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1. Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia

Author

J. Oborski, Esther Kurth, Earl Mcdonald, Florencia Rago, Audrey Kauffmann, Jessi Ambrose, Zainab Jagani, Kathleen Sprouffske, Lindsey Rodrigues, Peter Aspesi, Julie T. Chen, Felipa A. Mapa, Tinya Abrams, Hyo-eun C. Bhang, David A. Ruddy, GiNell Elliott, and M. Bonney

Subjects
Cancer Research, Carcinogenesis, genetic processes, Biology, Chromatin remodeling, Small hairpin RNA, medicine, Animals, Humans, Molecular Biology, Transcription factor, Adenosine Triphosphatases, Mammals, DNA Helicases, Nuclear Proteins, Myeloid leukemia, Chromatin Assembly and Disassembly, medicine.disease, SWI/SNF, Cell biology, Chromatin, Leukemia, Myeloid, Acute, enzymes and coenzymes (carbohydrates), Leukemia, Oncology, SMARCA4, Cancer research, Transcription Factors
Abstract

Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myelogenous leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared with other lineages. This result was striking in comparison with data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes, including MYC, a well-established target of BRG1 activity in AML. Overall, small-molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes. Implications: Our studies reveal the breadth of SWI/SNF dependency in leukemia and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.

Published
2022
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2. Supplementary Tables from The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma

Author

Zainab Jagani, Deborah Castelletti, Hyo-eun C. Bhang, David A. Ruddy, Audrey Kauffmann, Julien P.N. Papillon, Troy Smith, Rukundo Ntaganda, Simon Mathieu, Christopher D. Adair, Katsumasa Nakajima, Henrik Möbitz, Anthony Vattay, Anka Bric, Matthew D. Shirley, Yun Feng, Geoffrey Bushold, Kay X. Xiang, Ali Farsidjani, Julie T. Chen, Dorothee Abramowski, Aurore Desplat, Grainne Kerr, Kathleen Sprouffske, Ailing Li, GiNell Elliott, and Florencia Rago

Abstract

Supplementary Table S1 lists biochemical and cellular activity of BRG1/BRM inhibitors. Supplementary Table S2 lists BRM011 and BRM014 activity across cell line panel. Supplementary Table S3 lists cell lines generated for this study. Supplementary Table S4 lists antibody and qPCR probes used in this study.

Published
2023
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3. Supplementary Methods from The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma

Author

Zainab Jagani, Deborah Castelletti, Hyo-eun C. Bhang, David A. Ruddy, Audrey Kauffmann, Julien P.N. Papillon, Troy Smith, Rukundo Ntaganda, Simon Mathieu, Christopher D. Adair, Katsumasa Nakajima, Henrik Möbitz, Anthony Vattay, Anka Bric, Matthew D. Shirley, Yun Feng, Geoffrey Bushold, Kay X. Xiang, Ali Farsidjani, Julie T. Chen, Dorothee Abramowski, Aurore Desplat, Grainne Kerr, Kathleen Sprouffske, Ailing Li, GiNell Elliott, and Florencia Rago

Abstract

Additional method details for ATAC-Seq Data Analysis and ChIP-qPCR

Published
2023
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4. Supplementary Data from Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia

Author

Zainab Jagani, Hyo-eun C. Bhang, Tinya Abrams, Audrey Kauffmann, David A. Ruddy, Felipa A. Mapa, E. Robert McDonald, Julie T. Chen, Justin Oborski, Peter Aspesi, Jessi Ambrose, GiNell Elliott, Esther Kurth, Kathleen Sprouffske, Megan Bonney, Lindsey Ulkus Rodrigues, and Florencia Rago

Abstract

Supplementary Data from Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia

Published
2023
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5. Supplementary Material and Methods from Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers

Author

Emma Lees, William R. Sellers, Seth A. Ettenberg, Jeffrey A. Engelman, Francesco Hofmann, Juliet Williams, Hui Gao, Xiuxia Sun, Molly A. McShea, Kalli C. Catcott, Nicholas C. Yoder, Vivien W. Chan, Mary J. Janatpour, Jason E. Faris, Matthew J. Meyer, Aaron Bourret, Duc Nguyen, Markus Kurz, William R. Tschantz, Anne Serdakowski London, Tina Rubic-Schneider, Emily K. Meseck, Keith G. Mansfield, Meghan M. Flaherty, Jessica C. Piel, Artur Veloso, GiNell Elliott, Joel P. Wagner, Wei Jiang, Vladimir Capka, Ivana Liric Rajlic, Sanela Bilic, Tiancen Hu, Lance Ostrom, David Lee, Rebecca Mosher, Yeonju Shim, Pierric Prieur, Bruno Lafont, Clemens Dürr, Xiamei Zhang, Parmita Saxena, Xiao Li, Scott D. Collins, and Carl U. Bialucha

Abstract

This file describes supplementary material and methods used.

Published
2023
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6. Supplementary Tables 1 through 11 from Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers

Author

Emma Lees, William R. Sellers, Seth A. Ettenberg, Jeffrey A. Engelman, Francesco Hofmann, Juliet Williams, Hui Gao, Xiuxia Sun, Molly A. McShea, Kalli C. Catcott, Nicholas C. Yoder, Vivien W. Chan, Mary J. Janatpour, Jason E. Faris, Matthew J. Meyer, Aaron Bourret, Duc Nguyen, Markus Kurz, William R. Tschantz, Anne Serdakowski London, Tina Rubic-Schneider, Emily K. Meseck, Keith G. Mansfield, Meghan M. Flaherty, Jessica C. Piel, Artur Veloso, GiNell Elliott, Joel P. Wagner, Wei Jiang, Vladimir Capka, Ivana Liric Rajlic, Sanela Bilic, Tiancen Hu, Lance Ostrom, David Lee, Rebecca Mosher, Yeonju Shim, Pierric Prieur, Bruno Lafont, Clemens Dürr, Xiamei Zhang, Parmita Saxena, Xiao Li, Scott D. Collins, and Carl U. Bialucha

Abstract

This file contains supplementary tables describing parameters for antitumor activity (T/C analyses), PK and protein crystallography.

Published
2023
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7. Supplementary Figure Legends from Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers

Author

Emma Lees, William R. Sellers, Seth A. Ettenberg, Jeffrey A. Engelman, Francesco Hofmann, Juliet Williams, Hui Gao, Xiuxia Sun, Molly A. McShea, Kalli C. Catcott, Nicholas C. Yoder, Vivien W. Chan, Mary J. Janatpour, Jason E. Faris, Matthew J. Meyer, Aaron Bourret, Duc Nguyen, Markus Kurz, William R. Tschantz, Anne Serdakowski London, Tina Rubic-Schneider, Emily K. Meseck, Keith G. Mansfield, Meghan M. Flaherty, Jessica C. Piel, Artur Veloso, GiNell Elliott, Joel P. Wagner, Wei Jiang, Vladimir Capka, Ivana Liric Rajlic, Sanela Bilic, Tiancen Hu, Lance Ostrom, David Lee, Rebecca Mosher, Yeonju Shim, Pierric Prieur, Bruno Lafont, Clemens Dürr, Xiamei Zhang, Parmita Saxena, Xiao Li, Scott D. Collins, and Carl U. Bialucha

Abstract

This file contains the figure legends for supplementary figures S1-S7.

Published
2023
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8. Supplementary Figures from The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma

Author

Zainab Jagani, Deborah Castelletti, Hyo-eun C. Bhang, David A. Ruddy, Audrey Kauffmann, Julien P.N. Papillon, Troy Smith, Rukundo Ntaganda, Simon Mathieu, Christopher D. Adair, Katsumasa Nakajima, Henrik Möbitz, Anthony Vattay, Anka Bric, Matthew D. Shirley, Yun Feng, Geoffrey Bushold, Kay X. Xiang, Ali Farsidjani, Julie T. Chen, Dorothee Abramowski, Aurore Desplat, Grainne Kerr, Kathleen Sprouffske, Ailing Li, GiNell Elliott, and Florencia Rago

Abstract

Supplementary Figure S1 shows additional shRNA knockdown data in uveal melanoma cell lines. Supplementary Figure S2 shows additional dual BRG1/BRM knockdown data and BRG1 rescue data. Supplementary Figure S3 shows basal SWI/SNF subunit expression, additional caspase activity and viability data in compound treated and shRNA knockdown cell lines, and SWI/SNF mutations in uveal melanoma cells lines. Supplementary Figure S4 shows additional MITF knockdown data and further RNA-Seq and ATAC-Seq data set analyses. Supplementary Figure S5 shows target gene modulation by compound treatment in uveal melanoma cell lines and additional MITF overexpression rescue data. Supplementary Figure S6 shows genomic location of primers used in ChIP-qPCR experiment.

Published
2023
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9. Supplementary Figure S1 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Ovarian cancer cell lines do not reproduce the clinical association between BRCA loss of function and sensitivity to olaparib, but patient-derived ovarian tumor xenografts do.

Published
2023
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10. Supplementary Table 2 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Ovarian PDX raw growth and sequencing data.

Published
2023
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11. Supplementary Figure S3 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Candidate biomarkers are not independently prognostic of survival in primary ovarian tumor samples from TCGA.

Published
2023
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12. Supplementary Figure S2 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Genomic landscape analysis of epithelial ovarian carcinoma of PDXs, patient tumors (TCGA) and cell lines (CCLE).

Published
2023
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13. Data from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody–drug conjugates, is a viable alternative. A panel of patient-derived ovarian cancer xenografts (PDX), similar in genetics and chemotherapy responsiveness to human tumors, was exposed to 21 monotherapies and combination therapies. Three monotherapies and one combination were found to be active in different subsets of PDX. Analysis of gene expression data identified biomarkers associated with responsiveness to each of the three targeted therapies, none of which directly inhibits an oncogenic driver. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. The distribution of biomarker positivity in The Cancer Genome Atlas data suggests the potential for a similar precision approach in human patients.Significance:This study exploits a panel of patient-derived xenografts to demonstrate that most ovarian tumors can be matched to effective biomarker-guided treatments.

Published
2023
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14. Supplementary Table 4 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Mean tumor volume change difference between best monotherapy and each of 9 combinations. Hazard ratio for combination versus independent action simulation PFS.

Published
2023
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15. Supplementary Figure S4 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Most ovarian tumors respond to one of four biomarker-guided treatments.

Published
2023
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16. Supplementary Materials from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Supplementary Material PDF, including supplementary methods and supplementary figures 1-4

Published
2023
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17. Supplementary Table 1 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Compound dose, dosing schedule, administration route, target and drug type.

Published
2023
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18. Supplementary Table 3 from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts

Author

Peter K. Sorger, Juliet A. Williams, William R. Sellers, Hans Bitter, Jeffrey A. Engelman, Esther Kurth, Alice Loo, Ronald Meyer, Paul Fordjour, GiNell Elliott, Daniel P. Rakiec, Stacy Rivera, Caroline Bullock, Julie Muszynski, Colleen Kowal, David A. Ruddy, Margaret E. McLaughlin, Roberto Velazquez, Xiamei Zhang, John Green, Guizhi Yang, Joshua M. Korn, Hui Gao, Deborah Plana, and Adam C. Palmer

Abstract

Ovarian PDX response category by therapy.

Published
2023
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19. The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma

Author

Matthew D. Shirley, Julie T. Chen, Ailing Li, Anthony Vattay, David A. Ruddy, Anka Bric, Kay X. Xiang, Simon Mathieu, Troy Smith, Julien Papillon, Deborah Castelletti, Rukundo Ntaganda, Kathleen Sprouffske, Hyo-eun C. Bhang, Yun Feng, Dorothee Abramowski, Ali Farsidjani, Audrey Kauffmann, Grainne Kerr, Aurore Desplat, Geoffrey Bushold, Katsumasa Nakajima, Henrik Möbitz, GiNell Elliott, Christopher D. Adair, Zainab Jagani, and Florencia Rago

Subjects
Uveal Neoplasms, 0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, cells, genetic processes, macromolecular substances, Biology, Chromatin remodeling, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Melanoma, Transcription factor, GNA11, Cancer, Microphthalmia-associated transcription factor, medicine.disease, Chromatin, SWI/SNF, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biological phenomena, cell phenomena, and immunity, GNAQ, Transcription Factors
Abstract

Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles for the mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) in various cancer lineages. Here, we find evidence that the SWI/SNF complex is essential through analysis of functional genomics screens and further validation in a panel of uveal melanoma cell lines using both genetic tools and small-molecule inhibitors of SWI/SNF. In addition, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage–specific transcription factor Microphthalmia-associated Transcription Factor, suggesting that these two factors cooperate to drive a transcriptional program essential for uveal melanoma cell survival. These studies highlight a critical role for SWI/SNF in uveal melanoma, and demonstrate a novel path toward the treatment of this cancer.

Published
2020
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20. A proof of concept for biomarker-guided targeted therapy against ovarian cancer based on patient-derived tumor xenografts

Author

Joshua M. Korn, Ronald Meyer, Juliet Williams, Colleen Kowal, Roberto Velazquez, Paul Fordjour, Esther Kurth, Adam C. Palmer, Hans Bitter, Xiamei Zhang, Deborah Plana, GiNell Elliott, Margaret E. McLaughlin, Alice Loo, Julie Muszynski, David A. Ruddy, William R. Sellers, Daniel P. Rakiec, Stacy Rivera, Guizhi Yang, Jeffrey A. Engelman, Caroline Bullock, Hui Gao, Peter K. Sorger, and John Green

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Antineoplastic Agents, Drug resistance, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Proof of Concept Study, Article, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Carcinoma, Biomarkers, Tumor, Distribution (pharmacology), Humans, Molecular Targeted Therapy, Precision Medicine, Ovarian Neoplasms, Chemotherapy, business.industry, medicine.disease, Precision medicine, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Ovarian cancer, business
Abstract

Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody–drug conjugates, is a viable alternative. A panel of patient-derived ovarian cancer xenografts (PDX), similar in genetics and chemotherapy responsiveness to human tumors, was exposed to 21 monotherapies and combination therapies. Three monotherapies and one combination were found to be active in different subsets of PDX. Analysis of gene expression data identified biomarkers associated with responsiveness to each of the three targeted therapies, none of which directly inhibits an oncogenic driver. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. The distribution of biomarker positivity in The Cancer Genome Atlas data suggests the potential for a similar precision approach in human patients. Significance: This study exploits a panel of patient-derived xenografts to demonstrate that most ovarian tumors can be matched to effective biomarker-guided treatments.

Published
2020

21. Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers

Author

Keith Mansfield, Carl Uli Bialucha, Jeffrey A. Engelman, Kalli C. Catcott, William R. Sellers, Vivien W. Chan, Rebecca Mosher, Duc Nguyen, Pierric Prieur, Hui Gao, Seth Ettenberg, Tiancen Hu, Joel Wagner, Clemens Dürr, Jessica C. Piel, Anne Serdakowski London, Mary J. Janatpour, Sanela Bilic, William R. Tschantz, Bruno Lafont, Wei Jiang, Juliet Williams, GiNell Elliott, Yeonju Shim, Vladimir Capka, Meghan Flaherty, Matthew J. Meyer, Francesco Hofmann, Lance Ostrom, Artur Veloso, David M. Lee, Markus Kurz, Jason E. Faris, Emily K. Meseck, Ivana Liric Rajlic, Aaron Bourret, Xiao Li, Scott D. Collins, Xiuxia Sun, Molly A. McShea, Xiamei Zhang, Tina Rubic-Schneider, Nicholas C. Yoder, Parmita Saxena, and Emma Lees

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Population, Mice, Nude, Antineoplastic Agents, Bioinformatics, 03 medical and health sciences, In vivo, Internal medicine, medicine, Animals, Humans, Biomarker Analysis, education, Ovarian Neoplasms, Kidney, education.field_of_study, Cadherin, business.industry, Cancer, Cadherins, medicine.disease, Xenograft Model Antitumor Assays, Kidney Neoplasms, Rats, Clinical trial, Macaca fascicularis, 030104 developmental biology, medicine.anatomical_structure, Pharmacodynamics, Female, business
Abstract

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell–cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody–drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models—a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030–45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920

Published
2017
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22. Biomarker-guided treatment strategies for ovarian cancer identified from a heterogeneous panel of patient-derived tumor xenografts

Author

Deborah Plana, GiNell Elliott, David A. Ruddy, Xiamei Zhang, Stacy Rivera, Joshua M. Korn, Jeffrey A. Engelman, Margaret E. McLaughlin, Ronald Meyer, John Green, Paul Fordjour, Hui Gao, Esther Kurth, Adam C. Palmer, Julie Goldovitz, Guizhi Yang, Caroline Bullock, William R. Sellers, Roberto Velazquez, Daniel P. Rakiec, Colleen Kowal, Peter K. Sorger, Juliet Williams, Hans Bitter, and Alice Loo

Subjects
Oncology, Response rate (survey), 0303 health sciences, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Disease, medicine.disease, 3. Good health, Targeted therapy, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Biomarker (medicine), Distribution (pharmacology), business, Ovarian cancer, 030304 developmental biology
Abstract

Advanced ovarian cancers are a leading cause of cancer-related death in women. Such cancers are currently treated with surgery and chemotherapy which is often temporarily successful but exhibits a high rate of relapse after which treatment options are few. Here we assess the responses of a panel of patient-derived ovarian cancer xenografts (PDXs) to 19 mono and combination therapies, including small molecules and antibody-drug conjugates. The PDX panel aimed to mimic the heterogeneity of disease observed in patients, and exhibited a distribution of responsiveness to standard of care chemotherapy similar to human clinical data. Three monotherapies and one drug combination were found to be active in different subsets of PDXs. By analyzing gene expression data we identified gene expression biomarkers predictive of responsiveness to each of three novel targeted therapy regimens. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. Biomarker frequency was similar in human patients, suggesting the possibility of a new therapeutic approach to ovarian cancer and demonstrating the potential power of PDX-based trials in broadening the reach of precision cancer medicine.

Published
2020
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23. Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

Author

Raechel Harnoto, Morgan C. Anderson, Amy Z. Xu, Heather Hedeen, Arnaldo J. Santiago-Sanabria, Brandy L. Hammond, Kenneth Saville, Ross D. Kooienga, Christopher Chesley, Robert W. Morris, Aubree T. Gillis, Brittney Offenbacker, Katherine C. Palozola, Trisha Tomkins, Nicole Yu, Matthew Kwong, Megan E. Aldrup, Jordan E. Kus, Chelsey Friedrichs, Kenneth Stapleton, Carly E. Pelchen, Norma Chamma, Joshua F. Machone, Danielle Kulich, Andre Kennedy, Matt J. Crowley, Daniel Broomfield, Adeola Adebayo, Nicolas Ragland, Shady Messiah, Jonathan Misch, Meghan B. Rooney, Eva N. Rubio-Marrero, Will Sherrill, Joyce Stamm, Rachel R. Leads, Lindsey Shantzer, Alexis J. Scott, Andrew W. Waggoner, Kristen M. Cooper, Adam Haberman, Carmen A. Watchinski, Marcos A. Perez, Lisa Kadlec, Kiara N. Medina-Ortega, Kayla Chapman, Cheryl Bailey, Nicholas Fazzio, Insun Chong, Lasse Schmidt, Darla M. Balthaser, Megan DeShetler, Jien Shim, Anna Rogers, Chris Uitvlugt, Bryan Yarrington, Ruth A. Howe, Andrea Ochoa, Gregory J. Mullen, Young Lu Kim, Olivia L Knowles, Kevin M. Levine, Matthew M. Villerot, Thomas J. Rose, Jonathan E. Smith, Sukhjit Kaur, Roshni Patel, Olivia Plante, Tenzin Choeying, Jennifer R. Ramthun, Tiffany Y. Y. Choi, Michael Rahimi, Guzal Khayrullina, Lauren R. Boudreaux, James E. J. Bedard, Brian A. Dow, Christopher A. Louie, Kenneth S. Smith, Joannee Zumkehr, Marcus Gostelow, Melissa A. Tache, Tiffany Dai, Joan D. Zambrana-Burgos, Lauren R. Meyer, Carter Brown, Adam Brown, Travis Lamb, Carissa Belella, Hannah Gilman, David DuPuis, Ramón E. Rivera-Vicéns, Priyanka Naik, Anna L. Shipman, Jad El-Adaimi, Eric Spencer, Jonathan D. Marra, Melissa D. Patao, Sharon Ibarra, Jiayu Zhang, Ashley Vetor, Bobbi Botsford, Jenifer Winters, Nelson A. Valentín-Feliciano, Lauren M. Robinson, Christopher R. Macchi, Jennifer Hernández-Muñiz, E. Gloria C. Regisford, Jaelyn L. Johnson, Cory M. Dauphin, Tezin A. Walji, Matthew A. Zaborowicz, Stacey Winkler, Shannon M. Lowell, Marly R. McCracken, Andrew Adams, Lindsay A. Spaeder, Matthew W. Wolski, Adrese Kandahari, Fabiola Robles-Juarbe, Bryce A. Turner, Ángel L. Laboy-Corales, David T. Watson, Elaine J. Durchholz, Vanessa Rodriguez, Emily J. Teepe, Alaina C. Conturso, Eric Nyabeta Onsarigo, Tijana Martinov, Rohit Venkat, Charles R. Hauser, Priya Srikanth, Marwan Ibrahem, Karl E. Smith, Jessica M. Tucci, Ethan J. Brock, Aparna Sreenivasan, Jasmine Hales, Brianna K. Barnard, Andrew P. Stein, Jessica G. Thomas, Mallory Perella, Lorraine Rodriguez-Bonilla, Shekerah Primus, Zachary D. Moore, Caitlin M. Ament, Amber N. Hare, Brad Pamnani, Eugenia A. Soliterman, Christina Paluskievicz, Yashira M. Valentín-Feliciano, Alexandra K. Eckardt, Anya Goodman, Joseph W. Noynaert, Ashlee G. Johnson, Tyneshia C. P. Henry, Camille D. Ratliff, Ian O. Chase, Michel A. Conn, Jessica Koehler, Daniela Martiniuc, Allison J. Schepers, Megan B. Vylonis, Chrystel Dol, William Dirkes, Michelle S. Rivera-Llovet, Susana Rodríguez-Santiago, Heather L. Eisler, Mary L. Preuss, Daymon Peterson, Martin G. Burg, Aaditya Khatri, John R. Woytanowski, Holly Schiedermayer, Dara Cohn, Leah E Waldman, William M. Morris, Sharon C. Ehret, Marianna Defendini-Ávila, Jessica Fese, Suzette M. Arias-Mejias, Anna Kammrath, William D. Barshop, Edwin G. Ramírez-Aponte, Luis A. Jimenez, Carolina Marques dos Santos Vieira, Cody D. Kern, Francheska M. Delgado-Peraza, Tiffany Wan, Janice L. Krumm, Osagie Ighile, Eric D. Sassu, Jess M. Darusz, Laura Rodela, Daniel S. Nicolas, Shubha Govind, Mary Miller, Joseph E Marcus, Jason Pollack, Rostislav Castillo, Daniel Coomes, Matthew J. Borr, Diana Pérez-Afanador, Lucas A. Watson, Hannah C. Koaches, Amber Quintana, Faith H. Kung, Cameron B. Harris, Bridget M. Janssen, Cristina Zambrana-Echevarría, Jennifer K. Jones, Ian Dobbe, Benjamin M. Lewis, Lena N. Lupey, Julia A. Hilbrands, Cristina Montero Diez, Jorge L. Santiago-Ortiz, Dustin S. Woyski, Sandy D. Mach, Joseph Perez-Otero, Karim A. Sharif, Carlos Mendoza, John D. Fitzgibbons, Nelson H. Knudsen, Christy MacKinnon, Hayley M. Faber, Kwabea Agbley, Michelle Heslop, Olivia Cyrankowski, Priscilla Rodriguez, Melissa Jones, Jean M. Strelitz, Ryan A. Grove, Rachel A Greenstein, Michael Murillo, Elizabeth Greiner-Sosanko, Ciani Jean Sparks, Darryl McFarland, Franca G. Rossi, Heran Gebreyesus, Chris Kay, Danielle Ladzekpo, Chris Harward, Jordan S. Christie, Consuelo J. Alvarez, Elaine V. Morlock, Geoff Scott, Kelsey Hockenberger, Sepo Musokotwane, Adam Fearnow, Lauren J. Keny, Alaina J. Grantham, Evangelina Reza, Mike Colgan, Melanie K. Regan, Stephanie J. Potocny, Sasha L. Dorsett, Tara Skorupa, Valerie M. Gónzalez-Pérez, Vinayak S. Nikam, Anne C. Meier, Varun Sundaram, Helen B. Rankin, Andrew B. Nylander, Mariela Gines-Rosario, Laurell MacMillian, Jeannette M. Osterloh, Robert H. Allen, Melanie A. Smith, Sarah J. Spencer, Cheri M. Ackerman, Jeffrey L. Poet, Amanda J. Hay, Isaac O. Armistead, Laura K. Reed, Don W. Paetkau, Bib Yang, Enid M. Quintana-Torres, Kathryn L. Golden, Lauren A. DiLorenzo, Alen Ramic, Mark T. LeBlanc, Carl J. Minniti, Robert J. Bailey, Kristen M. Thomsen, Ashley L. Adams, Chad A. Koplinsky, Eliezer O. Perez-Colomba, Nicole A. Howey, Katie A. TerMeer, Stephanie Intriago, Christina N. Kufel, Mary Waters, Bo Liu, Thomas J. Bahr, Ashley R. Miller, Claire Pattison, Morgan R. Light, Amy T. Hark, Jennifer S. Doty, Catherine M. Mageeney, Adam J. Ronk, Nadezhda Fefelova, Andrew R. Armstrong, Maida Chen, Elizabeth Macias, Kim M. Chau, Paul Bilinski, Trevor G. Floyd, Cassidy T. Lee, Jenna C. Tenney, Bob Gardner, Patricia Ortiz-Ortiz, Elizabeth S. Jewell, Gabi Lucas, Brandon Lee, Jenifer N. Jarrell, Jimmy Hsiang-Chun Chang, Lorraine Malkowitz, Ulises Marrero-Llerena, Gabriel Stancu, Matthew R. Unzicker, Andrea P. Burgos-Bula, Michelle L. Miller, Elisandra Rivera, Kate Bagaeva, Jessica W. Polk, Jordan E. Carney, Maureen Corrielus, Jana Nietmann, Jeff Howenstein, Elizabeth Kiernan, Sabya A. Rauf, Brandon M. Katz, Elizabeth C. Nordman, Devon Shallman, Eric M. Clark, Lenin Lopez, Karen J. Kraftmann, Leslie Guadron, Julia Kuhn, Allison R. Schneiter, Satish C. Bhalla, Emily J. Howell, Blair Undem, Jeffrey S. Thompson, Arelys Flores-Vazquez, John Kiley, Cody M. Morrow, Joseline Serrano-González, John Mark Knepper, Christopher Beck, Calise Debow, Anna L. Smith, Angelica Garcia, Shelbi Christgen, Shadie Emiah, Tammy Mazur, Rachel E. VanDyken, Frank R. Soto delValle, Zachary Nichols, William R. Kennedy, Ameer Zidan, Douglas A. Herrick, Thomas Q. Xu, Elizabeth Shoop, Jessica A. Kampmeier, John M. Kerber, Caitlin Pozmanter, Emily L. Hong, Frederic J. Deuschle, Allyson B. Rivard, William Neutzling, Joseph V. Moran, Benjamin K. Johnson, Jacob Jipp, Shannon R. McCartha, Abby Vrable, Z. Goodwin, Suchita Rastogi, Alyssa M. Newman, Lionel Ortiz-Fuentes, Arjun A. Anilkumar, Bryan M. Hennessy, Hui-Min Chung, Katie L. Goeller, Carlos E. Santos-Ramos, Adam Dillman, Christine D. Wilson, Sarah J. Peacock, Andrew J. Kim, Carol I. Morales-Caraballo, Briana Brinkley, Justin Alldredge, Rebecca Krock, Kristen C. Davis, David Dunbar, Joshua L. Manghelli, Erica K. Earl, Katherine Gavinski, Sheryl T. Smith, Portia Mason, Lindsay J. Hoogenboom, Jessen T. Havill, Sonya G. Méndez-Castellanos, Darrin T. Schultz, Katherine J. Faber, Allison O’Rouke, Emily G. Miller, Yara Ashrawi, Curtiss E. Lane, Saryleine Ortiz-DeChoudens, Michael W. Sandusky, Andrew Montgomery, Rita Kabaso, Todd Aronhalt, Jonathan D. Foust, Jorge Ruiz, Eric Helmreich, Todd T. Eckdahl, Charlotte Lea, Kevin Coulson, Kristin M. French, Kate A. Woodard, Brandon J. Burkhart, Kylie McNeil, Curtis R. Edwards, Jimmy Ma, Darcie D. Elder, Tia DiTommaso, Nicholaus Monsma, Sarah A. Jelgerhuis, Stephanie J. Adams, Nichole Rigby, Heather L. Holderness, Charlotte Williams, Megan Donegan, Taylor S. Harding, Javier O. Martinez-Rodriguez, Sandeep Venkataram, Tiffany Wong, Anika Toorie, Jenny L. Rose, Ashley S. Brown, Sarah A. Popelka, Matthew Williams, Julie Bryant, Sarah C. R. Elgin, Sonali Kumar, Joshua Burkhardt, William J. Puetz, Erica L. Alvendia, Richard A. Tumminello, Kesley Parry, Joshua R. Smith, Ashley F. Custer, Carlos E. Ortiz, Yedda Li, April E. Bednarski, Simon Ng, Max Mandelbaum, Arlene J. Hoogewerf, Chelsea A. Walker, Ryan S. Lee, Jeannette Wong, Isabella Theresa Felzer-Kim, Harrison Friedman, Megan Bourland, Luis R. Colón-Cruz, Lucy Liu, Nicole C. Olson, Yi Ren, Adam P Lousararian, José M. Cruz-García, Charlie Manchee, Kyle Zoll, Kristina M. Stemler, Juliana Belén-Rodríguez, Ashley S. Timko, Jane Lopilato, England Raimey, Amy D. Melton, Joshua D. Forsyth, Christopher D. Savell, Himabindu Reddy, Alica B. Allen, Amanda Maffa, Daniel W. Cassidy, Luciann Bracero-Quiñones, Eric Lemmon, Justina R. Bartling, Bradley J. Ogden, Petros Svoronos, Mary Spratt, Lisa Sudmeier, Héctor A. Martell-Martínez, James F. Geary, Bridget J. Sessions, Christopher Campana, Kaitlyn A. Downey, Seth G. Dawson, Daniella Menillo, Casey Hanson, James M. Bellush, Justin A. Gonzales, Roy Song, Karvyn Torchon, Betsy Hoover, Michael Closser, Lacey Neufeld, Micah Shelton, Benjamin R. Does, Juan Carlos Martínez-Cruzado, Jordan S. Baumgardner, Nicole Chichearo, Mary T. Reilly, Colleen V. Kelley, Monica Yalamanchili, Dawn Lau, Abbie Morgan, Alyssa Cifelli, Milton R. Herrold, Ambreen Khan, James Messler, Kyle Westphal, James L. Kehoe, Juliana A. Wurzler, Garrett Salzman, Tracy Wang, Charlene Emerson, Lyndsey A. Reynolds, Alysha Moretti, Marita K. Abrams, Mara G. Cole, Michael B. Schultz, Samantha Cruz, Natalie Ngai, Nadia Safa, Vicente Velasquez, Ashley Townsend, Jonathan L. Crooke-Rosado, Amber M. Gygi, Ishwar S. Gill, Christopher McLaughlin, Dorianmarie Vargas-Franco, Alissa Beckett, Samantha Vue, Nadine L. Rossi, Justina Chinwong, Ryan Michael Rempe, Trip Freeburg, Amy J. Johnson, Omolara Glenn, Jade Lea Rekai, Hashini Gunasinghe, Vivienne Echendu, Marshall Strother, Morgan Baker, Christopher D. Smith, Paolo A. DaSilva, Noelle Delacruz, Tiara Tirasawasdichai, Yakov Shevin, Wilfried Guiblet, Shane M. Patao, Peterson R. Cullimore, Giancarlo F. Garbagnati, Adam E. Musick, Sarah C. Butzler, Jonathan D. Presley, Ana I. Correa-Muller, Christopher D. Shaffer, Chunguang Du, Ryan D. Mitchell, Jonathan P. Rennhack, Barbara L. Hopkins, Mary E. Shaw, Jessica E. Hill, Jeremy N. Wong, Anna Kim, Christopher B. Khoury, Julia Chapman, Amanda T. Mercer, Jessica A. Shuen, Joyce H. Lau, I.N. Falk, Sunil Rathore, Christopher J. Jones, Laura Simone Bisogno, Nighat P. Kokan, Paul Yenerall, Amber L. Price, Kelsey T. Bushhouse, Stephen L. McDaniel, Andrew P. Drake, Johnathan D. English, Sampson K. Boham, Robert A. Herbstsomer, Daniel S. Fosselman, Kevin Babilonia-Figueroa, Matthew Simon, Anne G. Rosenwald, Bryan J. Rupley, Heather Cohen, Victoria Scala, Avery B. Cromwell, Christopher E. Blunden, Yelena P. Davis, William B. Armstrong, Kristine Ostby, Joanna Haye, Lauren M. Wysocki, Lena Christiansen, Allison A. Throm, Sarah Flohr, Matthew Wawersik, Rebecca J. Cotteleer, Kristen R Ramirez, Dontae A. Jacobs, Sarah Woehlke, Gregory S. Messenger, Soham Aso, Nicole Clarke-Medley, Bryant R. Swanson, Lindsay K. Brouwer, S. Catherine Silver Key, Stephanie Zarrasola, Michael S. Salgado, Dong K. Rhee, Mai Abdelnabi, Eve VanEck, Jeremy Buhler, Sarah Kong, Turner Conrad, Jennifer Roecklein-Canfield, Marykathryn Tynon, Brian J. Maniaci, Alexa M. McDonough, Ivan G. Llavona-Cartagena, J. Devin Spencer, Todd D. Johnson, Azita Bashiri, Kimberley Ramsey, Mike Polen, Hien P Nguyen, Seantay D. Patterson, Lucia Wande, Nicholas U. Schwartz, Han Yuan, Albeliz Santiago-Colón, Joseph Medina, Samuel Thomas Crowley, Emma Shoemaker, Alex J. Feliciano-Cancela, Alexander J. Kujawski, Lillyann Asencio-Zayas, Gentry L. Pickett, Matt J. Randazzo, Erica Stagaard, Kristin M. LaForge, Gabriela A. Llaurador-Caraballo, Anastasia K. Yemelyanova, Alan Tseng, Erika E. Menyes, Julie Azarewicz, Christa Burke, Samuel I. Smith, Nazanin Ghavam, Carolina Gomez, Cameron Fick, Anthony Pinto, Lindsay Rios, Gary A Kuleck, Ashley Rich, Kayla A. Florian, Martin N. Cheramie, Yuki Kwan Wa Shum, Atlee Baker, LaJerald Augustine, Alyson Greenwell, Rasleen K. Saluja, Jason S. Macias, Wesley W. Winn, Samantha M. Schmuecker, Michelle E. M. Eisen, Pedro Benitez, Jeanette Hauke, Nora C. Goscinski, Justin R. DiAngelo, Carter T. Docking, David D. Xiong, Brittany D. Pasierb, Matt Van Camp, Yin Zheng, Nikie L. McCabe, Emily Reed, Katie Homa, Kimberly S. Kolibas, Elizabeth A. Karaska, Grace A. Dougherty, John P. Fanning, Michael Fasano, Joseph E. Sable, Robert W. Schulz, San Francisco Nguyen, Michael L. Rojas-Vargas, Kierstin L. Naylor, Emily Peoples, Jessica Neely, Lejla Cesko, Brionna D. Davis-Reyes, Roxanne Banker, Amanda K. Tilot, Jordan P. Brand, William H. Newhart, Lauriaun Johnson, Michelle M. Giddens, Nicole B. Clark, Anant Agarwalla, Thomas F. Minton, Dana W. Brooks, Amanda D. Garrett, Bethany M. Klett, Kristin M. Starkey, Antoinette E. Fafara-Thompson, Michael R. Rubin, Jonathon M. Benson, Erica Enoch, Amanda M. Damsteegt, Zackary W. Scott, Elisabeth A. Kelly, Jason M. Barnett, Wilson Leung, Luke J. Rodriguez-Giron, Krishna C. Mudumbi, Francis J. May, Nadyan M. Vargas-Barreto, Geeta Statton, José L. Torres-Castillo, Sarah Hirsch, Rachel M. Reem, Linghui Li, Deirdre Robinett, Jason Caronna, Abneris E. Rodríguez-Laboy, Samantha Lawrence, Katherine R. Reynolds, Corinne Weeks, Allison M. Sterling, Chun Leung Ng, Roman E. Ramirez, Daron C. Barnard, Leming Zhou, Eric P. Spana, John A. Toth, Alvin Lu, Krizia C. Menéndez-Serrano, Jonathan M. Heckman, Ben Chlebina, Matthew C. Fadus, Helmet T. Karim, Shailly Gaur, Timothy R. Jelsema, Nicholas Keysock, Thomas J. Carr, Zach Fusco, Evan M. Verbofsky, Monal Naik, Amanda H. Flores, Kristin A. Knouse, Olga R. Kopp, Elizabeth Feenstra, Edward P. Sweeney, Christen Johnson, Justin Crawford, Damian Urick, Victor W. Mullen, Carrie A. Dunham, Gabriella A. DeMichele, Mengyang Sun, William Harrington, Jessica M. Bodenberg, Xavier A. Collado-Méndez, T. Aaron Wiles, Michelle K. Powers, Phillip J. Minnick, Lourdes N. Irizarry-González, Valeria Silva, Steven Ovu, Nik Kolba, Peter Lindbeck, Jerome M. Molleston, Ifeanyi Obiorah, David Carranza, Lauren R. Beck, Alina M. Tamayo-Figueroa, Elaine R. Mardis, Rachel N. Lippert, Ingrid T. Rivera-Pagán, Mahdi Soos, Trung T. Nguyen, Megan Martinez, Van Kim, Benjamin L. Danner, Randall J. DeJong, Melissa M. Trieu, Andrea M. Senquiz-Gonzalez, Mary Grace Schueler, Emily E. Magnuson, Lesley E. Jackson, Hendrick Pagán-Torres, Fareed Sanusi, Dana Koenig, Vidya Chandrasekaran, Chinmoy I. Bhatiya, Dongyeon Kim, Paul J. Overvoorde, Reece Watson, Jennifer Schottler, Devry Lin, Jim Youngblom, Taylor Schauder, Nigel Madden, Isabel Valdez, Thomas John Reynolds, Kelly M. Deranek, Anne A. Welker, Jackie X. White, Nicole C. Riddle, Jacob Pfeil, Aldo Heredia-Negrón, Christine Langner, Tao Jian He, Jonathan P. Mecoli, Lissett Mayorga, Scott Chiang, Rishi Singhal, Julia C. Peairs, Michael Quach, Anne M. Eime, GiNell Elliott, Meleah J. Gross, Melissa Drewry, Julia A. Emerson, Anthony K. Lambright, Isaac Appiah, Gregory M. Robertson, Nathaniel Regenold, Philip Pham, George Odisho, Alexi Archambault, Matthew Dothager, Shana M. Baldassari, Paul J. Lee, Callie R. Merry, Jesse R. Farek, Archana Tare, Srebrenka Robic, William Vernon, Tam Vuong, Bethany Grace Bonifield, Katrina Thistle, Rose M. Dowd, Noor Tazudeen, Jennifer Weaver, Manpreet Kaur, Nicole M. Caesar, Yi Zhang, Michael C. Cristostomo, Albert Tzeng, Kayla Vondy, Emily Perling, Ramiro A. Chavez, Lanor S. Horton, Matt Kroll, Levent H. Beken, Justin R. Starcher, Sam Asinof, Nathalia M. Cruz, Eunice George, Adam T. Morrow, Heather Milnthorp, Cheryl Mazzeo, Kristen R. Hatfield, Anna L. Boudoures, Ashley A. Tewilliager, Edna P. Tascón-Peñaranda, Vilma F. Huerta, Sarah Tuberty, Mallory A. Williams, Rachel E. Weber, Sarah Spencer, Emily C. Leatherman, Yuying Gosser, Steve DeFazio, Patrick Ng, Jeri Sparks, Pavan Bhat, Mindy E. Bower, Jordan E. Matthews, Cyrus E. Kuschner, Anne Bertolet, Matt Kusner, Thomas C. Giarla, Jessica Penn, Gerard P. McNeil, Mariam Meghdari, Michael J. Wolyniak, Matthew Juergens, Karla I. Velázquez-Soto, Maria Kaisler, Jeanine Schibler, Alexis Nagengast, Susan Parrish, Frances Marín-Maldonado, Shiv Mohini, Jessica King, Danny Mammo, Katherine S. Harker, Allyson P. Hawkins, Kelly Drumm, Jennifer A. Lammers, Allyson P Mallya, Ashley Bryant, Katie Weihbrecht, Pete Wendland, Gabriela V. Bernal-Vega, Nestor A. Gutierrez, Armando G. Bermudez-Capo, Luke R. Salbert, Kirk Haltaufderhyde, Michelle L. Kappes, Mary A. Smith, York Chen, Miguel Vélez-Vázquez, Brittany E. Plescher, Francis D. Beauchamp-Pérez, Alyssa Ward, Andrea N. Clary, Don Foret, Mitchell J McDonald, Mariela Colon-Vazquez, Amanda L. Blaker, Hao Yang, James Z. Liu, Austin B. Limle, Henry Huang, Luis Vilanova-Velez, Edgar Garibay, Philip J. Freda, Laura L. Mays Hoopes, Maureen S. Hammond, Marian M. Kaehler, Rebecca Shuford, Ray Sunjed, Cynthia K. Hanson, Marielle VanderVennen, Idaliz M. Martínez-Traverso, Jack Y. Yu, Spencer L. Franchi, Michael Snavely, John E. Anderson, Lainey S. Rubin, Kelly K. Jones, Stephanie F. Mel, Stacey Lytle, Danny L. Tran, Chelsea R. Barberi, Max Mian Liu, Eric A. Nollet, Sarah E. Muller, Diana Norton, John M. Braverman, Thu A. Phan, Nelson Membreno, Colin Khoshabian, John Gooch, Cassandra Kubricky, Priscila M. Rodríguez-García, Anna Wylie, Diana L. E. Johnson, Anna K. Unruh, Deborah Hammett, Jon Sarezky, Marie Brown, Carolina Riascos-Cuero, Emily J. Diekema, Emmy E. Ogawa, Miranda Chavez, Zuzana Kocsisova, Dennis Revie, Anniken M. Lydon, Peter A. Cognetti, Ashley A. Collins, Tariq Abusheikh, Erin K. Luippold, Kevin Myirski, Brian O. Rodríguez-Echevarría, Haley J. Plasman, Lara Baatenburg, Jesse Hendriksma, Christopher R. Knob, Max Semon, Cassandra Farrar, Xiao Zhu, Ali Dobbe, Marie-Isabelle B. Seydoux, Griffin Sadovsky, Shreya Prasad, Victoria Newcomb, Chad Gier, Dmitri Serjanov, Jules Wellinghoff, Maxwell T. Smith-Gee, and Alexandra H. Scoma

Subjects
Transposable element, Codon Adaptation Index, Euchromatin, Heterochromatin, transposons, evolution of heterochromatin, Investigations, Genome, Evolution, Molecular, 03 medical and health sciences, gene size, 0302 clinical medicine, melting characteristics, Species Specificity, codon bias, Genetics, Animals, Drosophila Proteins, Selection, Genetic, Codon, Molecular Biology, Genetics (clinical), 030304 developmental biology, Polytene Chromosomes, Repetitive Sequences, Nucleic Acid, Gene Rearrangement, 0303 health sciences, biology, Computational Biology, Molecular Sequence Annotation, Gene rearrangement, Exons, Genomics, biology.organism_classification, Introns, Drosophila melanogaster, Codon usage bias, DNA Transposable Elements, Drosophila, 030217 neurology & neurosurgery
Abstract

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Published
2015

24. Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm

Author

Ginell Elliott, Taoping Shi, Junchen Gu, Marco A. Marra, Philippe Gascard, Yan Zhou, Xiaoyun Xing, Daofeng Li, Chibo Hong, Angela Tam, Joseph F. Costello, Ting Wang, Pamela A. F. Madden, Nan Lin, Bo Zhang, Hyung Joo Lee, Michael Stevens, Peggy J. Farnham, Theresa A. Kadlecek, Henriette O'Geen, Baoxue Zhang, Arthur Weiss, Jia Zhou, Thea D. Tlsty, Martin Hirst, Vasavi Sundaram, Richard A. Moore, Raman P. Nagarajan, Keith L. Ligon, Jeffrey B. Cheng, Mahvash Sigaroudinia, Cecile L. Maire, and Rebecca F. Lowdon

Subjects
Genetics, Genome, Human, genetic processes, Bisulfite sequencing, Method, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, DNA Methylation, Biology, Differentially methylated regions, Organ Specificity, Data Interpretation, Statistical, DNA methylation, Humans, Illumina Methylation Assay, natural sciences, Methylated DNA immunoprecipitation, Epigenetics, RNA-Directed DNA Methylation, Algorithms, Genetics (clinical), Epigenomics
Abstract

DNA methylation plays key roles in diverse biological processes such as X chromosome inactivation, transposable element repression, genomic imprinting, and tissue-specific gene expression. Sequencing-based DNA methylation profiling provides an unprecedented opportunity to map and compare complete DNA methylomes. This includes one of the most widely applied technologies for measuring DNA methylation: methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq), coupled with a complementary method, methylation-sensitive restriction enzyme sequencing (MRE-seq). A computational approach that integrates data from these two different but complementary assays and predicts methylation differences between samples has been unavailable. Here, we present a novel integrative statistical framework M&M (for integration of MeDIP-seq and MRE-seq) that dynamically scales, normalizes, and combines MeDIP-seq and MRE-seq data to detect differentially methylated regions. Using sample-matched whole-genome bisulfite sequencing (WGBS) as a gold standard, we demonstrate superior accuracy and reproducibility of M&M compared to existing analytical methods for MeDIP-seq data alone. M&M leverages the complementary nature of MeDIP-seq and MRE-seq data to allow rapid comparative analysis between whole methylomes at a fraction of the cost of WGBS. Comprehensive analysis of nineteen human DNA methylomes with M&M reveals distinct DNA methylation patterns among different tissue types, cell types, and individuals, potentially underscoring divergent epigenetic regulation at different scales of phenotypic diversity. We find that differential DNA methylation at enhancer elements, with concurrent changes in histone modifications and transcription factor binding, is common at the cell, tissue, and individual levels, whereas promoter methylation is more prominent in reinforcing fundamental tissue identities.

Published
2013
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25. Intermediate DNA methylation is a conserved signature of genome regulation

Author

Keith L. Ligon, Philippe Gascard, Peggy J. Farnham, Cristian Coarfa, Ting Wang, Jonathan Mill, Xin Zhou, Chibo Hong, Mahvash Sigaroudinia, Misha Bilenky, Gary D. Stormo, Manolis Kellis, Joseph F. Costello, Ginell Elliott, Aleksandar Milosavljevic, Marco A. Marra, Thea D. Tlsty, Martin Hirst, Xiaoyun Xing, R. Alan Harris, Cecile L. Maire, Daofeng Li, Leonard C. Schalkwyk, Robert J.A. Bell, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, and Kellis, Manolis

Subjects
Epigenomics, General Physics and Astronomy, Biology, Synteny, Article, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, Mice, 03 medical and health sciences, 0302 clinical medicine, Epigenetics of physical exercise, Histone methylation, Animals, Humans, RNA-Directed DNA Methylation, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Genome, Human, General Chemistry, Methylation, DNA Methylation, Molecular biology, Histone Code, Gene Expression Regulation, Histone methyltransferase, DNA methylation, Illumina Methylation Assay, 030217 neurology & neurosurgery
Abstract

The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage., Many loci in the mammalian genome are intermediately methylated. Here, by comprehensively identifying these loci and quantifying their relationship with gene activity, the authors show that intermediate methylation is an evolutionarily conserved epigenomic signature of gene regulation.

Published
2014

26. Integrative analysis of 111 reference human epigenomes

Author

Daofeng Li, Tim R. Mercer, Wei Li, Lisa Helbling Chadwick, Jesse R. Dixon, Pouya Kheradpour, Joseph F. Costello, Pradipta R. Ray, John W. Whitaker, Peggy J. Farnham, Angela Tam, Vitor Onuchic, Robert A. Waterland, Misha Bilenky, James A. Thomson, Zhizhuo Zhang, Yaping Liu, Gerald Quon, Andrew J. Mungall, Steven J.M. Jones, Bradley E. Bernstein, Alexander Meissner, Melina Claussnitzer, Charles B. Epstein, Andreas R. Pfenning, Li-Huei Tsai, Laurie A. Boyer, Angela Yen, Ting Wang, Rajinder Kaul, Alireza Heravi-Moussavi, Danny Leung, Noam Shoresh, Michael T. McManus, Michael Stevens, John A. Stamatoyannopoulos, Mukul S. Bansal, Thea D. Tlsty, Susan J. Fisher, Manolis Kellis, Michael Q. Zhang, Aleksandar Milosavljevic, Viren Amin, Martin Hirst, Matthew D. Schultz, Joseph R. Ecker, Xinchen Wang, Jie Wu, Marco A. Marra, Kyle Siebenthall, Wei Wang, Ashwinikumar Kulkarni, Peter J. Sabo, R. Scott Hansen, Jianrong Wang, Michael J. Ziller, Richard A. Moore, Shane Neph, Richard C Sallari, Robert E. Thurman, Paz Polak, Wei Xie, Eric Chuah, Jason Ernst, Bing Ren, Nisha Rajagopal, Anshul Kundaje, Xin Zhou, Yi-Chieh Wu, Shamil R. Sunyaev, Ginell Elliott, Philippe Gascard, Soheil Feizi, Chibo Hong, R. Alan Harris, Ah Ram Kim, Philip L. De Jager, Rosa Karlic, R. David Hawkins, Matthew L. Eaton, Ryan Lister, Rebecca F. Lowdon, Annaick Carles, Elizabeta Gjoneska, David Haussler, Abhishek Sarkar, Nicholas A Sinnott-Armstrong, Wouter Meuleman, Lucas D. Ward, Kai How Farh, Richard Sandstrom, Arthur E. Beaudet, Theresa K. Canfield, Cristian Coarfa, Bo Zhang, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Picower Institute for Learning and Memory, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Yen, Angela, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ward, Lucas D., Sarkar, Abhishek Kulshreshtha, Quon, Gerald, Eaton, Matthew Lucas, Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Bansal, Mukul S., Feizi-Khankandi, Soheil, Kim, Ah Ram, Cowper Sal-lari, Richard, Sinnott-Armstrong, Nicholas A., Kellis, Manolis, Boyer, Laurie, Gjoneska, Elizabeta, and Tsai, Li-Huei

Subjects
Epigenomics, Datasets as Topic, ATAC-seq, Computational biology, Biology, Article, Epigenesis, Genetic, Histones, Reference Values, Computational epigenetics, Chromosomes, Human, Humans, Cell Lineage, Epigenetics, Cells, Cultured, Genetics, Regulation of gene expression, Multidisciplinary, Base Sequence, Genome, Human, Genetic Variation, DNA, Epigenome, DNA Methylation, Chromatin, Human genetics, Enhancer Elements, Genetic, Organ Specificity, RNA, Human genome, chromatin, histone, epigenome, tissue specificity, Genome-Wide Association Study
Abstract

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease., National Human Genome Research Institute (U.S.) (RC1HG005334), National Human Genome Research Institute (U.S.) (R01HG004037), National Human Genome Research Institute (U.S.) (R01HG004037-S1), National Human Genome Research Institute (U.S.) (RO1NS078839), National Science Foundation (U.S.) (CAREER Award 1254200)

Published
2014

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