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32 results on '"Naomi Laing"'

1. Supplementary Materials and Methods and Supplementary Figures 1 through 9 from Novel Neutralizing Hedgehog Antibody MEDI-5304 Exhibits Antitumor Activity by Inhibiting Paracrine Hedgehog Signaling

Author

Vahe Bedian, David C. Blakey, Diane M. Simeone, Robert E. Hollingsworth, Christopher Frantz, Meina Liang, Elaine Hurt, David W. Jenkins, Naomi Laing, Jelena Jovanović, Jaspal S. Kang, Lidong Wang, Matthew A. Belmonte, Mark J. Hynes, Jon W. Chesebrough, Sanjoo Jalla, Axel Hernandez, Anne Marie Mazzola, Jerold J. Jordan, Kristen A. McEachern, Youzhen Wang, and Neil R. Michaud

Abstract

Supplementary Materials and Methods; Supplementary Figure S1. Binding kinetics of hedgehog antibodies to human and mouse hedgehog proteins using surface plasmon resonance. Supplementary Figure S2. Hedgehog ligands stimulate mGLI1 reporter activity and osteoblast differentiation in a dose-dependent manner. Supplementary Figure S3. Selective inhibition of mGLI1 or mPTC1 induction in C3H10T1/2 cells by hedgehog antibodies. Supplementary Figure S4. MEDI-5304 inhibits GLI1 expression in Colo205 xenograft stromal cells but not tumor cells. Supplementary Figure S5. Hedgehog pathway component RNA expression in primary pancreatic tumor explant model P479 and effects of MEDI-5304 on tumorspheres derived from pancreatic explant model 947. Supplementary Figure S6. Pharmacokinetics of MEDI-5304 in rats. Supplementary Figure S7. Exploratory toxicology of MEDI-5304 in rats. Supplementary Figure S8. Pharmacokinetics of MEDI-5304 from preliminary toxicology study in cynomolgus monkeys. Supplementary Figure S9. Pharmacodynamics of MEDI-5304 in cynomolgus monkeys.

Published
2023

2. Supplementary material and tables from A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Author

Kathleen Moore, Eric H. Rubin, Shelonitda Rose, Jingjun Qiu, Ji Liu, Mark A. Lee, Tomoko Freshwater, Michael Tracy, Naomi Laing, Robert M. Wenham, Johanne I. Weberpals, Denise Uyar, Diane Provencher, Frederik Marmé, Marcia Hall, Eva-Maria Grischke, Maria Estevez-Diz, and Amit M. Oza

Abstract

Supplementary material and tables

Published
2023

5. Supplementary Figure 2 from A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Author

Kathleen Moore, Eric H. Rubin, Shelonitda Rose, Jingjun Qiu, Ji Liu, Mark A. Lee, Tomoko Freshwater, Michael Tracy, Naomi Laing, Robert M. Wenham, Johanne I. Weberpals, Denise Uyar, Diane Provencher, Frederik Marmé, Marcia Hall, Eva-Maria Grischke, Maria Estevez-Diz, and Amit M. Oza

Abstract

Supplementary Figure 2

Published
2023

7. Data from A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Author

Kathleen Moore, Eric H. Rubin, Shelonitda Rose, Jingjun Qiu, Ji Liu, Mark A. Lee, Tomoko Freshwater, Michael Tracy, Naomi Laing, Robert M. Wenham, Johanne I. Weberpals, Denise Uyar, Diane Provencher, Frederik Marmé, Marcia Hall, Eva-Maria Grischke, Maria Estevez-Diz, and Amit M. Oza

Abstract

Purpose:Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer.Patients and Methods:Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.Results:A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).Conclusions:Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Published
2023

9. Supplementary Figure 3 from A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Author

Kathleen Moore, Eric H. Rubin, Shelonitda Rose, Jingjun Qiu, Ji Liu, Mark A. Lee, Tomoko Freshwater, Michael Tracy, Naomi Laing, Robert M. Wenham, Johanne I. Weberpals, Denise Uyar, Diane Provencher, Frederik Marmé, Marcia Hall, Eva-Maria Grischke, Maria Estevez-Diz, and Amit M. Oza

Abstract

Supplementary Figure 3

Published
2023

10. Data from TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor–Positive Breast Cancer

Author

Luca Malorni, Angelo Di Leo, Myles Brown, Eric P. Winer, Naomi Laing, Martina Bonechi, Cristina Guarducci, Jonas De Tribolet-Hardy, Jin Zhao, Chiara Biagioni, Ilenia Migliaccio, William T. Barry, and Rinath Jeselsohn

Abstract

Purpose: Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor–positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer.Experimental Design: Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant.Results: Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC.Conclusions: We identified biologic pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755–64. ©2016 AACR.

Published
2023

12. Supplementary Figure 1 from A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Author

Kathleen Moore, Eric H. Rubin, Shelonitda Rose, Jingjun Qiu, Ji Liu, Mark A. Lee, Tomoko Freshwater, Michael Tracy, Naomi Laing, Robert M. Wenham, Johanne I. Weberpals, Denise Uyar, Diane Provencher, Frederik Marmé, Marcia Hall, Eva-Maria Grischke, Maria Estevez-Diz, and Amit M. Oza

Abstract

Supplementary Figure 1

Published
2023

14. A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Author

Shelonitda Rose, Eric H. Rubin, Kathleen N. Moore, Denise Uyar, Amit M. Oza, Maria D P Estevez-Diz, Marcia Hall, Frederik Marmé, Eva-Maria Grischke, Tomoko Freshwater, Naomi Laing, Robert M. Wenham, Michael Tracy, Ji Liu, Diane Provencher, Mark A Lee, Johanne I Weberpals, and Jingjun Qiu

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Placebo, medicine.disease, Carboplatin, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Paclitaxel, chemistry, Tolerability, Maintenance therapy, 030220 oncology & carcinogenesis, Internal medicine, medicine, Biomarker (medicine), Ovarian cancer, business
Abstract

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer. Patients and Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib. Results: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%). Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Published
2020

15. Ramucirumab and durvalumab for previously treated, advanced non–small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ)

Author

Laetitia Dahan, Victor Moreno, Yung-Jue Bang, Laura W. Goff, Zev A. Wainberg, Filippo de Braud, Naomi Laing, Gu Mi, Talia Golan, Chia-Chi Lin, Joana M Oliveira, Heather Wasserstrom, Ravit Geva, Siqing Fu, Keunchil Park, and Martin Reck

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, Durvalumab, Esophageal Neoplasms, Antineoplastic Agents, Adenocarcinoma, Antibodies, Monoclonal, Humanized, Gastroenterology, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, Carcinoma, Non-Small-Cell Lung, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lung cancer, Adverse effect, Aged, Aged, 80 and over, Hepatitis, business.industry, Liver Neoplasms, Antibodies, Monoclonal, Middle Aged, medicine.disease, digestive system diseases, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cohort, Female, business
Abstract

Background Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti–PD-L1 IgG1, in previously treated patients with advanced non–small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC). Patients and methods A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0–1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC). Results Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment–related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression. Conclusion Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression.

Published
2020

16. A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive

Author

Amit M, Oza, Maria, Estevez-Diz, Eva-Maria, Grischke, Marcia, Hall, Frederik, Marmé, Diane, Provencher, Denise, Uyar, Johanne I, Weberpals, Robert M, Wenham, Naomi, Laing, Michael, Tracy, Tomoko, Freshwater, Mark A, Lee, Ji, Liu, Jingjun, Qiu, Shelonitda, Rose, Eric H, Rubin, and Kathleen, Moore

Subjects
Adult, Aged, 80 and over, Ovarian Neoplasms, Paclitaxel, Pyrimidinones, Middle Aged, Progression-Free Survival, Carboplatin, Double-Blind Method, Antineoplastic Combined Chemotherapy Protocols, Mutation, Biomarkers, Tumor, Humans, Pyrazoles, Female, Tumor Suppressor Protein p53, Response Evaluation Criteria in Solid Tumors, Aged
Abstract

Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizesFollowing safety run-in, this double-blind phase II trial (NCT01357161) randomized women withA total of 121 patients were randomized to adavosertib (A+C;Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Published
2020

17. Defining actionable mutations for oncology therapeutic development

Author

Brian Dougherty, Francisco Cruzalegui, Naomi Laing, J. Carl Barrett, Robert McEwen, Jonathan R. Dry, Darren Hodgson, T. Hedley Carr, Zara Ghazoui, Zhongwu Lai, Simon J. Hollingsworth, and Justin Johnson

Subjects
0301 basic medicine, Lung Neoplasms, Genomic profiling, General Mathematics, medicine.medical_treatment, Multiple hypotheses, Patient subgroups, MEDLINE, Pyrimidinones, Biology, Bioinformatics, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, medicine, Humans, In patient, Rapid testing, Applied Mathematics, Clinical trial, Pyrimidines, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Pyrazoles, Tumor Suppressor Protein p53
Abstract

Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.

Published
2016

18. Smac mimetic with TNF-α targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields

Author

Naomi Laing, Goodwin G. Jinesh, and Ashish M. Kamat

Subjects
0301 basic medicine, Mitochondrion, Cycloheximide, Biology, medicine.disease_cause, Biochemistry, Fas ligand, Mitochondrial Proteins, 03 medical and health sciences, chemistry.chemical_compound, Transformation, Genetic, Proto-Oncogene Proteins c-pim-1, Biomimetic Materials, Cell Line, Tumor, medicine, Humans, Protein Isoforms, Molecular Biology, chemistry.chemical_classification, Reactive oxygen species, Tumor Necrosis Factor-alpha, Kinase, Intracellular Signaling Peptides and Proteins, Cell Biology, Cell biology, 030104 developmental biology, chemistry, Cancer cell, Phosphorylation, Apoptosis Regulatory Proteins, Reactive Oxygen Species, Carcinogenesis
Abstract

Cancer cells are capable of sphere formation (transformation) through reactive oxygen species (ROS) and glycolysis shift. Transformation is linked to tumorigenesis and therapy resistance, hence targeting regulators of ROS and glycolysis is important for cancer therapeutic candidates. Here, we demonstrate that Smac mimetic AZ58 in combination with tumour necrosis factor-α (TNF-α) was able to inhibit the production of ROS, inhibit glycolysis through Pim-1 kinase-mediated Ser-112 phosphorylation of BAD, and increase depolarization of mitochondria. We also identified mitochondrial isoforms of Pim-1 kinase that were targeted for degradation by AZ58 in combination with TNF-α or AZ58 in combination with Fas ligand (FasL) plus cycloheximide (CHX) through caspase-3 to block transformation. Our study demonstrates that Smac mimetic in combination with TNF-α is an ideal candidate to target Pim-1 expression, inhibit ROS production and to block transformation from blebbishields.

Published
2015

19. Ramucirumab (Ram) and durvalumab (Durva) treatment of metastatic non-small cell lung cancer (NSCLC), gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, and hepatocellular carcinoma (HCC) following progression on systemic treatment(s)

Author

Chia-Chi Lin, Gu Mi, Laetitia Dahan, Martin Reck, Yung-Jue Bang, Victor Moreno, Laura W. Goff, Talia Golan, Siqing Fu, Ravit Geva, Heather Wasserstrom, and Naomi Laing

Subjects
Cancer Research, Durvalumab, biology, business.industry, VEGF receptors, non-small cell lung cancer (NSCLC), Gastroesophageal Junction, medicine.disease, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cancer research, biology.protein, Medicine, Adenocarcinoma, business, 030215 immunology
Abstract

2528 Background: A Phase 1b study (NCT02572687) was conducted to examine the combined effects of Ram (anti VEGFR2) and Durva (anti PD-L1). Methods: Patients (pts) with previously-treated, advanced NSCLC (Cohort [CH] A), G/GEJ adenocarcinoma (CH B), HCC (CH C), ECOG PS 0-1, and no prior Ram or IO therapy, received Ram (10 mg/kg) + Durva (1125 mg) Q3W (CH A) or Ram (8 mg/kg) + Durva (750 mg) Q2W (CH B, C). Primary objective was to assess safety; efficacy was also examined. PD-L1 expression of tumor cells (TC) +/- immune cells (IC) in pretreatment tumor biopsies were assessed using SP263 immunohistochemistry. “High” PD-L1 is ≥25% TC for NSCLC and ≥25% TC or IC for G/GEJ, HCC. Results: CH A, B and C enrolled pts with ECOG PS 1 (%) of 43, 66, 68; and average of 2, 2, 1 prior regimens, respectively. The most common grade 3/4 treatment-emergent adverse events (AE) are hypertension (HTN) (14.3, 17.2, 17.9%), anemia (3.6, 24.1, 21.4%), and fatigue (10.7, 10.3, 10.7%). Grade 3/4 AEs of special interest ( > 5% total pts) for Ram: HTN, bleeding events (3.6, 10.3, 10.7%), Venous thromboembolic events (0, 10.3, 7.1%); for Durva: increase in lipase (10.7, 3.4, 10.6%) and AST (3.6, 3.4, 17.9 %). Data from CH B,C suggest a trend toward increased efficacy in pts with high PD-L1 expressing tumors. Conclusions: Ram + Durva generated no unexpected toxicities and demonstrated antitumor activity. Results in pts with high PD-L1 HCC and G/GEJ cancer warrant further evaluation. Clinical trial information: NCT02572687. [Table: see text]

Published
2019

20. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016

21. TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer

Author

Ilenia Migliaccio, Jonas de Tribolet-Hardy, Luca Malorni, Chiara Biagioni, William T. Barry, Myles Brown, Angelo Di Leo, Naomi Laing, Martina Bonechi, Eric P. Winer, Rinath Jeselsohn, Christina Guarducci, and Jin Zhao

Subjects
0301 basic medicine, Hepatocyte Nuclear Factor 3-alpha, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Estrogen receptor, Breast Neoplasms, Disease-Free Survival, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Double-Blind Method, Internal medicine, medicine, Humans, Fulvestrant, Epidermal Growth Factor, Estradiol, business.industry, Gene Expression Profiling, Cancer, Middle Aged, medicine.disease, Metastatic breast cancer, Primary tumor, Gene expression profiling, Postmenopause, 030104 developmental biology, Endocrinology, Oncology, Receptors, Estrogen, Transcription Factor AP-2, 030220 oncology & carcinogenesis, Cancer research, Female, FOXA1, business, Transcriptome, medicine.drug, Signal Transduction
Abstract

Purpose: Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor–positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer. Experimental Design: Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant. Results: Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC. Conclusions: We identified biologic pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755–64. ©2016 AACR.

Published
2016

22. A multicentre phase II study of AZD1775 plus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer

Author

Jayanthi S. Lea, Erika Hamilton, Karen Cadoo, H. A. Burris, Naomi Laing, Denise Uyar, Suzanne F. Jones, Setsuko K. Chambers, Ganesh Mugundu, Sharad A. Ghamande, Donald K Strickland, David R. Spigel, D. Spitz, Panagiotis A. Konstantinopoulos, Gottfried E. Konecny, L.M. Chen, Kathleen N. Moore, and Amit M. Oza

Subjects
0301 basic medicine, Oncology, Chemotherapy, medicine.medical_specialty, Peritoneal cancer, business.industry, medicine.medical_treatment, Phases of clinical research, Hematology, Gastroenterology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Internal medicine, medicine, In patient, business, Platinum resistant, Fallopian tube
Published
2017

23. Abstract CT177: Epacadostat plus durvalumab in patients with advanced solid tumors: preliminary results of the ongoing, open-label, phase I/II ECHO-203 study

Author

Manish Patel, John Nemunaitis, Adi Diab, Aung Naing, John D. Powderly, Gongfu Zhou, Gerald Steven Falchook, Jose Lutzky, Naomi Laing, Judy S. Wang, Michelle Niewood, Benjamin C. Creelan, and Xiaohua Gong

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, education.field_of_study, Durvalumab, business.industry, Nausea, Population, Peripheral edema, Cmax, Cancer, medicine.disease, Rash, Gastroenterology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Internal medicine, medicine, medicine.symptom, business, education, Adverse effect
Abstract

Introduction: Epacadostat, a potent and highly selective oral inhibitor of the indoleamine 2,3- dioxygenase 1 (IDO1) enzyme, plus durvalumab, an anti-PD-L1 antibody, is being studied in patients with advanced solid tumors (NCT02318277). Phase 1 preliminary safety data for the overall population and efficacy data for patients with advanced pancreatic cancer (PC) are reported as of 29 Oct 2017 data cutoff.Methods: Adult patients with PC, melanoma, NSCLC, or SCCHN were enrolled in the 3+3 dose-escalation phase 1. Prior treatment with immune checkpoint inhibitors (in unapproved indications) or IDO inhibitors was not allowed. Patients received epacadostat (25, 50, 75, 100, or 300 mg twice daily [BID]) plus durvalumab (3 or 10 mg/kg every 2 weeks [Q2W]). Safety was assessed in patients receiving ≥1 treatment dose. Response was measured in evaluable patients (≥1 postbaseline scan or discontinued/died before the first scan) per modified RECIST v1.1.Results: Thirty-four patients were enrolled in phase 1. Median age (range) was 68 (46-84) years; most patients were male (62%) and had an ECOG PS of 1 (82%). There was 1 dose-limiting toxicity (grade 3 rash requiring systemic steroids; epacadostat 300 mg BID plus durvalumab 10 mg/kg Q2W) during the 42-day observation period. The most common (≥10%) treatment-related adverse events (TRAEs) were fatigue (32%), pruritus (15%), diarrhea, nausea, and rash (12% each). Grade ≥3 TRAEs occurring in >1 patient included fatigue and rash (n=3 [9%] each). Five patients (15%) discontinued because of TRAEs (grade 1 pneumonitis, grade 2 diarrhea, grade 2 subarachnoid hemorrhage, grade 2 peripheral edema, and grade 3 dyspnea). There were no TRAEs leading to death.Fifteen patients with PC were enrolled across multiple dose levels. Median age (range) was 66 (46-72) years, 67% had liver metastases, and 87% had an ECOG PS of 1. Fourteen patients had received ≥1 prior therapy. PD-L1 expression test results were available in 7/15 patients: 2 had detectable (≥1%) staining of tumor cells; 5 did not. No responses were observed among patients with PC; the disease control rate was 27% (4 SD) per RECIST v1.1 (1 of 4 patients with SD discontinued treatment because of clinical progression). The median duration of disease control was 156 days (95% CI, 91-219).Epacadostat exposure was consistent with previous reports, except in patients with PC where somewhat lower peak exposures (Cmax) were observed.Conclusions: Epacadostat plus durvalumab was generally well tolerated in patients with advanced cancers; the safety profile was consistent with previous reports of durvalumab and epacadostat as monotherapies. In unselected patients with PC, no objective responses were observed; a phase 2 expansion for PC was not conducted. Epacadostat 100 and 300 mg BID are being evaluated in the ongoing phase 2 expansions, including patients with NSCLC, SCCHN, and urothelial carcinoma. Citation Format: Aung Naing, John D. Powderly, Gerald Falchook, Benjamin Creelan, John Nemunaitis, Jose Lutzky, Adi Diab, Judy S. Wang, Naomi Laing, Michelle Niewood, Xiaohua Gong, Gongfu Zhou, Manish Patel. Epacadostat plus durvalumab in patients with advanced solid tumors: preliminary results of the ongoing, open-label, phase I/II ECHO-203 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT177.

Published
2018

24. Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D)

Author

Yoon-Koo Kang, Siqing Fu, Gu Mi, Heather Wasserstrom, Naomi Laing, Chia-Chi Lin, Talia Golan, Yung-Jue Bang, Zev A. Wainberg, Jin Jin, Samuel McNeely, and Laura W. Goff

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Durvalumab, business.industry, Angiogenesis, medicine.medical_treatment, Locally advanced, Immunosuppression, medicine.disease, Gastroesophageal Junction, Ramucirumab, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Adenocarcinoma, In patient, business
Abstract

92 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This global phase 1 trial evaluates the combination of R (anti-VEGFR2) and D (anti-PD-L1) in pts with G/GEJ by simultaneously targeting these two processes. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02572687) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on 1 or 2 lines of systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 expression was assessed using the SP-263 IHC; MSI status was determined using PCR. Enrolled pts received R (8 mg/kg IV) and D (750 mg IV) every two weeks on a 28-day cycle. Primary objective was to assess safety and tolerability of R+D; preliminary efficacy was also examined. Results: As of 26-May-2017, 29 G/GEJ adenocarcinoma pts were treated. The median age was 55 y; 69% were male; 66% had ECOG PS of 1; 48% had PD-L1 ≥25% expression in tumor or immune cells, 3.5% were MSI-high; and 72% received study treatment as second line for advanced disease. Median duration of treatment was 2.5 mo for R and 3.0 mo for D. Treatment-emergent adverse events (TEAEs) occurred in 29 (100%) pts and 21 (72%) pts experienced grade 3/4 TEAEs, while treatment-related AEs (TRAE) occurred in 24 (83%) pts; none resulted in treatment discontinuation. Ten (35%) pts had grade 3 TRAEs, and no grade 4 or 5. All grade TRAEs occurring in ≥10% of pts were hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%) and decreased appetite (10%). Five pts (17%) reported a serious adverse event related to study treatment. Preliminary efficacy data (RECIST v1.1) showed 5 of 29 pts (17%) achieved a confirmed PR. Only 1 responding pt was MSI high. The overall response rate for pts with PD-L1 ≥25% was 36%. Median PFS was 2.6 mo (95% CI, 1.45 to 6.28). As of data cut-off, 6 pts (21%) remain on treatment. Conclusions: R+D generated no unexpected toxicity, and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02572687.

Published
2018

25. A multi-cohort phase 1 study of ramucirumab plus durvalumab: Preliminary safety and clinical activity in patients with locally advanced and unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma

Author

Siqing Fu, Gu Mi, Talia Golan, Maria Karasarides, Naomi Laing, Heather Wasserstrom, Yung-Jue Bang, and Chia-Chi Lin

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Durvalumab, business.industry, Locally advanced, Hematology, Gastroesophageal Junction Adenocarcinoma, Gastroenterology, Ramucirumab, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Cohort, medicine, In patient, business
Published
2017

26. Phase II studies of AZD1775, a WEE1 kinase inhibitor, and chemotherapy in non-small-cell lung cancer (NSCLC): Lead-in cohort results

Author

J.T. Beck, Suzanne F. Jones, Carol Greenlees, F.Y. Tsai, Naomi Laing, C.D. Webb, Tim French, Ganesh Mugundu, Melissa Lynne Johnson, David R. Spigel, A. Sadiq, Carl Cook, Dawn Michelle Stults, Shaker R. Dakhil, H. A. Burris, Sreedevi K. Menon, and Donald K Strickland

Subjects
Oncology, Chemotherapy, medicine.medical_specialty, biology, Kinase, business.industry, medicine.medical_treatment, non-small cell lung cancer (NSCLC), Hematology, medicine.disease, Wee1, Internal medicine, Cohort, medicine, biology.protein, Cancer research, Lead (electronics), business
Published
2016

27. Abstract 337: Genetic analysis of tumors from a phase II trial evaluating AZD1775, carboplatin and paclitaxel in patients with TP53-mutant ovarian cancer

Author

J. Carl Barrett, Amit M. Oza, David Lawrence, Naomi Laing, Mark J. O'Connor, and Zhongwu Lai

Subjects
Oncology, Cancer Research, Chemotherapy, medicine.medical_specialty, business.industry, medicine.medical_treatment, BRCA mutation, Cancer, Subgroup analysis, Bioinformatics, medicine.disease, Carboplatin, law.invention, chemistry.chemical_compound, Randomized controlled trial, chemistry, law, Internal medicine, medicine, Kinase activity, business, Ovarian cancer
Abstract

Background: AZD1775 (formerly MK-1775) is a selective inhibitor of WEE1 kinase, which has been shown to sensitize TP53-mutant cancer cells to genotoxic agents such as platinum-based chemotherapies. Mutation of TP53 abrogates the G1/S checkpoint in cells, which may enhance their dependency on the G2/M checkpoint and WEE1 kinase activity for control of the cell cycle and effective repair of DNA damage. The results from a randomized Phase II trial (NCT01357161) evaluating the effects of adding AZD1775 to carboplatin and paclitaxel in patients with TP53-mutant ovarian cancer showed an increase in progression-free survival (PFS) for the AZD1775 arm versus placebo (enhanced RECIST: median PFS 34.14 vs 31.86 weeks; HR = 0.63, 80% CI: 0.45-0.89, P = 0.080; RECIST 1.1: median PFS 42.86 vs 34.86 weeks; HR = 0.55, 80% CI 0.39-0.79, P = 0.030; Oza et al, ASCO 2015). We investigated whether particular genetic factors were associated with an increased response to the combination of AZD1775 and chemotherapy in this trial. Methods: A retrospective analysis was performed to determine whether any specific subtype of TP53 alteration was associated with a greater response to the AZD1775 combination compared with placebo. In addition, next-generation sequencing (NGS) was performed on archival tumors from a subset of patients who provided consent in an effort to identify additional genetic alterations that may predict increased clinical benefit following the addition of AZD1775 to chemotherapy. Results: TP53 data were available for 136 patients (15 patients from an initial open-label safety run-in and 121 patients from the randomized trial) and 133 patients were evaluable for response. Fifty-five patients provided additional consent for NGS of tumor samples. The genetic aberrations observed in the NGS subset of tumors from this trial were heterogeneous, and the total mutational load in cancer-related genes was also variable across tumors. Although the small number of patients with a tumor BRCA mutation limited the statistical power of the comparison between randomized arms, the median PFS was longer in those patients treated with AZD1775 (53.86 weeks, 95% CI 24.43-66.57) versus placebo (45.86 weeks, 95% CI 35.71-55.86) in this BRCA-mutated subgroup. TP53 subgroup analyses showed a similar benefit for patients with missense mutations compared to those with splice site, nonsense and frameshift TP53 mutations. The heterogeneity of the G1/S checkpoint gene aberrations limited the statistical power of the subgroup analysis, but specific genes that warrant further investigation were identified. Conclusions: These results highlight a number of potential candidate genes for increased response to AZD1775 and chemotherapy compared with chemotherapy alone. Citation Format: Naomi Laing, Zhongwu Lai, J. Carl Barrett, Mark J. O’Connor, Amit M. Oza, David Lawrence. Genetic analysis of tumors from a phase II trial evaluating AZD1775, carboplatin and paclitaxel in patients with TP53-mutant ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 337.

Published
2016

28. A Phase Ib, Open-Label, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of AZD1775 Monotherapy in Patients with Advanced Solid Tumors: Expansion Cohorts

Author

J. Thaddeus Beck, Kathleen N. Moore, Melissa Lynne Johnson, Naomi Laing, David R. Spigel, Carl Cook, Todd M. Bauer, Philip J. Jewsbury, Dawn Michelle Stults, Howard A. Burris, Jeffrey R. Infante, Ganesh Mugundu, Mark J. O'Connor, Tim French, J. Carl Barrett, Carol Greenlees, Andrew J. Pierce, and Suzanne F. Jones

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, DNA repair, DNA damage, Cell cycle, medicine.disease, 03 medical and health sciences, Wee1, 030104 developmental biology, 0302 clinical medicine, Breast cancer, Refractory, Pharmacokinetics, 030220 oncology & carcinogenesis, Internal medicine, medicine, biology.protein, business, Ovarian cancer
Abstract

TPS2608Background: Many cancers are associated with DNA repair and cell cycle mutations that result in G1/S checkpoint deficiencies and high levels of endogenous damage and replication stress. This can lead to dependence on WEE1 kinase, which provides an important G2/M checkpoint, allowing repair of DNA damage prior to mitosis. AZD1775 is a highly selective, small-molecule WEE1 inhibitor being developed for the treatment (tx) of advanced solid tumors. It has previously shown single-agent activity in patients (pts) with BRCA-1/2 mutations (Do, JCO 2015). We described initial safety and efficacy of the dose escalation portion of an open Phase Ib study (NCT02482311) of AZD1775 in pts with refractory solid tumors, and a dose of AZD1775 175 mg PO BID was identified (submitted to AACR 2016). Here we describe the expansion portion of this study in 6 matched cohorts: BRCA-1/2-mutant and wildtype (WT) ovarian cancer (OvC); cyclin-E (CCNE1)-amplified and non-amplified triple-negative breast cancer (TNBC); and any o...

Published
2016

29. Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis

Author

Li Huang, Naomi Laing, Menashe Bar-Eli, Gordon B. Mills, Jennifer R. Molina, Goodwin G. Jinesh, and Ashish M. Kamat

Subjects
0301 basic medicine, Cancer Research, Necrosis, Immunology, Cell Biology, Biology, Fas ligand, Article, Cell biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Transformation (genetics), 030104 developmental biology, Apoptosis, Cancer stem cell, Cancer cell, medicine, Glycolysis, Blebbishield emergency program, medicine.symptom, biological phenomena, cell phenomena, and immunity
Abstract

Apoptosis culminates in secondary necrosis due to lack of ATP. Cancer stem cells form spheres after apoptosis by evoking the blebbishield emergency program. Hence, determining how blebbishields avoid secondary necrosis is crucial. Here we demonstrate that N-Myc and VEGFR2 control transformation from blebbishields, during which oligomers of K-Ras, p27, BAD, Bax, and Bak boost glycolysis to avoid secondary necrosis. Non-apoptotic cancer cells also utilize oligomers to boost glycolysis, which differentiates the glycolytic function of oligomers from their apoptotic action. Smac mimetic in combination with TNF-α or TRAIL but not in combination with FasL abrogates transformation from blebbishields by inducing secondary necrosis. Thus blebbishield-mediated transformation is dependent on glycolysis, and Smac mimetics represent potential candidates to abrogate the blebbishield emergency program.

Published
2016

30. Multicenter randomized Phase II study of AZD1775 plus chemotherapy versus chemotherapy alone in patients with platinum-resistant TP53-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer

Author

Erika Hamilton, Donald K Strickland, Howard A. Burris, D. Scott McMeekin, Suzanne F. Jones, Naomi Laing, Dawn Michelle Stults, David R. Spigel, and Kathleen N. Moore

Subjects
Oncology, Cancer Research, Cyclin-dependent kinase 1, Chemotherapy, medicine.medical_specialty, Peritoneal cancer, biology, business.industry, Kinase, DNA damage, medicine.medical_treatment, Phases of clinical research, Wee1, medicine.anatomical_structure, Internal medicine, biology.protein, Cancer research, Medicine, biological phenomena, cell phenomena, and immunity, business, Fallopian tube
Abstract

TPS5608 Background: WEE1 is DNA damage cell-cycle checkpoint protein that inactivates cyclin-dependent kinase 1 (CDC2) and is overexpressed in a variety of malignancies. Pts with deficient p53 expr...

Published
2015

31. Abstract S1-01: TransCONFIRM: The correlative analysis of breast tumors from patients with advanced hormone receptor positive disease identifies a genetic signature associated with decreased benefit from single agent fulvestrant

Author

Rinath Jeselsohn, Cristina Guarducci, Eric P. Winer, Naomi Laing, Ilenia Migliaccio, Angelo Di Leo, Gilles Buchwalter, Luca Malorni, Chiara Biagioni, Jin Zhao, William T. Barry, Martina Bonechi, Myles Brown, and Yuri Rukazenkov

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Fulvestrant, Proportional hazards model, business.industry, Cancer, Disease, medicine.disease, Breast cancer, Internal medicine, Cohort, medicine, Progression-free survival, Stage (cooking), business, medicine.drug
Abstract

Introduction: Several multi-gene expression based assays have been developed to assess the prognosis and predict response to endocrine treatments in early stage hormone receptor positive (HR+) breast cancer. Although a significant number of patients with metastatic ER+ disease will not respond to endocrine treatments, molecular assays to predict response in this setting are limited. In addition, tissue specimens of metastatic lesions for molecular studies are not always available. In this study we sought to identify a molecular profile in the primary tumors of patients who developed disease recurrence that could predict response to endocrine treatment in metastatic disease. Methods: We used the primary breast tumor samples from a subgroup of patients participating in the randomized phase III CONFIRM trial, which compared 500mg versus 250mg of fulvestrant in post-menopausal women with HR+ advanced breast cancer. Formalin- fixed paraffin embedded tumors were collected from 130 of the participants and were centrally reviewed for ER, PR, HER2 and Ki67. RNA was sufficient for gene expression profiling in 112 of the cases using the NuGEN Ovation FFPE WTA System and Affymetrix HTA 2.0 GeneChip. The majority of the patients in this analysis developed metastatic disease during adjuvant endocrine treatment (N=55) or had de-novo metastatic disease (N=39) versus relapse after adjuvant treatment (N=18). The association between gene expression and progression free survival (PFS) was investigated using a multivariate Cox proportional hazard model adjusting for statistically significant clinicopatholgical factors. In addition we performed pathway-level analysis and evaluated the PAM50 subtype predictor and Risk of Relapse (ROR) score. Results: The median PFS was 8 months in our cohort. HER2 level by immunohistochemistry above 1+, high PR level, defined as Allred score of above 6, and Ki67 of above 50% were significantly associated with PFS and were included in the multivariate model. Dose of fulvestrant was not associated with PFS in this cohort. We identified a signature of 25 genes that is inversely associated with PFS on fulvestrant treatment (FDR 20%). When compared to other published datasets of breast cancer tumors, these genes are enriched in tumors with poor outcome and triple negative cancers. Pathway analysis revealed an association between activation of the EGFR pathway and decreased PFS (P=0.01). PAM50 subtypes varied with the luminal subtype being the most common (65%) and were generally concordant with the clinical subtype. However, we did not detect a significant trend between PAM50 subtype or ROR score and PFS or overall survival. Conclusions: In this cohort of patients with early and de-novo metastatic disease we identified a gene signature in the primary tumors that is associated with decreased response to fulvestrant treatment in metastatic disease. This signature warrants further validation to determine it’s predictive value and potential to assist in treatment decision making for patients with HR+ metastatic disease. Citation Format: Rinath M Jeselsohn, William T Barry, Jin Zhao, Gilles Buchwalter, Cristina Guarducci, Ilenia Migliaccio, Chiara Biagioni, Martina Bonechi, Naomi Laing, Yuri Rukazenkov, Eric P Winer, Myles Brown, Angelo Di Leo, Luca Malorni. TransCONFIRM: The correlative analysis of breast tumors from patients with advanced hormone receptor positive disease identifies a genetic signature associated with decreased benefit from single agent fulvestrant [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-01.

Published
2015

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