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2. DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance

Author

Conway, Kathleen, Edmiston, Sharon N., Vondras, Amanda, Reiner, Allison, Corcoran, David L., Shen, Ronglai, Parrish, Eloise A., Hao, Honglin, Lin, Lan, Kenney, Jessica M., Ilelaboye, Gbemisola, Kostrzewa, Caroline E., Kuan, Pei Fen, Busam, Klaus J., Lezcano, Cecilia, Lee, Tim K., Hernando, Eva, Googe, Paul B., Ollila, David W., Moschos, Stergios, Gorlov, Ivan, Amos, Christopher I., Ernstoff, Marc S., Cust, Anne E., Wilmott, James S., Scolyer, Richard A., Mann, Graham J., Vergara, Ismael A., Ko, Jennifer, Rees, Judy R., Yan, Shaofeng, Nagore, Eduardo, Bosenberg, Marcus, Rothberg, Bonnie Gould, Osman, Iman, Lee, Jeffrey E., Saenger, Yvonne, Bogner, Paul, Thompson, Cheryl L., Gerstenblith, Meg, Holmen, Sheri L., Funchain, Pauline, Brunsgaard, Elise, Depcik-Smith, Natalie D., Luo, Li, Boyce, Tawny, Orlow, Irene, Begg, Colin B., Berwick, Marianne, Thomas, Nancy E., Berwick, Marianne, Luo, Li, Boyce, Tawny W., Reynolds, Adam Z., Wiggins, Charles, Thomas, Nancy E., Conway, Kathleen, Edmiston, Sharon N., Ollila, David W., Hao, Honglin, Parrish, Eloise, Googe, Paul B., Moschos, Stergios J., Corcoran, David, Vondras, Amanda, Tsai, Yihsuan S., Lin, Lan, Shen, Ronglai, Begg, Colin B., Arora, Arshi, Seshan, Venkatraman, Reiner, Allie, Kostrzewa, Caroline E., Busam, Klaus J., Orlow, Irene, Lezcano, Cecilia, Kenney, Jessica M., Sadeghi, Keimya D., OʼConnell, Kelli, Ilelaboye, Gbemisola Elizabeth, Parmar, Heta, Leong, Siok, Corrales, Sergio, Scolyer, Richard A., Cust, Anne E., Wilmott, James S., Mann, Graham J., Shang, Ping, Burke, Hazel, Ferguson, Peter M., Jakrot, Valerie, Lee, Tim K., Hernando, Eva, Osman, Iman, Hanniford, Douglas, Argibay, Diana, Moran, Una, Heguy, Adriana, Ramaswami, Sitharam, Amos, Christopher I., Gorlov, Ivan P., Zhu, Dakai, Ernstoff, Marc, Bogner, Paul N., Lee, Jeffrey E., Rees, Judy R., Yan, Shaofeng, Gerstenblith, Meg R., Thompson, Cheryl, Ko, Jennifer S., Funchain, Pauline, Ngo, Peter, Bosenberg, Marcus, Gould Rothberg, Bonnie E., Panse, Gauri, Saenger, Yvonne M., Fullerton, Benjamin T., Holmen, Sheri L., Colman, Howard, Brunsgaard, Elise K., Wada, David, Nagore, Eduardo, Manrique-Silva, Esperanza, Requena, Celia, Traves, Victor, Millan-Esteban, David, and Rainka, Michelle

Published
2024
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5. Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st–3rd, 2022—Naples, Italy)

Author

Ascierto, Paolo A., Agarwala, Sanjiv S., Warner, Allison Betof, Ernstoff, Marc S., Fox, Bernard A., Gajewski, Thomas F., Galon, Jérôme, Garbe, Claus, Gastman, Brian R., Gershenwald, Jeffrey E., Kalinski, Pawel, Krogsgaard, Michelle, Leidner, Rom S., Lo, Roger S., Menzies, Alexander M., Michielin, Olivier, Poulikakos, Poulikos I., Weber, Jeffrey S., Caracò, Corrado, Osman, Iman, Puzanov, Igor, and Thurin, Magdalena

Published
2023
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7. An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma

Author

Davalos, Veronica, Lovell, Claudia D., Von Itter, Richard, Dolgalev, Igor, Agrawal, Praveen, Baptiste, Gillian, Kahler, David J., Sokolova, Elena, Moran, Sebastian, Piqué, Laia, Vega-Saenz de Miera, Eleazar, Fontanals-Cirera, Barbara, Karz, Alcida, Tsirigos, Aristotelis, Yun, Chi, Darvishian, Farbod, Etchevers, Heather C., Osman, Iman, Esteller, Manel, Schober, Markus, and Hernando, Eva

Published
2023
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10. TERT, BRAF, and NRAS Mutational Heterogeneity between Paired Primary and Metastatic Melanoma Tumors.

Author

Chang, Gregory, Wiggins, Jennifer, Corless, Broderick, Syeda, Mahrukh, Tadepalli, Jyothirmayee, Blake, Shria, Fleming, Nathaniel, Darvishian, Farbod, Pavlick, Anna, Berman, Russell, Shapiro, Richard, Shao, Yongzhao, Karlin-Neumann, George, Spittle, Cindy, Osman, Iman, and Polsky, David

Subjects
Antineoplastic Agents, DNA Mutational Analysis, Drug Resistance, Neoplasm, Female, GTP Phosphohydrolases, Genetic Heterogeneity, Humans, Longitudinal Studies, Male, Melanoma, Membrane Proteins, Middle Aged, Mutation, Neoplasms, Second Primary, Prospective Studies, Proto-Oncogene Proteins B-raf, Skin, Skin Neoplasms, Telomerase
Abstract

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, TERT-124C>T, and TERT-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%), and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT-124C>T and TERT-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one had different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in at least one of their metastases. Overall, we identified mutational heterogeneity in 18 of 99 patients (18%). These results suggest that some primary melanomas may be composed of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

Published
2020

13. Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition

Author

Chat, Vylyny, Ferguson, Robert, Simpson, Danny, Kazlow, Esther, Lax, Rebecca, Moran, Una, Pavlick, Anna, Frederick, Dennie, Boland, Genevieve, Sullivan, Ryan, Ribas, Antoni, Flaherty, Keith, Osman, Iman, Weber, Jeffrey, and Kirchhoff, Tomas

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Clinical Trials and Supportive Activities, Autoimmune Disease, Genetics, Cancer, Prevention, Human Genome, Aetiology, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Autoimmune Diseases, Biomarkers, Tumor, CTLA-4 Antigen, Female, Genetic Predisposition to Disease, Germ Cells, Humans, Immunotherapy, Interleukin-2, Interleukins, Male, Melanoma, Middle Aged, Polymorphism, Single Nucleotide, Programmed Cell Death 1 Receptor, Risk Factors, Autoimmunity, Germline variants, Immune-checkpoint inhibition, Oncology and carcinogenesis
Abstract

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

Published
2019

16. Deep Learning and Pathomics Analyses Reveal Cell Nuclei as Important Features for Mutation Prediction of BRAF-Mutated Melanomas

Author

Kim, Randie H., Nomikou, Sofia, Coudray, Nicolas, Jour, George, Dawood, Zarmeena, Hong, Runyu, Esteva, Eduardo, Sakellaropoulos, Theodore, Donnelly, Douglas, Moran, Una, Hatzimemos, Aristides, Weber, Jeffrey S., Razavian, Narges, Aifantis, Iannis, Fenyo, David, Snuderl, Matija, Shapiro, Richard, Berman, Russell S., Osman, Iman, and Tsirigos, Aristotelis

Published
2022
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17. Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations

Author

Kugel, Curtis H, Douglass, Stephen M, Webster, Marie R, Kaur, Amanpreet, Liu, Qin, Yin, Xiangfan, Weiss, Sarah A, Darvishian, Farbod, Al-Rohil, Rami N, Ndoye, Abibatou, Behera, Reeti, Alicea, Gretchen M, Ecker, Brett L, Fane, Mitchell, Allegrezza, Michael J, Svoronos, Nikolaos, Kumar, Vinit, Wang, Daniel Y, Somasundaram, Rajasekharan, Hu-Lieskovan, Siwen, Ozgun, Alpaslan, Herlyn, Meenhard, Conejo-Garcia, Jose R, Gabrilovich, Dmitry, Stone, Erica L, Nowicki, Theodore S, Sosman, Jeffrey, Rai, Rajat, Carlino, Matteo S, Long, Georgina V, Marais, Richard, Ribas, Antoni, Eroglu, Zeynep, Davies, Michael A, Schilling, Bastian, Schadendorf, Dirk, Xu, Wei, Amaravadi, Ravi K, Menzies, Alexander M, McQuade, Jennifer L, Johnson, Douglas B, Osman, Iman, and Weeraratna, Ashani T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Vaccine Related, Immunization, Aging, 2.1 Biological and endogenous factors, Aetiology, Age Factors, Animals, Antineoplastic Agents, Immunological, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Immunomodulation, Melanoma, Mice, Mice, Transgenic, Neoplasms, Programmed Cell Death 1 Receptor, T-Lymphocytes, Regulatory, Tumor Microenvironment, Xenograft Model Antitumor Assays, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347-56. ©2018 AACR See related commentary by Pawelec, p. 5193.

Published
2018

18. Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 2nd – 4th, 2021, Italy)

Author

Ascierto, Paolo A., Agarwala, Sanjiv S., Blank, Christian, Caracò, Corrado, Carvajal, Richard D., Ernstoff, Marc S., Ferrone, Soldano, Fox, Bernard A., Gajewski, Thomas F., Garbe, Claus, Grob, Jean-Jacques, Hamid, Omid, Krogsgaard, Michelle, Lo, Roger S., Lund, Amanda W., Madonna, Gabriele, Michielin, Olivier, Neyns, Bart, Osman, Iman, Peters, Solange, Poulikakos, Poulikos I., Quezada, Sergio A., Reinfeld, Bradley, Zitvogel, Laurence, Puzanov, Igor, and Thurin, Magdalena

Published
2022
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22. Association of Initial Viral Load in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Patients with Outcome and Symptoms

Author

Argyropoulos, Kimon V., Serrano, Antonio, Hu, Jiyuan, Black, Margaret, Feng, Xiaojun, Shen, Guomiao, Call, Melissa, Kim, Min J., Lytle, Andrew, Belovarac, Brendan, Vougiouklakis, Theodore, Lin, Lawrence H., Moran, Una, Heguy, Adriana, Troxel, Andrea, Snuderl, Matija, Osman, Iman, Cotzia, Paolo, and Jour, George

Published
2020
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25. Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma

Author

Femel, Julia, primary, Hill, Cameron, additional, Illa Bochaca, Irineu, additional, Booth, Jamie L., additional, Asnaashari, Tina G., additional, Steele, Maria M., additional, Moshiri, Ata S., additional, Do, Hyungrok, additional, Zhong, Judy, additional, Osman, Iman, additional, Leachman, Sancy A., additional, Tsujikawa, Takahiro, additional, White, Kevin P., additional, Chang, Young H., additional, and Lund, Amanda W., additional

Published
2024
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28. A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer

Author

Lazar, Vladimir, Rubin, Eitan, Depil, Stephane, Pawitan, Yudi, Martini, Jean-François, Gomez-Navarro, Jesus, Yver, Antoine, Kan, Zhengyin, Dry, Jonathan R, Kehren, Jeanne, Validire, Pierre, Rodon, Jordi, Vielh, Philippe, Ducreux, Michel, Galbraith, Susan, Lehnert, Manfred, Onn, Amir, Berger, Raanan, Pierotti, Marco A, Porgador, Angel, Pramesh, CS, Ye, Ding-wei, Carvalho, Andre L, Batist, Gerald, Le Chevalier, Thierry, Morice, Philippe, Besse, Benjamin, Vassal, Gilles, Mortlock, Andrew, Hansson, Johan, Berindan-Neagoe, Ioana, Dann, Robert, Haspel, Joel, Irimie, Alexandru, Laderman, Steve, Nechushtan, Hovav, Omari, Amal S Al, Haywood, Trent, Bresson, Catherine, Soo, Khee Chee, Osman, Iman, Mata, Hilario, Lee, Jack J, Jhaveri, Komal, Meurice, Guillaume, Palmer, Gary, Lacroix, Ludovic, Koscielny, Serge, Eterovic, Karina Agda, Blay, Jean-Yves, Buller, Richard, Eggermont, Alexander, Schilsky, Richard L, Mendelsohn, John, Soria, Jean-Charles, Rothenberg, Mace, Scoazec, Jean-Yves, Hong, Waun Ki, and Kurzrock, Razelle

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Lung, Biotechnology, Cancer, Lung Cancer, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Precision Medicine, Transcriptome, Tri-therapy, NSCLC, targeted therapies, algorithm, pathway, tri-therapy, Oncology and carcinogenesis
Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.

Published
2015

29. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies

Author

Lin, Luping, Sabnis, Amit J, Chan, Elton, Olivas, Victor, Cade, Lindsay, Pazarentzos, Evangelos, Asthana, Saurabh, Neel, Dana, Yan, Jenny Jiacheng, Lu, Xinyuan, Pham, Luu, Wang, Mingxue M, Karachaliou, Niki, Cao, Maria Gonzalez, Manzano, Jose Luis, Ramirez, Jose Luis, Torres, Jose Miguel Sanchez, Buttitta, Fiamma, Rudin, Charles M, Collisson, Eric A, Algazi, Alain, Robinson, Eric, Osman, Iman, Muñoz-Couselo, Eva, Cortes, Javier, Frederick, Dennie T, Cooper, Zachary A, McMahon, Martin, Marchetti, Antonio, Rosell, Rafael, Flaherty, Keith T, Wargo, Jennifer A, and Bivona, Trever G

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Cancer, Adaptor Proteins, Signal Transducing, Animals, Biomarkers, Tumor, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Gene Knockdown Techniques, Genes, ras, HEK293 Cells, HT29 Cells, Heterografts, Hippo Signaling Pathway, Humans, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Targeted Therapy, Mutation, Phosphoproteins, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins B-raf, Transcription Factors, YAP-Signaling Proteins, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

Published
2015

31. Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 3rd–5th, 2020, Italy)

Author

Ascierto, Paolo A., Blank, Christian, Dummer, Reinhard, Ernstoff, Marc S., Ferrone, Soldano, Fox, Bernard A., Gajewski, Thomas F., Garbe, Claus, Hwu, Patrick, Kalinski, Pawel, Krogsgaard, Michelle, Lo, Roger S., Luke, Jason J., Neyns, Bart, Postow, Michael A., Quezada, Sergio A., Teng, Michele W. L., Trinchieri, Giorgio, Testori, Alessandro, Caracò, Corrado, Osman, Iman, Puzanov, Igor, and Thurin, Magdalena

Published
2021
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37. Copy number and gene expression differences between African American and Caucasian American prostate cancer

Author

Rose, Amy E, Satagopan, Jaya M, Oddoux, Carole, Zhou, Qin, Xu, Ruliang, Olshen, Adam B, Yu, Jessie Z, Dash, Atreya, Jean-Gilles, Jerome, Reuter, Victor, Gerald, William L, Lee, Peng, and Osman, Iman

Abstract

Abstract Background The goal of our study was to investigate the molecular underpinnings associated with the relatively aggressive clinical behavior of prostate cancer (PCa) in African American (AA) compared to Caucasian American (CA) patients using a genome-wide approach. Methods AA and CA patients treated with radical prostatectomy (RP) were frequency matched for age at RP, Gleason grade, and tumor stage. Array-CGH (BAC SpectralChip2600) was used to identify genomic regions with significantly different DNA copy number between the groups. Gene expression profiling of the same set of tumors was also evaluated using Affymetrix HG-U133 Plus 2.0 arrays. Concordance between copy number alteration and gene expression was examined. A second aCGH analysis was performed in a larger validation cohort using an oligo-based platform (Agilent 244K). Results BAC-based array identified 27 chromosomal regions with significantly different copy number changes between the AA and CA tumors in the first cohort (Fisher's exact test, P < 0.05). Copy number alterations in these 27 regions were also significantly associated with gene expression changes. aCGH performed in a larger, independent cohort of AA and CA tumors validated 4 of the 27 (15%) most significantly altered regions from the initial analysis (3q26, 5p15-p14, 14q32, and 16p11). Functional annotation of overlapping genes within the 4 validated regions of AA/CA DNA copy number changes revealed significant enrichment of genes related to immune response. Conclusions Our data reveal molecular alterations at the level of gene expression and DNA copy number that are specific to African American and Caucasian prostate cancer and may be related to underlying differences in immune response.

Published
2010

38. Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-Risk Resected Melanoma

Author

Goodman, Rachel S., primary, Lawless, Aleigha, additional, Woodford, Rachel, additional, Fa’ak, Faisal, additional, Tipirneni, Asha, additional, Patrinely, J. Randall, additional, Yeoh, Hui Ling, additional, Rapisuwon, Suthee, additional, Haydon, Andrew, additional, Osman, Iman, additional, Mehnert, Janice M., additional, Long, Georgina V., additional, Sullivan, Ryan J., additional, Carlino, Matteo S., additional, Menzies, Alexander M., additional, and Johnson, Douglas B., additional

Published
2023
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42. Perspectives in melanoma: meeting report from the “Melanoma Bridge” (December 5th–7th, 2019, Naples, Italy)

Author

Ascierto, Paolo A., Puzanov, Igor, Agarwala, Sanjiv S., Blank, Christian, Carvajal, Richard D., Demaria, Sandra, Dummer, Reinhard, Ernstoff, Marc, Ferrone, Soldano, Fox, Bernard A., Gajewski, Thomas F., Garbe, Claus, Hwu, Patrick, Lo, Roger S., Long, Georgina V., Luke, Jason J., Osman, Iman, Postow, Michael A., Sullivan, Ryan J., Taube, Janis M., Trinchieri, Giorgio, Zarour, Hassane M., Caracò, Corrado, and Thurin, Magdalena

Published
2020
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43. Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes.

Author

Ibrahim, Milad, Illa-Bochaca, Irineu, Fa'ak, Faisal, Monson, Kelsey R., Ferguson, Robert, Lyu, Chen, Vega-Saenz de Miera, Eleazar, Johannet, Paul, Chou, Margaret, Mastroianni, Justin, Darvishian, Farbod, Kirchhoff, Tomas, Zhong, Judy, Krogsgaard, Michelle, and Osman, Iman

Subjects
THERAPEUTIC use of antineoplastic agents, GENETIC mutation, IMMUNE checkpoint inhibitors, MELANOMA, CELL receptors, CANCER patients, GENOTYPES, DESCRIPTIVE statistics, RESEARCH funding, CELL lines, PHENOTYPES, ANTIGENS
Abstract

Simple Summary: Despite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can achieve complete and durable remission. Herein, we provide evidence that the kinase domain receptor (KDR) pathogenic germline variant Q472H confers more angiogenic and proliferative tumors, a more immune-suppressive microenvironment, and more resistance to therapy. Data suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype. Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Supplementary Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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47. Supplementary Table from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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48. Supplementary Figure from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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49. Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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