. These analyses showed high YAP1 nuclear expression in tumors with frequent genetic alterations, that may help guide the development of IK-930. Mesothelioma ranks top among tumor types evaluated, due to high prevalence of YAP1 nuclear expression and Hippo pathway genetic alterations, which are predominantly mutations and copy number alterations in the tumor suppressor NF2. In summary, Hippo pathway dysregulation has been implicated in the etiology of multiple tumor types, including mesothelioma. IK-930 is a selective and potent TEAD inhibitor expected to enter the clinic in early 2022. Our analysis pointed to tumors with genetic alterations driving aberrant Hippo signaling. IK-930 demonstrates efficacy in tumor models representing these indications and beneficial combination activity with other targeted therapies. Taken together, these data have informed the clinical development plan for IK-930. Citation Format: Benjamin S. Amidon, Marta Sanchez-Martin, Wilmin Bartolini, Sakeena Syed, Karen McGovern, Lan Xu, Jeffrey Ecsedy, X. Michelle Zhang, Alex Constan, Alfredo C. Castro. IK-930 is a novel TEAD inhibitor for the treatment of cancers harboring mutations in the Hippo signal transduction pathway [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 2156.
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- 2022
35. Abstract P216: IK-930 mediated TEAD inhibition decreases and delays tumor growth and enhances targeted apoptosis in lung and colon cancer xenografts when combined with MEK or EGFR inhibitors
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Benjamin Amidon, Hyejin Frosch, Sakeena Syed, Jill Cavanaugh, Chelsea Turcotte, Katie O'Callaghan, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, and Alfredo Castro
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Cancer Research ,Oncology - Abstract
The Hippo signaling cascade is an important pathway that plays a role in controlling cell proliferation and limiting apoptosis, but when dysregulated can contribute to cancer initiation, progression, and therapeutic resistance. The TEAD family of transcription factors, in conjunction with YAP1 or WWTR1/TAZ, are regulated by Hippo pathway signaling and modulate cell growth and proliferation. IK-930 inhibits the growth of TEAD-dependent human cancer xenografts. By exploiting synthetic lethality, the IK-930 single agent activity in TEAD-dependent cancers could expand to other indications upon inhibition of certain oncogenic pathways. Literature indicates that activation of TEAD-dependent transcription by other oncogenes such as mutant EGFR or KRAS mediates resistance to multiple targeted therapies. Additionally, genetic loss of YAP1 leads to increased apoptosis in osimertinib and trametinib treated mutant EGFR NSCLC cell lines (Kurppa, 2020). Here, we present preclinical data that support the use of IK-930 combination therapies to enhance anti-tumor impact of EGFR and MEK blockade in mutant EGFR NSCLC, or with MEK inhibition in several BRAF and KRAS mutant cancers. In these studies, EGFR and MEK1/2 were inhibited and IK-930 used to enhance anti-tumor activity in EGFR-mutant NSCLC cells. These NSCLC cell lines that are largely insensitive to osimertinib and/or trametinib, were observed to have a marked increase in apoptosis in vitro when treated with the combination of osimertinib, trametinib, and IK-930. We also observed increased nuclear accumulation of YAP1 after treatment of NSCLC cells with osimertinib alone, or osimertinib and trametinib and upregulation of TEAD-dependent transcription. In NSCLC xenografts, the combination of osimertinib and IK-930 prevented tumor growth and the triple combination of osimertinib, IK-930, and trametinib drove complete tumor regression and demonstrated greater efficacy than any single agent or double combination. A second set of studies tested the synthetic lethality effect of IK-930 and MEK inhibition in RAF- and RAS-mutant tumors. The combination of TEAD inhibition with MEK inhibition enhanced apoptosis in several KRAS-mutant NSCLC, PDAC, CRC KRAS-mutant cell lines and BRAF-mutant melanoma. The combination of trametinib and IK-930 prevented tumor growth in these xenografts, where either single agent had either modest or little activity. In summary, the Hippo pathway has been implicated in multiple tumor types, including those with resistance mechanisms to EGFR and MEK blockade. IK-930-mediated TEAD inhibition has been investigated to suppress the bypass pathway activation mechanism to the targeted therapies. These data demonstrated the potential to further expand single agent patient benefit by combining IK-930 with MEK and/or EGFR inhibition in a wide variety of cancer indications, including mutant EGFR-driven NSCLC and mutant KRAS colon, lung, and pancreatic cancers. Taken together, these data are informing the clinical development plan and combination strategy for IK-930, a novel TEAD inhibitor. Citation Format: Benjamin Amidon, Hyejin Frosch, Sakeena Syed, Jill Cavanaugh, Chelsea Turcotte, Katie O'Callaghan, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo Castro. IK-930 mediated TEAD inhibition decreases and delays tumor growth and enhances targeted apoptosis in lung and colon cancer xenografts when combined with MEK or EGFR inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P216.
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- 2021
36. Abstract P212: Systems biology-guided indication selection to inform the clinical development of a novel TEAD inhibitor
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Marta Sanchez-Martin, Sakeena Syed, Hyejin Frosch, Chelsea Turcotte, Benjamin Amidon, Karen McGovern, Jeffrey Ecsedy, and Michelle X. Zhang
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Cancer Research ,Oncology - Abstract
TEAD transcription factors are the final effectors of the Hippo pathway, a signaling cascade comprising multiple tumor suppressors (NF2, MST1/2, LATS1/2) critical in regulating proliferation, survival, and tissue homeostasis. Activated Hippo signaling suppresses TEAD-dependent transcription through the phosphorylation and degradation of TEAD co-activators YAP1 and TAZ in the cytosol. Consistently, genetic alterations in NF2, LATS1/2, YAP1 or TAZ lead to aberrant TEAD activation and are implicated in tumor initiation, progression, and therapeutic resistance in cancer. Here we present a unique systems biology approach integrating genomic, transcriptional and tissue-based analysis, to inform clinical development, indication and patient selection biomarkers for a novel inhibitor of TEAD being developed by Ikena. To identify cancers dependent on TEAD activity, tumor types were evaluated based on the cumulative incidence of genetic alterations in Hippo pathway genes including NF2, LATS1/2, YAP1, TAZ and others. This novel analysis pointed to a subset of tumors with high frequency of genetic alterations driving aberrant Hippo signaling including mesothelioma and NSCLC. This same subset was found to highly express a transcriptional signature indicative of YAP1/TEAD-dependency, confirming increased activation of TEAD transcription and pointing to the dependency of these tumors on TEAD activity. A proprietary IHC method was used to further assess YAP1/TAZ activation by assessing expression of either protein in the nucleus in multiple tumor tissue microarrays. Tissue-based analysis showed high YAP1 nuclear expression in tumors with frequent genetic alterations and high YAP1/TEAD-signature. Mesothelioma in particular ranks top among these indications, due to high frequency of NF2 deficiency and other Hippo pathway alterations. Consistently, TEAD inhibition showed single agent activity in two xenograft models of mesothelioma with NF2 deficiency and LAST1/2 alterations respectively. Hippo pathway alterations frequently co-occur with mutations in other oncogenic signaling pathways, e.g. EGFR. Importantly, YAP1/TAZ have been implicated in acquired resistance to targeted therapies in cancer including EGFR inhibitors in EGFR mutant tumors. Indeed, PDX models derived from patients who relapsed on osimertinib treatment showed high YAP1 protein expression in the nucleus. In addition, combination of TEAD and EGFR inhibitors induced apoptosis in vitro and greater antitumor activity than either drug as a single agent in vivo in EGFR mutant cancer models. In summary, the integration of multi-disciplinary bioinformatics, pharmacologic and tissue-based approaches enabled the identification of cancer types with high dependency on Hippo signaling. Moreover, these studies support the for monotherapy and combination of TEAD inhibitors with other targeted therapies including EGFR inhibitors. Altogether this unique approach has identified cancer patients who may benefit from TEAD inhibition and has informed the clinical development plan of a novel TEAD inhibitor. Citation Format: Marta Sanchez-Martin, Sakeena Syed, Hyejin Frosch, Chelsea Turcotte, Benjamin Amidon, Karen McGovern, Jeffrey Ecsedy, Michelle X. Zhang. Systems biology-guided indication selection to inform the clinical development of a novel TEAD inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P212.
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- 2021
37. Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells
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Lihong Wang, Ahmed M. Katsha, Janet Arras, Omar M. Omar, Abbes Belkhiri, Jeffrey Ecsedy, and Wael El-Rifai
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0301 basic medicine ,Cancer Research ,Cell Survival ,Cell ,Apoptosis ,Adenocarcinoma ,Biology ,Article ,Proto-Oncogene Proteins c-myc ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Humans ,Everolimus ,Protein Kinase Inhibitors ,Protein kinase B ,Aurora Kinase A ,Gastrointestinal Neoplasms ,Gene knockdown ,TOR Serine-Threonine Kinases ,EIF4E ,Protein phosphatase 2 ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Eukaryotic Initiation Factor-4E ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Alisertib ,Cancer research - Abstract
Purpose: Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus). Experimental Design: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo. Results: Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib. Conclusions: Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA–EIF4E–c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC. Clin Cancer Res; 23(14); 3756–68. ©2017 AACR.
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- 2017
38. Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation
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Pin-Yi Wang, Katherine E. Chaney, Brian Hutzen, Meghan Franczek, Timothy P. Cripe, Joe Conner, Brooke Nartker, Chun-Yu Chen, Tilat A. Rizvi, Les Sprague, Ami V. Patel, Nancy Ratner, Jeffrey Ecsedy, Keri A. Streby, and Mark A. Currier
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Cytotoxicity, Immunologic ,0301 basic medicine ,medicine.medical_specialty ,Blotting, Western ,Aurora A kinase ,Mice, Nude ,Antineoplastic Agents ,Malignant peripheral nerve sheath tumor ,Herpesvirus 1, Human ,Oncolytic herpes virus ,Mice ,Neuroblastoma ,03 medical and health sciences ,chemistry.chemical_compound ,MPNST ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Virotherapy ,Aurora Kinase A ,oHSV ,Oncolytic Virotherapy ,Hematology ,business.industry ,Azepines ,Flow Cytometry ,medicine.disease ,Combined Modality Therapy ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Virology ,Immunity, Innate ,3. Good health ,Oncolytic virus ,Pyrimidines ,030104 developmental biology ,Oncology ,chemistry ,Alisertib ,Cancer research ,Female ,business ,Neurilemmoma ,Priority Research Paper - Abstract
// Mark A. Currier 1 , Les Sprague 1 , Tilat A. Rizvi 2 , Brooke Nartker 1 , Chun-Yu Chen 1 , Pin-Yi Wang 1 , Brian J. Hutzen 1 , Meghan R. Franczek 1 , Ami V. Patel 2 , Katherine E. Chaney 2 , Keri A. Streby 1,3 , Jeffrey A. Ecsedy 4 , Joe Conner 5 , Nancy Ratner 2 and Timothy P. Cripe 1,3 1 Center for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio, USA 2 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center; Cincinnati, Ohio, USA 3 Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio, USA 4 Takeda Pharmaceuticals International Co, Cambridge, MA, USA 5 Virttu Biologics, Ltd, Biocity, Scotland, Newhouse, United Kingdom Correspondence to: Timothy P. Cripe, email: // Keywords : oHSV, Aurora A kinase, neuroblastoma, MPNST Received : November 07, 2016 Accepted : January 17, 2017 Published : February 02, 2017 Abstract Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma. We found the enhanced antitumor effect was due to multiple mechanisms that likely each contribute to the combination effect. First, oncolytic herpes virus increased the sensitivity of uninfected cells to alisertib cytotoxicity, a process we term virus-induced therapeutic adjuvant (VITA). Second, alisertib increased peak virus production and slowed virus clearance from tumors, both likely a consequence of it preventing virus-mediated increase of intratumoral NK cells. We also found that alisertib inhibited virus-induced accumulation of intratumoral myeloid derived suppressor cells, which normally are protumorigenic. Our data suggest that clinical trials of the combination of oHSV and alisertib are warranted in patients with neuroblastoma or MPNST.
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- 2017
39. Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines
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Yunguang Sun, Jifeng Sun, Ningbo Liu, Yong Antican Wang, Ping Wang, Xue Li, and Jeffrey Ecsedy
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0301 basic medicine ,Alisertib ,Lung Neoplasms ,Cell ,Mice, Nude ,Biology ,Radiation Tolerance ,Radiosensitivity ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Lung cancer ,Clonogenic assay ,Mitosis ,Aurora Kinase A ,Retrospective Studies ,lcsh:RC705-779 ,AURKA ,P53 ,MLN8237 ,Oncogene ,Cell growth ,Research ,lcsh:Diseases of the respiratory system ,Azepines ,medicine.disease ,Xenograft Model Antitumor Assays ,Pyrimidines ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Female - Abstract
Background In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC). Methods Here, we first analyzed AURKA expression in 63 NSCLC tumor samples by immunohistochemistry (IHC) and used an MTS assay to compare cell survival by targeting AURKA with MLN8237 (Alisertib) in H460 and HCC2429 (P53-competent), and H1299 (P53-deficient) cell lines. The radiosensitivity of MLN8237 was further evaluated by clonogenic assay. Finally, we examined the effect of combining radiation and AURKA inhibition in vivo with a xenograft model and explored the potential mechanism. Results We found that increased AURKA expression correlated with decreased time to progression and overall survival (p = 0.0447 and 0.0096, respectively). AURKA inhibition using 100 nM MLN8237 for 48 h decreases cell growth in a partially P53-dependent manner, and the survival rates of H460, HCC2429, and H1299 cells were 56, 50, and 77%, respectively. In addition, the survival of H1299 cells decreased 27% after ectopic restoration of P53 expression, and the radiotherapy enhancement was also influenced by P53 expression (DER H460 = 1.33; HCC2429 = 1.35; H1299 = 1.02). Furthermore, tumor growth of H460 was delayed significantly in a subcutaneous mouse model exposed to both MLN8237 and radiation. Conclusions Taken together, our results confirmed that the expression of AURKA correlated with decreased NSCLC patient survival, and it might be a promising inhibition target when combined with radiotherapy, especially for P53-competent lung cancer cells. Modulation of P53 function could provide a new option for reversing cell resistance to the AURKA inhibitor MLN8237, which deserves further investigation.
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- 2019
40. Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses
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Alberto Chiappori, Huifeng Niu, Hyunjin Shin, Eric Kong, C study investigators, Anne C. Chiang, Jeffrey Ecsedy, Miguel Williams, E. Jane Leonard, Margarita Majem, Zsuzsanna Mark, Christina S. Baik, Cong Li, Jaromír Roubec, Christos Chouaid, Krisztina Czebe, G. Speranza, Lauren Averett Byers, David R. Spigel, Tibor Csoszi, Brittany Bahamon, John Simmons, Sunita Badola, Chandra P. Belani, Edgardo S. Santos, Claudio Dansky Ullmann, Gyula Ostoros, Vitezslav Kolek, Manish R. Patel, Jesus Corral Jaime, Anil Abraham Joy, Lisa Bedford, Emily Sheldon-Waniga, Sian Jones, Kristiaan Nackaerts, Taofeek K. Owonikoko, and Matthew Bryant
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Alisertib ,Lung Neoplasms ,Paclitaxel ,Population ,Phases of clinical research ,Placebo ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Refractory ,Double-Blind Method ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,small-cell lung cancer ,Humans ,education ,Retrospective Studies ,education.field_of_study ,business.industry ,Hazard ratio ,SCLC ,Azepines ,Phase II ,030104 developmental biology ,Pyrimidines ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Aurora A kinase ,Neoplasm Recurrence, Local ,business ,Biomarkers - Abstract
INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:15 issue:2 pages:274-287 ispartof: location:AUSTRIA, Vienna status: published
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- 2019
41. Abstract 2474: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
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Sakeena Syed, Hyejin Frosch, Ben Amidon, Jill Cavanaugh, Jeffrey Ecsedy, Alfredo C. Castro, Karen McGovern, and Prabitha Natarajan
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Cancer Research ,Hippo signaling pathway ,Tumor microenvironment ,Oncology ,Downregulation and upregulation ,Palmitoylation ,Cell culture ,Cellular differentiation ,Cancer research ,Wild type ,Biology ,Gene knockout - Abstract
The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. The Hippo pathway is heavily mutated across many cancer indications through loss of function mutations in genes such as NF2. These pro-tumor mutations lead to the constitutive activation of the downstream transcriptional coactivators YAP and TAZ that drive the expression of many pro-survival and proliferation genes through the essential interaction with a TEAD protein family member. In addition, this unrestrained transcriptional program drives enhanced immune suppression in the tumor microenvironment. To target this oncogenic pathway we identified novel small molecule inhibitors that selectively bind to TEAD and disrupt their interaction with YAP and TAZ thereby downregulating YAP- and TAZ-dependent transcription. These inhibitors prevent TEAD palmitoylation which is essential for the interaction between YAP and TEAD. Furthermore, they inhibit in vitro proliferation of YAP-dependent (i.e. Hippo pathway-deficient cancer cell lines), but not Hippo pathway wild type cancer cell lines. An attraction of targeting this pathway is that many differentiated cells and tissues do not rely on the Hippo pathway, but notable exceptions have been demonstrated with tissue specific mouse knockouts in the bile duct and kidney podocytes. Importantly, our compounds did not affect survival of a differentiated mouse podocyte cell line or compromise mouse kidney histology. Subsequent experiments in vivo demonstrate these inhibitors downregulate YAP-dependent genes in human tumor xenografts after oral dosing. In addition, these inhibitors exhibit single agent tumor growth inhibition of human tumor xenografts in mice at well tolerated oral doses. These data demonstrate the potential for targeting this critical pathway in cancers with small molecules. Additional studies to identify tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress. Citation Format: Ben Amidon, Sakeena Syed, Jill Cavanaugh, Hyejin Frosch, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo C. Castro. Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2474.
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- 2020
42. Inhibition of AURKA Reduces Proliferation and Survival of Gastrointestinal Cancer Cells With Activated KRAS by Preventing Activation of RPS6KB1
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Zheng Chen, R.D. Beauchamp, Jialiang Wang, Albert C. Lockhart, Keeli B. Lewis, Safia N. Salaria, Kay Washington, Ahmed Gomaa, Wael El-Rifai, Lihong Wang-Bishop, and Jeffrey Ecsedy
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0301 basic medicine ,Mice, Nude ,medicine.disease_cause ,Sensitivity and Specificity ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Random Allocation ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gastrointestinal cancer ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Aurora Kinase A ,Cell Proliferation ,Gastrointestinal Neoplasms ,Hepatology ,Cell Death ,Kinase ,Cell growth ,Gastroenterology ,Azepines ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Pyrimidines ,chemistry ,Apoptosis ,Ribosomal protein s6 ,Alisertib ,Cancer research ,030211 gastroenterology & hepatology ,KRAS ,Signal Transduction - Abstract
BACKGROUND & AIMS: Activation of KRAS signaling and overexpression of the aurora kinase A (AURKA) are often detected in luminal gastrointestinal cancers. We investigated regulation of ribosomal protein S6 kinase B1 (RPS6KB1) by AURKA and the effects of alisertib, an AURKA inhibitor, in mice xenograft tumors grown from human gastrointestinal cancer cells with mutant, activated forms of KRAS. METHODS: We tested the effects of alisertib, or AURKA overexpression or knock down, in 10 upper gastrointestinal or colon cancer cell lines with KRAS mutations or amplifications using the CellTiter-Glo luminescence and clonogenic cell survival assays. We used the proximity ligation in situ assay to evaluate protein co-localization and immunoprecipitation to study protein interactions. Nude mice with xenograft tumors grown from HCT116, SNU-601, SW480, or SNU-1 cells were given oral alisertib (40 mg/kg, 5 times/week) for 4 weeks. Tumor samples were collected and analyzed by immunoblots and immunohistochemistry. Tissue microarrays from 151 paraffin-embedded human colon tumors, with adjacent normal and adenoma tissues, were analyzed by immunohistochemistry for levels of AURKA. RESULTS: Alisertib reduced proliferation and survival of cell lines tested. AURKA knockdown or inhibition with alisertib reduced levels of phosphorylated RPS6KB1 (at T389), and increased levels of proteins that induce apoptosis including BIM, cleaved PARP, and cleaved caspase 3. AURKA co-localized and interacted with RPS6KB1, mediating RPS6KB1 phosphorylation at T389. We detected AURKA-dependent phosphorylation of RPS6KB1 in cell lines with mutations in KRAS, but not in cells with wild-type Ras. Administration of alisertib to mice with xenograft tumors significantly reduce tumor volumes (P < .001). The agent reduced phosphorylation of RPS6KB1 and Ki-67, and increased levels of cleaved caspase 3, in tumor tissues. In analyses of tissue microarrays, we found significant overexpression of AURKA in gastrointestinal tumor tissues compared with non-tumor tissues (P=.0003). CONCLUSION: In studies of gastrointestinal cancer cell lines with activated KRAS, we found AURKA to phosphorylate RPS6KB1 to promote cell proliferation and survival and growth of xenograft tumors in mice. Agents that inhibit AURKA might slow growth of gastrointestinal tumors with activation of KRAS.
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- 2018
43. The Origins of Cancer
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Jeffrey Ecsedy and David J. Hunter
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Cancer ,medicine.disease ,business - Abstract
In order to evaluate risk factors and preventive behaviors in cancer, one must consider the complex and interwoven mechanisms that lead to the development of cancer. By understanding such mechanisms, an epidemiologist should be able to integrate biological plausibility into his or her research. An understanding of cancer biology is desirable because the natural history of cancer should be accounted for in epidemiologic research and often dictates conceptual and statistical approaches in different situations—for example, in studying factors that initiate rather than promote carcinogenesis. Even a basic understanding of carcinogenic mechanisms is helpful in assessing the plausibility of epidemiologic associations. The intent of this chapter is to convey basic molecular and cellular concepts essential to understanding cancer biology; it is not intended to give a complete overview of cancer biology.
- Published
- 2018
44. Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells
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Tyler A. Davis, Gregory D. Ayers, Yan Liu, Linda W. Horton, Mark C. Kelley, Ann Richmond, Anna E. Vilgelm, Jeffrey N. Johnston, Clinton F. Stewart, Jeffrey A. Sosman, Jessica Smith, Jeff S. Pawlikowski, Jeffrey Ecsedy, Oriana E. Hawkins, David C. Essaka, David C. Turner, Colt M. McClain, and Kevin P. Weller
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Senescence ,Cancer Research ,Melanoma, Experimental ,Mice, Nude ,Apoptosis ,Piperazines ,Article ,CCL5 ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Melanoma ,Protein Kinase Inhibitors ,Aurora Kinase A ,Cell Proliferation ,Mice, Inbred BALB C ,biology ,Cell growth ,Imidazoles ,Proto-Oncogene Proteins c-mdm2 ,Azepines ,medicine.disease ,Mice, Inbred C57BL ,Pyrimidines ,Oncology ,Cancer cell ,Cancer research ,biology.protein ,Mdm2 - Abstract
Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53. In the model studied, this effect is accompanied by proliferation arrest, mitochondrial depolarization, apoptosis, and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon Ccl5, Ccl1, and Cxcl9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to coadministered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof of concept for a combination treatment that leverages both senescence and immune surveillance to therapeutic ends. Cancer Res; 75(1); 181–93. ©2014 AACR.
- Published
- 2015
45. Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor
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Brittany Bahamon, Kimberly Perez, Jeffrey Ecsedy, Elizabeth Claire Dees, Robert L. Coleman, Angela DeMichele, Russell J. Schilder, Ursula A. Matulonis, Hadi Danaee, Dirk Huebner, Antoine Adenis, Kian Behbakht, Piotr Sawrycki, Bohuslav Melichar, Hyunjin Shin, Gerald Steven Falchook, Huifeng Niu, Jacob Zhang, Feng Gao, Millenium Pharmaceuticals, Molecular Carcinogenesis [Sutton], Institute of cancer research, Laboratoire de Mecanique des Fluides et d'Acoustique (LMFA), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine and Dentistry [Univ Palacký], Palacky University Olomouc, Jefferson (Philadelphia University + Thomas Jefferson University), Department of Mathematics [Berkeley], University of California [Berkeley], University of California-University of California, University of Colorado Cancer Center, University of Colorado [Denver], Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, University of Colorado School of Medicine, Colorado Prevention Center, University of Colorado Anschutz [Aurora], Abramson Cancer Center, University of Pennsylvania [Philadelphia], Lineberger Comprehensive Cancer Center (UNC Lineberger), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Dana-Farber Cancer Institute [Boston], University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Université de Lille-UNICANCER, and University of Pennsylvania
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0301 basic medicine ,Oncology ,Male ,lcsh:Medicine ,Bioinformatics ,Aurora A kinase inhibitor ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Genotype ,Precision Medicine ,Aurora Kinase A ,lcsh:R5-920 ,General Medicine ,Azepines ,Middle Aged ,Prognosis ,3. Good health ,SNP genotyping ,Predictive biomarker ,Treatment Outcome ,Paclitaxel ,030220 oncology & carcinogenesis ,Female ,lcsh:Medicine (General) ,Research Paper ,Adult ,medicine.medical_specialty ,Alisertib ,Aurora A kinase ,SNP ,Single-nucleotide polymorphism ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Disease-Free Survival ,03 medical and health sciences ,MESH: Azepines ,Disease free-survival ,Middle aged ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Allele ,Protein Kinase Inhibitors ,Alleles ,Aged ,Neoplasm Staging ,Correlative analysis ,lcsh:R ,030104 developmental biology ,Pyrimidines ,chemistry ,Commentary - Abstract
Background Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. Methods This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n = 62) or paclitaxel alone (n = 60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. Findings TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p, Highlights • Aurora A contains two single nucleotide polymorphisms (SNPs) at codons 31 and 57 that lead to functional amino acid changes • We evaluated the potential prognostic and predictive value of these SNPs and revealed the SNP at codon 57 may predict disease outcome and response to Alisertib in patients with solid tumors Alisertib, an investigational Aurora A kinase inhibitor, was evaluated in clinical trials and showed clinically meaningful benefit in patients with solid tumors. Two coding region single nucleotide polymorphisms (SNPs) in the Aurora A gene have been reported to be associated with functional changes of the protien. Here we assessed the prognostic and predictive value of Aurora A SNPs in a range of solid tumors. The results suggest that codon 57 SNP may predict disease outcome and response to alisertib in patients. These findings warrant further investigation and may ultimately provide a patient selection strategy for alisertib in certain cancers.
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- 2017
46. Patient Enrichment for Precision-Based Cancer Clinical Trials: Using Prospective Cohort Surveillance as an Approach to Improve Clinical Trials
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William S. Dalton, Jeffrey Ecsedy, Michael A. Caligiuri, and Daniel C. Sullivan
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0301 basic medicine ,medicine.medical_specialty ,MEDLINE ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Informed consent ,Neoplasms ,Commentaries ,medicine ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,Prospective Studies ,Registries ,Precision Medicine ,Prospective cohort study ,Intensive care medicine ,Pharmacology ,Clinical Trials as Topic ,Informed Consent ,business.industry ,Data Collection ,Patient Selection ,Cancer ,medicine.disease ,Precision medicine ,Clinical trial ,Observational Studies as Topic ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Cohort study ,Perspectives - Abstract
Technological advances have led to the identification of biomarkers and development of novel target-based therapies. While some novel therapies have improved patient outcomes, the prevalence and diversity of biomarkers and targets in patient populations, especially patients with cancer, has created a challenge for the design and performance of clinical trials. To address this challenge we propose that prospective cohort surveillance of patients may be a solution to promote clinical trial matching for patients in need.
- Published
- 2017
47. Translational Exposure–Efficacy Modeling to Optimize the Dose and Schedule of Taxanes Combined with the Investigational Aurora A Kinase Inhibitor MLN8237 (Alisertib)
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Marc L. Hyer, Andy Dorner, Arijit Chakravarty, Jerome T. Mettetal, Mark Manfredi, Jeffrey Ecsedy, Karuppiah Kannan, Xiaofei Zhou, Jessica Huck, Mengkun Zhang, Karthik Venkatakrishnan, Robert W. Kleinfield, Vaishali Shinde, and Wen Chyi Shyu
- Subjects
Cancer Research ,Paclitaxel ,Aurora A kinase ,Antineoplastic Agents ,Docetaxel ,Mice, SCID ,Pharmacology ,Drug Administration Schedule ,Translational Research, Biomedical ,Mice ,chemistry.chemical_compound ,Breast cancer ,Text mining ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Aurora Kinase A ,Mice, Inbred BALB C ,business.industry ,Cancer ,Azepines ,Neoplasms, Experimental ,medicine.disease ,Pyrimidines ,Oncology ,chemistry ,Area Under Curve ,Alisertib ,Female ,Taxoids ,business ,Neoplasm Transplantation ,medicine.drug - Abstract
Aurora A kinase orchestrates multiple key activities, allowing cells to transit successfully into and through mitosis. MLN8237 (alisertib) is a selective Aurora A inhibitor that is being evaluated as an anticancer agent in multiple solid tumors and heme-lymphatic malignancies. The antitumor activity of MLN8237 when combined with docetaxel or paclitaxel was evaluated in in vivo models of triple-negative breast cancer grown in immunocompromised mice. Additive and synergistic antitumor activity occurred at multiple doses of MLN8237 and taxanes. Moreover, significant tumor growth delay relative to the single agents was achieved after discontinuing treatment; notably, durable complete responses were observed in some mice. The tumor growth inhibition data generated with multiple dose levels of MLN8237 and paclitaxel were used to generate an exposure–efficacy model. Exposures of MLN8237 and paclitaxel achieved in patients were mapped onto the model after correcting for mouse-to-human variation in plasma protein binding and maximum tolerated exposures. This allowed rank ordering of various combination doses of MLN8237 and paclitaxel to predict which pair would lead to the greatest antitumor activity in clinical studies. The model predicted that 60 and 80 mg/m2 of paclitaxel (every week) in patients lead to similar levels of efficacy, consistent with clinical observations in some cancer indications. The model also supported using the highest dose of MLN8237 that can be achieved, regardless of whether it is combined with 60 or 80 mg/m2 of paciltaxel. The modeling approaches applied in these studies can be used to guide dose-schedule optimization for combination therapies using other therapeutic agents. Mol Cancer Ther; 13(9); 2170–83. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 2139][1] [1]: /lookup/volpage/13/2139?iss=9
- Published
- 2014
48. Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation
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Jeffrey Ecsedy, Nicole F. Neel, Vaishali Shinde, Channing J. Der, Jeran K. Stratford, Jen Jen Yeh, and Timothy D. Martin
- Subjects
Cancer Research ,endocrine system diseases ,Carcinogenesis ,medicine.medical_treatment ,Aurora A kinase ,Biology ,medicine.disease_cause ,Article ,Targeted therapy ,Proto-Oncogene Proteins p21(ras) ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Pancreatic cancer ,Biomarkers, Tumor ,medicine ,Humans ,Phosphorylation ,Aurora Kinase A ,Azepines ,medicine.disease ,digestive system diseases ,RALA ,Ki-67 Antigen ,Pyrimidines ,Oncology ,Ral GTP-Binding Proteins ,Mutation ,ras Proteins ,Cancer research ,ral GTP-Binding Proteins ,KRAS ,Carcinoma, Pancreatic Ductal - Abstract
The high prevalence of KRAS mutations and importance of the RalGEF–Ral pathway downstream of activated K-ras in pancreatic ductal adenocarcinoma (PDAC) emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought to evaluate the AAK-selective inhibitor MLN8237 as a potential indirect anti-RalA–targeted therapy for PDAC. We used a site-specific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatment may be effective for a subset of patients with PDAC independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment. Mol Cancer Ther; 13(1); 122–33. ©2013 AACR.
- Published
- 2014
49. The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells In Vitro and In Vivo
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Zhongfa Zhang, Yvonne Parker, Daniel J Lindner, Donna E. Hansel, Maria Carmen Mir, Jeffrey Ecsedy, Robert Dreicer, Kamini Singh, Alexandru Almasan, Bin Tean Teh, and Ning Zhou
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Cell cycle checkpoint ,Paclitaxel ,Cell Survival ,Aurora inhibitor ,Gene Expression ,Apoptosis ,Protein Serine-Threonine Kinases ,Biology ,urologic and male genital diseases ,Deoxycytidine ,Article ,Mice ,Aurora kinase ,Aurora Kinases ,Cell Line, Tumor ,medicine ,Animals ,Cluster Analysis ,Humans ,Neoplasm Invasiveness ,Aurora Kinase A ,Bladder cancer ,Gene Expression Profiling ,Cell Cycle ,Cancer ,Drug Synergism ,Azepines ,Cell Cycle Checkpoints ,Aneuploidy ,Mitotic spindle checkpoint ,medicine.disease ,Xenograft Model Antitumor Assays ,Gemcitabine ,Tumor Burden ,Spindle apparatus ,Phenotype ,Pyrimidines ,Urinary Bladder Neoplasms ,Oncology ,Cancer research ,M Phase Cell Cycle Checkpoints - Abstract
Purpose: Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target. Experimental Design: Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model. Results: A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells. Conclusions: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer. Clin Cancer Res; 19(7); 1717–28. ©2013 AACR.
- Published
- 2013
50. Enhancing value of clinical pharmacodynamics in oncology drug development: An alliance between quantitative pharmacology and translational science
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Karthik Venkatakrishnan and Jeffrey Ecsedy
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Value (ethics) ,Biomedical Research ,Antineoplastic Agents ,Pharmacology ,030226 pharmacology & pharmacy ,Translational Research, Biomedical ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Medicine ,Humans ,Pharmacology (medical) ,Clinical Trials as Topic ,business.industry ,Translational medicine ,Pharmacometrics ,Audit trail ,Drug development ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Drug Design ,Oncology drug ,Engineering ethics ,Translational science ,business - Abstract
Clinical pharmacodynamic evaluation is a key component of the “pharmacologic audit trail” in oncology drug development. We posit that its value can and should be greatly enhanced via application of a robust quantitative pharmacology framework informed by biologically mechanistic considerations. Herein, we illustrate examples of intersectional blindspots across the disciplines of quantitative pharmacology and translational science and offer a roadmap aimed at enhancing the caliber of clinical pharmacodynamic research in the development of oncology therapeutics. This article is protected by copyright. All rights reserved.
- Published
- 2016
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