15 results on '"Eliezer M, Van Allen"'
Search Results
2. Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer
- Author
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Paloma Cejas, Yingtian Xie, Alba Font-Tello, Klothilda Lim, Sudeepa Syamala, Xintao Qiu, Alok K. Tewari, Neel Shah, Holly M. Nguyen, Radhika A. Patel, Lisha Brown, Ilsa Coleman, Wenzel M. Hackeng, Lodewijk Brosens, Koen M. A. Dreijerink, Leigh Ellis, Sarah Abou Alaiwi, Ji-Heui Seo, Sylvan Baca, Himisha Beltran, Francesca Khani, Mark Pomerantz, Alessandra Dall’Agnese, Jett Crowdis, Eliezer M. Van Allen, Joaquim Bellmunt, Colm Morrisey, Peter S. Nelson, James DeCaprio, Anna Farago, Nicholas Dyson, Benjamin Drapkin, X. Shirley Liu, Matthew Freedman, Michael C. Haffner, Eva Corey, Myles Brown, and Henry W. Long
- Subjects
Science - Abstract
Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.
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- 2021
- Full Text
- View/download PDF
3. Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer
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Tanya E. Keenan, Jennifer L. Guerriero, Romualdo Barroso-Sousa, Tianyu Li, Tess O’Meara, Anita Giobbie-Hurder, Nabihah Tayob, Jiani Hu, Mariano Severgnini, Judith Agudo, Ines Vaz-Luis, Leilani Anderson, Victoria Attaya, Jihye Park, Jake Conway, Meng Xiao He, Brendan Reardon, Erin Shannon, Gerburg Wulf, Laura M. Spring, Rinath Jeselsohn, Ian Krop, Nancy U. Lin, Ann Partridge, Eric P. Winer, Elizabeth A. Mittendorf, David Liu, Eliezer M. Van Allen, and Sara M. Tolaney
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Science - Abstract
A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates
- Published
- 2021
- Full Text
- View/download PDF
4. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma
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Ziad Bakouny, David A. Braun, Sachet A. Shukla, Wenting Pan, Xin Gao, Yue Hou, Abdallah Flaifel, Stephen Tang, Alice Bosma-Moody, Meng Xiao He, Natalie Vokes, Jackson Nyman, Wanling Xie, Amin H. Nassar, Sarah Abou Alaiwi, Ronan Flippot, Gabrielle Bouchard, John A. Steinharter, Pier Vitale Nuzzo, Miriam Ficial, Miriam Sant’Angelo, Juliet Forman, Jacob E. Berchuck, Shaan Dudani, Kevin Bi, Jihye Park, Sabrina Camp, Maura Sticco-Ivins, Laure Hirsch, Sylvan C. Baca, Megan Wind-Rotolo, Petra Ross-Macdonald, Maxine Sun, Gwo-Shu Mary Lee, Steven L. Chang, Xiao X. Wei, Bradley A. McGregor, Lauren C. Harshman, Giannicola Genovese, Leigh Ellis, Mark Pomerantz, Michelle S. Hirsch, Matthew L. Freedman, Michael B. Atkins, Catherine J. Wu, Thai H. Ho, W. Marston Linehan, David F. McDermott, Daniel Y. C. Heng, Srinivas R. Viswanathan, Sabina Signoretti, Eliezer M. Van Allen, and Toni K. Choueiri
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Science - Abstract
Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.
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- 2021
- Full Text
- View/download PDF
5. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant
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Tarek H. Mouhieddine, Adam S. Sperling, Robert Redd, Jihye Park, Matthew Leventhal, Christopher J. Gibson, Salomon Manier, Amin H. Nassar, Marzia Capelletti, Daisy Huynh, Mark Bustoros, Romanos Sklavenitis-Pistofidis, Sabrin Tahri, Kalvis Hornburg, Henry Dumke, Muhieddine M. Itani, Cody J. Boehner, Chia-Jen Liu, Saud H. AlDubayan, Brendan Reardon, Eliezer M. Van Allen, Jonathan J. Keats, Chip Stewart, Shaadi Mehr, Daniel Auclair, Robert L. Schlossman, Nikhil C. Munshi, Kenneth C. Anderson, David P. Steensma, Jacob P. Laubach, Paul G. Richardson, Jerome Ritz, Benjamin L. Ebert, Robert J. Soiffer, Lorenzo Trippa, Gad Getz, Donna S. Neuberg, and Irene M. Ghobrial
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Science - Abstract
Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
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- 2020
- Full Text
- View/download PDF
6. Metabolomic adaptations and correlates of survival to immune checkpoint blockade
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Haoxin Li, Kevin Bullock, Carino Gurjao, David Braun, Sachet A. Shukla, Dominick Bossé, Aly-Khan A. Lalani, Shuba Gopal, Chelsea Jin, Christine Horak, Megan Wind-Rotolo, Sabina Signoretti, David F. McDermott, Gordon J. Freeman, Eliezer M. Van Allen, Stuart L. Schreiber, F. Stephen Hodi, William R. Sellers, Levi A. Garraway, Clary B. Clish, Toni K. Choueiri, and Marios Giannakis
- Subjects
Science - Abstract
Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.
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- 2019
- Full Text
- View/download PDF
7. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
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David Liu, Philip Abbosh, Daniel Keliher, Brendan Reardon, Diana Miao, Kent Mouw, Amaro Weiner-Taylor, Stephanie Wankowicz, Garam Han, Min Yuen Teo, Catharine Cipolla, Jaegil Kim, Gopa Iyer, Hikmat Al-Ahmadie, Essel Dulaimi, David Y. T. Chen, R. Katherine Alpaugh, Jean Hoffman-Censits, Levi A. Garraway, Gad Getz, Scott L. Carter, Joaquim Bellmunt, Elizabeth R. Plimack, Jonathan E. Rosenberg, and Eliezer M. Van Allen
- Subjects
Science - Abstract
The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
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- 2017
- Full Text
- View/download PDF
8. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
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Viktor A. Adalsteinsson, Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah C. Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M. Francis, Cheng-Zhong Zhang, Ofir Cohen, Coyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O’Connor, Seong H. Jeong, Rachel Leeson, Rachel M. Barry, Joseph F. Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G. Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M. Oliver, Lori Marini, Adrienne G. Waks, Lauren C. Harshman, Sara M. Tolaney, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary-Ellen Taplin, Cory M. Johannessen, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz, J. Christopher Love, and Matthew Meyerson
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Science - Abstract
Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.
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- 2017
- Full Text
- View/download PDF
9. Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer
- Author
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Romualdo Barroso-Sousa, Tanya Keenan, Elizabeth A. Mittendorf, Anita Giobbie-Hurder, Ann H. Partridge, Sara M. Tolaney, Gerburg M. Wulf, Laura Spring, Rinath Jeselsohn, Jake Conway, Brendan Reardon, Tianyu Li, Tess O’Meara, Ian E. Krop, Ines Vaz-Luis, Jihye Park, Erin Shannon, Jiani Hu, Victoria Attaya, Meng Xiao He, Eric P. Winer, Leilani Anderson, Nabihah Tayob, Judith Agudo, Jennifer L. Guerriero, Eliezer M. Van Allen, Nan Lin, Mariano Severgnini, and David Liu
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Male ,Oncology ,General Physics and Astronomy ,Phases of clinical research ,Pembrolizumab ,B7-H1 Antigen ,chemistry.chemical_compound ,Breast cancer ,Antineoplastic Combined Chemotherapy Protocols ,Neoplasm Metastasis ,Immune Checkpoint Inhibitors ,Antigen Presentation ,Multidisciplinary ,Genomics ,Ketones ,Middle Aged ,Metastatic breast cancer ,Survival Rate ,Treatment Outcome ,Receptors, Estrogen ,Cytokines ,Biomarker (medicine) ,Female ,Receptors, Progesterone ,Signal Transduction ,Eribulin ,Adult ,medicine.medical_specialty ,Combination therapy ,Science ,Breast Neoplasms ,Antibodies, Monoclonal, Humanized ,Article ,General Biochemistry, Genetics and Molecular Biology ,Genetic Heterogeneity ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,medicine ,Humans ,Furans ,Aged ,Genome, Human ,business.industry ,Gene Expression Profiling ,Cancer ,Estrogens ,General Chemistry ,medicine.disease ,chemistry ,Drug Resistance, Neoplasm ,Mutation ,business - Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659., A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates
- Published
- 2021
10. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant
- Author
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Robert A. Redd, Matthew Leventhal, Irene M. Ghobrial, Nikhil C. Munshi, Christopher J. Gibson, Jerome Ritz, Amin Nassar, Chip Stewart, Jihye Park, Romanos Sklavenitis-Pistofidis, Marzia Capelletti, Cody J. Boehner, David P. Steensma, Saud H. AlDubayan, Daniel Auclair, Lorenzo Trippa, Muhieddine M. Itani, Benjamin L. Ebert, Kalvis Hornburg, Shaadi Mehr, Mark Bustoros, Robert L. Schlossman, Henry Dumke, Jacob P. Laubach, Adam S. Sperling, Gad Getz, Salomon Manier, Paul G. Richardson, Eliezer M. Van Allen, Tarek H. Mouhieddine, Sabrin Tahri, Kenneth C. Anderson, Robert J. Soiffer, Daisy Huynh, Donna Neuberg, Brendan Reardon, Chia Jen Liu, Jonathan J Keats, Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Department of Hematology [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Brigham and Women's Hospital [Boston], Massachusetts General Hospital [Boston], The Translational Genomics Research Institute (TGen), Multiple Myeloma Research Foundation [Norwalk, CT, États-Unis], Harvard T.H. Chan School of Public Health, We would also like to thank the International Myeloma Society (IMS) for their support. This work was supported by grants from the Multiple Myeloma Research Foundation (MMRF), Adelson Medical Research Foundation (AMRF), Stand Up to Cancer (SU2C) and the Leukemia and Lymphoma Society (LLS) awarded to Dr. Irene M. Ghobrial., Bodescot, Myriam, Lille Neurosciences & Cognition - U 1172 (LilNCog), and Harvard University-Massachusetts Institute of Technology (MIT)
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0301 basic medicine ,Oncology ,Male ,[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,Cancer therapy ,medicine.medical_treatment ,General Physics and Astronomy ,Myeloma ,DNA Methyltransferase 3A ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Cancer genomics ,DNA (Cytosine-5-)-Methyltransferases ,lcsh:Science ,Multiple myeloma ,Aged, 80 and over ,Multidisciplinary ,Hematopoietic Stem Cell Transplantation ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Middle Aged ,Progression-Free Survival ,3. Good health ,DNA-Binding Proteins ,Haematopoiesis ,030220 oncology & carcinogenesis ,Female ,Stem cell ,Multiple Myeloma ,Adult ,medicine.medical_specialty ,Science ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Transplantation, Autologous ,General Biochemistry, Genetics and Molecular Biology ,Article ,Dioxygenases ,03 medical and health sciences ,Young Adult ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Proto-Oncogene Proteins ,medicine ,Humans ,Progression-free survival ,Aged ,Chemotherapy ,Haematological cancer ,business.industry ,Induction chemotherapy ,Cancer ,General Chemistry ,medicine.disease ,Hematopoiesis ,Transplantation ,030104 developmental biology ,Mutation ,lcsh:Q ,Tumor Suppressor Protein p53 ,business - Abstract
Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003–2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p, Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
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- 2020
11. Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer
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Sarah Abou Alaiwi, Radhika A. Patel, Nicholas J. Dyson, Alba Font-Tello, Myles Brown, Wenzel M. Hackeng, Peter S. Nelson, Lisha G. Brown, Neel Shah, Himisha Beltran, Alok K. Tewari, Sylvan C. Baca, Michael C. Haffner, Paloma Cejas, Yingtian Xie, Benjamin J. Drapkin, Xintao Qiu, Sudeepa Syamala, Lodewijk A.A. Brosens, Colm Morrisey, Eva Corey, Holly M. Nguyen, Alessandra Dall’Agnese, Mark Pomerantz, Ilsa Coleman, Koen M.A. Dreijerink, Matthew L. Freedman, Leigh Ellis, Eliezer M. Van Allen, X. Shirley Liu, Francesca Khani, Klothilda Lim, Anna F. Farago, James A. DeCaprio, Ji-Heui Seo, Henry W. Long, Jett Crowdis, Joaquim Bellmunt, Internal medicine, CCA - Cancer biology and immunology, and Amsterdam Gastroenterology Endocrinology Metabolism
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Male ,Science ,Neuronal differentiation ,General Physics and Astronomy ,Biology ,Mutually exclusive events ,General Biochemistry, Genetics and Molecular Biology ,Article ,Epigenesis, Genetic ,Prostate cancer ,medicine ,Cancer genomics ,Basic Helix-Loop-Helix Transcription Factors ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Humans ,Epigenetics ,Transcription factor ,Multidisciplinary ,Prostatic Neoplasms ,General Chemistry ,medicine.disease ,Chromatin ,digestive system diseases ,Carcinoma, Neuroendocrine ,Gene Expression Regulation, Neoplastic ,ASCL1 ,Neuroendocrine cancer ,NEUROD1 ,Cancer research ,Transcription Factors - Abstract
Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy., Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.
- Published
- 2021
12. Metabolomic adaptations and correlates of survival to immune checkpoint blockade
- Author
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Levi A. Garraway, Dominick Bossé, Sabina Signoretti, David F. McDermott, Carino Gurjao, Christine Horak, Sachet A. Shukla, William R. Sellers, Shuba Gopal, Aly-Khan A. Lalani, Gordon J. Freeman, Megan Wind-Rotolo, Haoxin Li, Kevin Bullock, Marios Giannakis, Eliezer M. Van Allen, F. Stephen Hodi, Chelsea Jin, Clary B. Clish, Stuart L. Schreiber, David A. Braun, and Toni K. Choueiri
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Male ,0301 basic medicine ,Oncology ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,General Physics and Astronomy ,Kaplan-Meier Estimate ,chemistry.chemical_compound ,0302 clinical medicine ,Renal cell carcinoma ,lcsh:Science ,Melanoma ,Kynurenine ,Clinical Trials as Topic ,Multidisciplinary ,biology ,Tryptophan ,Middle Aged ,Adaptation, Physiological ,Kidney Neoplasms ,3. Good health ,Nivolumab ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Antibody ,medicine.medical_specialty ,Science ,Antineoplastic Agents ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Metabolomics ,Everolimus ,Carcinoma, Renal Cell ,Aged ,business.industry ,Cancer ,General Chemistry ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Blockade ,030104 developmental biology ,chemistry ,biology.protein ,lcsh:Q ,business ,Biomarkers - Abstract
Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors., Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.
- Published
- 2019
13. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma
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Xin Gao, Maxine Sun, Sabina Signoretti, Michael B. Atkins, Catherine J. Wu, Shaan Dudani, Thai H. Ho, Michelle S. Hirsch, Bradley Alexander McGregor, Ziad Bakouny, John A. Steinharter, Daniel Y.C. Heng, Miriam Sant'Angelo, Sylvan C. Baca, Eliezer M. Van Allen, David A. Braun, Lauren C. Harshman, Stephen Tang, Alice Bosma-Moody, Ronan Flippot, Pier Vitale Nuzzo, Kevin Bi, Amin Nassar, Yue Hou, Sarah Abou Alaiwi, Mark Pomerantz, Natalie I. Vokes, W. Marston Linehan, Megan Wind-Rotolo, Laure Hirsch, Giannicola Genovese, David F. McDermott, Jackson Nyman, Juliet Forman, Wanling Xie, Toni K. Choueiri, Jacob E. Berchuck, Jihye Park, Wenting Pan, Sabrina Y. Camp, Meng Xiao He, Gabrielle Bouchard, Xiao X. Wei, Matthew L. Freedman, Gwo-Shu Mary Lee, Petra Ross-Macdonald, Maura Sticco-Ivins, Sachet A. Shukla, Steven L. Chang, Leigh Ellis, Abdallah Flaifel, Srinivas R. Viswanathan, and Miriam Ficial
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0301 basic medicine ,Transcription, Genetic ,Programmed Cell Death 1 Receptor ,General Physics and Astronomy ,medicine.disease_cause ,B7-H1 Antigen ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Renal cell carcinoma ,CDKN2A ,Cancer genomics ,CTLA-4 Antigen ,Immune Checkpoint Inhibitors ,BAP1 ,Mutation ,Multidisciplinary ,High-Throughput Nucleotide Sequencing ,Phenotype ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Tumour immunology ,Ubiquitin Thiolesterase ,Signal Transduction ,Science ,Tumour heterogeneity ,Antigen presentation ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Carcinoma, Renal Cell ,Cyclin-Dependent Kinase Inhibitor p16 ,Rhabdoid Tumor ,Retrospective Studies ,Gene Expression Profiling ,Tumor Suppressor Proteins ,General Chemistry ,Immune Checkpoint Proteins ,medicine.disease ,Survival Analysis ,Gene expression profiling ,030104 developmental biology ,Cancer research ,Immunization - Abstract
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.
- Published
- 2021
14. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
- Author
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Gopa Iyer, Jonathan E. Rosenberg, Philip Abbosh, Brendan Reardon, Joaquim Bellmunt, Scott L. Carter, Jean H. Hoffman-Censits, Amaro Weiner-Taylor, Hikmat Al-Ahmadie, Garam Han, R. Katherine Alpaugh, Elizabeth R. Plimack, Eliezer M. Van Allen, Min Yuen Teo, Kent W. Mouw, Jaegil Kim, Daniel Keliher, Stephanie A. Wankowicz, Levi A. Garraway, Essel Dulaimi, Catharine Kline Cipolla, Diana Miao, Gad Getz, David Y.T. Chen, and David Liu
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0301 basic medicine ,Male ,Oncology ,medicine.medical_treatment ,DNA Mutational Analysis ,General Physics and Astronomy ,Cohort Studies ,Antineoplastic Combined Chemotherapy Protocols ,lcsh:Science ,Neoadjuvant therapy ,Aged, 80 and over ,Multidisciplinary ,Muscle invasive ,Middle Aged ,Neoadjuvant Therapy ,3. Good health ,Survival Rate ,Treatment Outcome ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Tumour heterogeneity ,Urology ,Science ,Urinary Bladder ,MEDLINE ,Cystectomy ,General Biochemistry, Genetics and Molecular Biology ,Article ,Clonal Evolution ,03 medical and health sciences ,Text mining ,Internal medicine ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Survival rate ,Aged ,Cisplatin ,Bladder cancer ,business.industry ,Carcinoma ,Cancer ,General Chemistry ,medicine.disease ,Immune checkpoint ,030104 developmental biology ,Urinary Bladder Neoplasms ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,Chemotherapy resistant ,lcsh:Q ,Transcriptome ,business - Abstract
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies., The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
- Published
- 2017
15. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
- Author
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Zhenwei Zhang, Laura Polacek, Sara M. Tolaney, Joshua M. Francis, Samuel S. Freeman, Paz Polak, Rachel Leeson, J. Christopher Love, Huiming Ding, Sairah Mahmud, Nelly Oliver, Rachel M. Barry, Atish D. Choudhury, Levi A. Garraway, Gregory Gydush, Andrea Saltzman, Eliezer M. Van Allen, Coyin Oh, Viktor A. Adalsteinsson, Justin Rhoades, Jesse S. Boehm, Sarah C. Reed, Seong Ho Jeong, Todd R. Golub, Karla Helvie, Matthew Meyerson, Lauren C. Harshman, Gad Getz, Ignaty Leshchiner, Jens G. Lohr, Chip Stewart, Heather A. Parsons, Jaegil Kim, Adrienne G. Waks, Mari Nakabayashi, Lori Marini, Mara Rosenberg, Edward P. O’Connor, Daniel Rosebrock, Denis Loginov, Daniel G. Stover, Rebecca A. Santiago, Nikhil Wagle, Joseph F. Kramkowski, Mary-Ellen Taplin, Eric P. Winer, Nan Lin, Ofir Cohen, Cheng-Zhong Zhang, Dimitri Livitz, Emily Lipscomb, Gavin Ha, Molly Schleicher, Denisse Rotem, Max Lloyd, Margaret S. Merrill, and Cory M. Johannessen
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Science ,Concordance ,DNA Mutational Analysis ,Sequencing data ,Gene Dosage ,General Physics and Astronomy ,Breast Neoplasms ,Metastatic tumor ,Gene dosage ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Antigens, Neoplasm ,Prostate ,Internal medicine ,Exome Sequencing ,Humans ,Medicine ,Prospective Studies ,Neoplasm Metastasis ,lcsh:Science ,Exome sequencing ,Multidisciplinary ,business.industry ,Prostatic Neoplasms ,DNA, Neoplasm ,General Chemistry ,Molecular biology ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Cell-free fetal DNA ,Female ,lcsh:Q ,business ,Cell-Free Nucleic Acids ,Software - Abstract
Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing., Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.
- Published
- 2017
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