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265 results on '"Halaban, R"'

1. A Variant in a MicroRNA complementary site in the 3′ UTR of the KIT oncogene increases risk of acral melanoma

Author

Godshalk, SE, Paranjape, T, Nallur, S, Speed, W, Chan, E, Molinaro, AM, Bacchiocchi, A, Hoyt, K, Tworkoski, K, Stern, DF, Sznol, M, Ariyan, S, Lazova, R, Halaban, R, Kidd, KK, Weidhaas, JB, and Slack, FJ

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, Genetics, Biotechnology, 2.1 Biological and endogenous factors, 3' Untranslated Regions, Case-Control Studies, Humans, Melanoma, MicroRNAs, Oncogenes, Protein Biosynthesis, Proto-Oncogene Proteins c-kit, RNA, Messenger, Risk, Skin Neoplasms, melanoma, acral, microRNA, cancer risk, miR-221, KIT, Clinical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

MicroRNAs (miRNAs) are small ∼22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3' untranslated region (3' UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be upregulated in some melanomas, and is also a target of the miRNA miR-221. Here, we describe a genetic variant in the 3' UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma.

Published
2011

4. Growth Regulation in Normal and Malignant Melanocytes

Author

Halaban, R., Herfarth, Ch., editor, Senn, H.-J., editor, Baum, M., editor, Diehl, V., editor, Gutzwiller, F., editor, Rajewsky, M. F., editor, Wannenmacher, M., editor, Hecker, Erich, editor, Jung, E. G., editor, Marks, F., editor, and Tilgen, W., editor

Published
1993
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10. Supplement II: Abstracts of the international symposium on Skin Carcinogenesis in man and in experimental models. Heidelberg, 29–31 October 1991 (pp S61–S88)

Author

Barrett, J. C., Afshari, C. A., Annab, L. A., Burkhart, B. A., Boyd, J. A., Owen, R. D., Futreal, P. A., Richter, K. H., Moses, H. L., Lavker, R. M., Miller, Stanley, Sun, T. -T., Stingl, G., Bianchi, A. B., Navone, N. M., Conti, C. J., Spencer, James M., Kahn, S., Weinstein, I. B., Silvers, D. S., DeLeo, V. A., Larcher, F., Bauluz, C., Quintanilla, M., Ballestin, C., Jorcano, J. L., Schön, M., Haas, M., Klein, C. E., Weber, L., Cerri, A., Tadini, G., Gitto, R., Berti, E., Cano, A., Caulín, C., Gómez, M., Gandarillas, A., Martín, M., Montes, A., Navarro, P., Bastian, B. C., Van der Piepen, U., Römisch, J., Pâques, E., Hartmann, A. A., Krieg, P., Schnapke, R., Feil, S., Fürstenberger, G., Marks, F., Missero, C., Cajal, S. Ramon y, Filvaroff, E., Dotto, G. P., Sherman, J., Albert, R. E., Baxter, C. S., Bauer, G., Höfler, P., Götschl, M., Viesel, E., Jürgensmeier, J., Schaefer, D., Picht, G., Grande, T., Real, A., Rünqer, T. M., Möller, K., Fuchs, P., Bauer, C., Epe' B., Gruner, S., Diezel, W., Macejewski, J., Weber, H., Eckert, R., Volk, H. D., Sönnichsen, N., Bavinck, Jan N. Bouwes, Vermeer, Bert J., Van Der Woude, Fokko J., Vandenbroucke, Jan P., Claas, Frans H. J., Griffin, E. F., Harris, H., Tilgen, W., Garbe, C., Østerlind, Anne, Weiss, J., Jung, E. G., Ruiter, D. J., Danen, E., Broecker, E. -B., Johnson, J. P., van Muijen, G. N. P., Halaban, R., Krüger-Krasagakes, S., Orfanos, C. E., Newton, J. A., Bataille, V., Cuzick, J., Bishop, T., Schwaaf, A., Azizi, E., Bröcker, E. B., Eberlein, B., Froschermaier, S., Gollhausen, R., Przybilla, B., Krasagakis, K., Abdel-Naser, M. B., Lopez-Bran, E., Robledo, A., Lopez-Bran, E., Heine, H., Hennig, B., Graf, G., Nährig, J., Niedner, R., Schöpf, E., Mailhammer, R., Reisbach, G., Kempkes, B., Hültner, L., Thalmeier, K., Anders, F., Zechel, C., Schleenbecker, U., Leers, J., Smith, A., Wagner, E., Burcin, U., Hug, H., Fiebich, B., Anders, A., Gröger, H., Schlatterer, B., Moll, I., Wollina, U., Leigh IM, Purkis PE, Markey A., Neill S., Proby C., Glover M., Lane EB, Klein-Szanto, A. J. P., Yaar, M., Garmyn, M., Gilani, A., Gilchrest, B. A., Bowden, G. T., Nelson, M., Levy, J., Tanooka, Hiroshi, Ootsuyama, Akira, Urbach, F., van der Leun, J. C., de Gruijl, F. R., Kripke, Margaret L., Yuspa, S. H., Glick, A., Lee, E., Diugosz, A., Balmain, A., Bums, P., Kemp, C. J., Stoler, A. B., Harks, F., Boukamp, P., Pascheberg, U., Breitkreutz, D., Hülsen, A., Altmeier, S., Tomakidi, P., Fusenig, N. E., Lowy, Douglas R., Sedman, Sylvia A., Cohen, Bruce D., Schiller, John T., Kricker, A., Armstrong, B. K., English, D., Heenan, P. J., Randell, P. L., de Gruijl, F. R., Kelfkens, G., van Weelden, H., van der Leun, J. C., Grabbe, S., Bruvers, S., Granstein, R. D., Albert, R., Miller, M., Cody, T., Baxter, C., Shukla, R., Ueda, M., Ichihashi, M., Yamamura, K., Hayashibe, K., Funasaka, Y., Mishima, Y., Fujiwara, Y., Ichihashi, M., Jimbo, T., Mishima, Y., Popanda, O., Thielmann, H. W., Jahrens, D., Edler, L., Ootsuyama, A., Tanooka, H., Sutter, C., Mukhtar, H., Strickland, P. T., Winter, H., Schweizer, J., Schmidt, R., Weber, E., Rippmann, F., Hecker, E., Kopp-Schneider, A., Lehmann, W. D., Stephan, M., Troll, W., Wei, H., Fujiki, H., Garte, S. J., Frenkel, K., Svetek, J., Schara, M., Pečar, S., Hergenhahn, M., Kinzel, V., Richards, J., Plein, P., Schiess, K., Kaszkin, M., Yamamoto, S., Wang, J. C., Kato, R., Kuroki, T., Hashimoto, Y., Osada, S., Ohno, S., Gilles, C., Piette, M., Foidart, J. -M., Ranki, A., Lassus, J., Lehmus, A., Niemi, K. -M., Friesel, H., Schneider, T., Steinbauer, B., Sorg, B., Winter, A., Krauter, G., Krauß, R., Roeser, H., Unger, Sylvia, Janiaud, Paul, Rueß, Doris, Mechler, Bernard M., Stanbridge, Eric J., Gross, Monika M., Buček, M., Klein-Bauernschmitt, P., Schlehofer, J. R., Kosters, R., Stark, H. -J., Okulov, V. B., Elgjo, K., Ushmorov, A. G., Danilov, A. O., Zubova, S. G., Furstenberger, G., and Faissner, A.

Published
1991
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13. AMPK promotes tolerance to Ras pathway inhibition by activating autophagy

Author

David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Gupta, Piyush, Mathis, Robert Austin, Sokol, Ethan Samuel, Sanduja, S, Feng, Y, Reinhardt, F, Halaban, R, David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Gupta, Piyush, Mathis, Robert Austin, Sokol, Ethan Samuel, Sanduja, S, Feng, Y, Reinhardt, F, and Halaban, R

Abstract

Targeted inhibitors of oncogenic Ras (rat sarcoma viral oncogene)-Raf signaling have shown great promise in the clinic, but resistance remains a major challenge: 30% of tumors with pathway mutations do not respond to targeted inhibitors, and of the 70% that do respond, all eventually develop resistance. Before cancer cells acquire resistance, they respond to initial drug treatment either by undergoing apoptosis ('addiction') or by surviving treatment albeit with reduced growth ('tolerance'). As these drug-tolerant cells serve as a reservoir from which resistant cells eventually emerge, inhibiting the pathways that confer tolerance could potentially delay or even prevent recurrence. Here, we show that melanomas and other cancers acquire tolerance to Ras-Raf pathway inhibitors by activating autophagy, which is mediated by the cellular energy sensor AMP-activated protein kinase (AMPK). Blocking this AMPK-mediated autophagy sensitizes drug-tolerant melanomas to Ras-Raf pathway inhibitors. Conversely, activating AMPK signaling and autophagy enables melanomas that would otherwise be addicted to the Ras-Raf pathway to instead tolerate pathway inhibition. These findings identify a key mechanism of tolerance to Ras-Raf pathway inhibitors and suggest that blocking either AMPK or autophagy in combination with these targeted inhibitors could increase tumor regression and decrease the likelihood of eventual recurrence., Melanoma Research Alliance (Grant 311800)

Published
2018

14. AMPK promotes tolerance to Ras pathway inhibition by activating autophagy

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Gupta, Piyush, Mathis, Robert Austin, Sokol, Ethan Samuel, Sanduja, S, Feng, Y, Reinhardt, F, Halaban, R, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Gupta, Piyush, Mathis, Robert Austin, Sokol, Ethan Samuel, Sanduja, S, Feng, Y, Reinhardt, F, and Halaban, R

Abstract

Targeted inhibitors of oncogenic Ras (rat sarcoma viral oncogene)-Raf signaling have shown great promise in the clinic, but resistance remains a major challenge: 30% of tumors with pathway mutations do not respond to targeted inhibitors, and of the 70% that do respond, all eventually develop resistance. Before cancer cells acquire resistance, they respond to initial drug treatment either by undergoing apoptosis ('addiction') or by surviving treatment albeit with reduced growth ('tolerance'). As these drug-tolerant cells serve as a reservoir from which resistant cells eventually emerge, inhibiting the pathways that confer tolerance could potentially delay or even prevent recurrence. Here, we show that melanomas and other cancers acquire tolerance to Ras-Raf pathway inhibitors by activating autophagy, which is mediated by the cellular energy sensor AMP-activated protein kinase (AMPK). Blocking this AMPK-mediated autophagy sensitizes drug-tolerant melanomas to Ras-Raf pathway inhibitors. Conversely, activating AMPK signaling and autophagy enables melanomas that would otherwise be addicted to the Ras-Raf pathway to instead tolerate pathway inhibition. These findings identify a key mechanism of tolerance to Ras-Raf pathway inhibitors and suggest that blocking either AMPK or autophagy in combination with these targeted inhibitors could increase tumor regression and decrease the likelihood of eventual recurrence., Melanoma Research Alliance (Grant 311800)

Published
2018

16. Abstracts from the 4th ImmunoTherapy of Cancer Conference

Author

Ženka, J., primary, Caisová, V., additional, Uher, O., additional, Nedbalová, P., additional, Kvardová, K., additional, Masáková, K., additional, Krejčová, G., additional, Paďouková, L., additional, Jochmanová, I., additional, Wolf, K. I., additional, Chmelař, J., additional, Kopecký, J., additional, Loumagne, L., additional, Mestadier, J., additional, D’agostino, S., additional, Rohaut, A., additional, Ruffin, Y., additional, Croize, V., additional, Lemaître, O., additional, Sidhu, S. S., additional, Althammer, S., additional, Steele, K., additional, Rebelatto, M., additional, Tan, T., additional, Wiestler, T., additional, Spitzmueller, A., additional, Korn, R., additional, Schmidt, G., additional, Higgs, B., additional, Li, X., additional, Shi, L., additional, Jin, X., additional, Ranade, K., additional, Koeck, S., additional, Amann, A., additional, Gamerith, G., additional, Zwierzina, M., additional, Lorenz, E., additional, Zwierzina, H., additional, Kern, J., additional, Riva, M., additional, Baert, T., additional, Coosemans, A., additional, Giovannoni, R., additional, Radaelli, E., additional, Gsell, W., additional, Himmelreich, U., additional, Van Ranst, M., additional, Xing, F., additional, Qian, W., additional, Dong, C., additional, Xu, X., additional, Guo, S., additional, Shi, Q., additional, Quandt, D., additional, Seliger, B., additional, Plett, C., additional, Amberger, D. C., additional, Rabe, A., additional, Deen, D., additional, Stankova, Z., additional, Hirn, A., additional, Vokac, Y., additional, Werner, J., additional, Krämer, D., additional, Rank, A., additional, Schmid, C., additional, Schmetzer, H., additional, Guerin, M., additional, Weiss, J. M., additional, Regnier, F., additional, Renault, G., additional, Vimeux, L., additional, Peranzoni, E., additional, Feuillet, V., additional, Thoreau, M., additional, Guilbert, T., additional, Trautmann, A., additional, Bercovici, N., additional, Doraneh-Gard, F., additional, Boeck, C. L., additional, Gunsilius, C., additional, Kugler, C., additional, Schmohl, J., additional, Kraemer, D., additional, Ismann, B., additional, Schmetzer, H. M., additional, Markota, A., additional, Ochs, C., additional, May, P., additional, Gottschlich, A., additional, Gosálvez, J. Suárez, additional, Karches, C., additional, Wenk, D., additional, Endres, S., additional, Kobold, S., additional, Hilmenyuk, T., additional, Klar, R., additional, Jaschinski, F., additional, Augustin, F., additional, Manzl, C., additional, Hoflehner, E., additional, Moser, P., additional, Zelger, B., additional, Köck, S., additional, Schäfer, G., additional, Öfner, D., additional, Maier, H., additional, Sopper, S., additional, Prado-Garcia, H., additional, Romero-Garcia, S., additional, Sandoval-Martínez, R., additional, Puerto-Aquino, A., additional, Lopez-Gonzalez, J., additional, Rumbo-Nava, U., additional, Van Hoylandt, A., additional, Busschaert, P., additional, Vergote, I., additional, Laengle, J., additional, Pilatova, K., additional, Budinska, E., additional, Bencsikova, B., additional, Sefr, R., additional, Nenutil, R., additional, Brychtova, V., additional, Fedorova, L., additional, Hanakova, B., additional, Zdrazilova-Dubska, L., additional, Allen, Chris, additional, Ku, Yuan-Chieh, additional, Tom, Warren, additional, Sun, Yongming, additional, Pankov, Alex, additional, Looney, Tim, additional, Hyland, Fiona, additional, Au-Young, Janice, additional, Mongan, Ann, additional, Becker, A., additional, Tan, J. B. L., additional, Chen, A., additional, Lawson, K., additional, Lindsey, E., additional, Powers, J. P., additional, Walters, M., additional, Schindler, U., additional, Young, S., additional, Jaen, J. C., additional, Yin, S., additional, Chen, Y., additional, Gullo, I., additional, Gonçalves, G., additional, Pinto, M. L., additional, Athelogou, M., additional, Almeida, G., additional, Huss, R., additional, Oliveira, C., additional, Carneiro, F., additional, Merz, C., additional, Sykora, J., additional, Hermann, K., additional, Hussong, R., additional, Richards, D. M., additional, Fricke, H., additional, Hill, O., additional, Gieffers, C., additional, Pinho, M. P., additional, Barbuto, J. A. M., additional, McArdle, S. E., additional, Foulds, G., additional, Vadakekolathu, J. N., additional, Abdel-Fatah, T. M. A., additional, Johnson, C., additional, Hood, S., additional, Moseley, P., additional, Rees, R. C., additional, Chan, S. Y. T., additional, Pockley, A. G., additional, Rutella, S., additional, Geppert, C., additional, Hartmann, A., additional, Kumar, K. Senthil, additional, Gokilavani, M., additional, Wang, S., additional, Redondo-Müller, M., additional, Heinonen, K., additional, Marschall, V., additional, Thiemann, M., additional, Zhang, L., additional, Mao, B., additional, Jin, Y., additional, Zhai, G., additional, Li, Z., additional, Wang, Z., additional, An, X., additional, Qiao, M., additional, Zhang, J., additional, Weber, J., additional, Kluger, H., additional, Halaban, R., additional, Sznol, M., additional, Roder, H., additional, Roder, J., additional, Grigorieva, J., additional, Asmellash, S., additional, Meyer, K., additional, Steingrimsson, A., additional, Blackmon, S., additional, Sullivan, R., additional, Sutanto, W., additional, Guenther, T., additional, Schuster, F., additional, Salih, H., additional, Babor, F., additional, Borkhardt, A., additional, Kim, Y., additional, Oh, I., additional, Park, C., additional, Ahn, S., additional, Na, K., additional, Song, S., additional, Choi, Y., additional, Poprach, A., additional, Lakomy, R., additional, Selingerova, I., additional, Demlova, R., additional, Kozakova, S., additional, Valik, D., additional, Petrakova, K., additional, Vyzula, R., additional, Aguilar-Cazares, D., additional, Galicia-Velasco, M., additional, Camacho-Mendoza, C., additional, Islas-Vazquez, L., additional, Chavez-Dominguez, R., additional, Gonzalez-Gonzalez, C., additional, Lopez-Gonzalez, J. S., additional, Yang, S., additional, Moynihan, K. D., additional, Noh, M., additional, Bekdemir, A., additional, Stellacci, F., additional, Irvine, D. J., additional, Volz, B., additional, Kapp, K., additional, Oswald, D., additional, Wittig, B., additional, Schmidt, M., additional, Kleef, R., additional, Bohdjalian, A., additional, McKee, D., additional, Moss, R. W., additional, Saeed, Mesha, additional, Zalba, Sara, additional, Debets, Reno, additional, ten Hagen, Timo L. M., additional, Javed, S., additional, Becher, J., additional, Koch-Nolte, F., additional, Haag, F., additional, Gordon, E. M., additional, Sankhala, K. K., additional, Stumpf, N., additional, Tseng, W., additional, Chawla, S. P., additional, Suárez, N. González, additional, Báez, G. Bergado, additional, Rodríguez, M. Cruz, additional, Pérez, A. Gutierrez, additional, García, L. Chao, additional, Fernández, D. Hernández, additional, Pous, J. Raymond, additional, Ramírez, B. Sánchez, additional, Jacoberger-Foissac, C., additional, Saliba, H., additional, Seguin, C., additional, Brion, A., additional, Frisch, B., additional, Fournel, S., additional, Heurtault, B., additional, Otterhaug, T., additional, Håkerud, M., additional, Nedberg, A., additional, Edwards, V., additional, Selbo, P., additional, Høgset, A., additional, Jaitly, T., additional, Dörrie, J., additional, Schaft, N., additional, Gross, S., additional, Schuler-Thurner, B., additional, Gupta, S., additional, Taher, L., additional, Schuler, G., additional, Vera, J., additional, Rataj, F., additional, Kraus, F., additional, Grassmann, S., additional, Chaloupka, M., additional, Lesch, S., additional, Heise, C., additional, Cadilha, B. M. Loureiro, additional, and Dorman, K., additional

Published
2017
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17. MEDME: An experimental and analytical methodology for the estimation of DNA methylation levels based on microarray derived MeDIP-enrichment

Author

Pelizzola, M, Koga, Y, Urban, A, Krauthammer, M, Weissman, S, Halaban, R, Molinaro, A, Pelizzola M., Koga Y., Urban A. E., Krauthammer M., Weissman S., Halaban R., Molinaro A. M., Pelizzola, M, Koga, Y, Urban, A, Krauthammer, M, Weissman, S, Halaban, R, Molinaro, A, Pelizzola M., Koga Y., Urban A. E., Krauthammer M., Weissman S., Halaban R., and Molinaro A. M.

Abstract

DNA methylation is an important component of epigenetic modifications that influences the transcriptional machinery and is aberrant in many human diseases. Several methods have been developed to map DNA methylation for either limited regions or genome-wide. In particular, antibodies specific for methylated CpG have been successfully applied in genome-wide studies. However, despite the relevance of the obtained results, the interpretation of antibody enrichment is not trivial. Of greatest importance, the coupling of antibody-enriched methylated fragments with microarrays generates DNA methylation estimates that are not linearly related to the true methylation level. Here, we present an experimental and analytical methodology, MEDME (modeling experimental data with MeDIP enrichment), to obtain enhanced estimates that better describe the true values of DNA methylation level throughout the genome. We propose an experimental scenario for evaluating the true relationship in a high-throughput setting and a model-based analysis to predict the absolute and relative DNA methylation levels. We successfully applied this model to evaluate DNA methylation status of normal human melanocytes compared to a melanoma cell strain. Despite the low resolution typical of methods based on immunoprecipitation, we show that model-derived estimates of DNA methylation provide relatively high correlation with measured absolute and relative levels, as validated by bisulfite genomic DNA sequencing. Importantly, the model-derived DNA methylation estimates simplify the interpretation of the results both at single-loci and at chromosome-wide levels.

Published
2008

18. Changes in serum IL8 levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small cell lung cancer patients

Author

Sanmamed, M.F., primary, Perez-Gracia, J.L., additional, Fusco, J.P., additional, Oñate, C., additional, Perez, G., additional, Alfaro, C., additional, Martín-Algarra, S., additional, González, A., additional, Rodriguez-Ruiz, M.E., additional, Andueza, M.P., additional, Wang, J., additional, Bacchiocchi, A., additional, Halaban, R., additional, Kluger, H., additional, Sznol, M., additional, and Melero, I., additional

Published
2016
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25. Future perspectives in melanoma research: Meeting report from the 'Melanoma Bridge', Napoli, December 5th-8th 2013

Author

Ascierto, PA, Grimaldi, AM, Anderson, AC, Bifulco, C, Cochran, A, Garbe, C, Eggermont, AM, Faries, M, Ferrone, S, Gershenwald, JE, Gajewski, TF, Halaban, R, Stephen Hodi, F, Kefford, R, Kirkwood, JM, Larkin, J, Leachman, S, Maio, M, Marais, R, Masucci, G, Melero, I, Palmieri, G, Puzanov, I, Ribas, A, Saenger, Y, Schilling, B, Seliger, B, Stroncek, D, Sullivan, R, Testori, A, Wang, E, Ciliberto, G, Mozzillo, N, Marincola, FM, Thurin, M, Ascierto, PA, Grimaldi, AM, Anderson, AC, Bifulco, C, Cochran, A, Garbe, C, Eggermont, AM, Faries, M, Ferrone, S, Gershenwald, JE, Gajewski, TF, Halaban, R, Stephen Hodi, F, Kefford, R, Kirkwood, JM, Larkin, J, Leachman, S, Maio, M, Marais, R, Masucci, G, Melero, I, Palmieri, G, Puzanov, I, Ribas, A, Saenger, Y, Schilling, B, Seliger, B, Stroncek, D, Sullivan, R, Testori, A, Wang, E, Ciliberto, G, Mozzillo, N, Marincola, FM, and Thurin, M

Abstract

The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent research in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, like BRAF and MEK inhibitors, as well as other signaling pathways inhibitors, are being tested in metastatic melanoma either as monotherapy or in combination, and have yielded promising results. Improved survival rates have also been observed with immune therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in melanoma as well. This meeting's specific focus was on advances in targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. Significant consideration was given to issues surrounding the development of novel therapeutic targets as further study of patterns of resistance to both immunologic and targeted drugs are paramount to future drug development to guide existing and future therapie

Published
2014

26. Future perspectives in melanoma research. Meeting report from the 'Melanoma Research: A bridge Naples-USA. Naples, December 6th-7 th2010'

Author

Ascierto, PA, De Maio, E, Bertuzzi, S, Palmieri, G, Halaban, R, Hendrix, M, Kashani-sabet, M, Ferrone, S, Wang, E, Cochran, A, Rivoltini, L, Lee, PP, Fox, BA, Kirkwood, JM, Ullmann, CD, Lehmann, FF, Sznol, M, Schwartzentruber, DJ, Maio, M, Flaherty, K, Galon, J, Ribas, A, Yang, J, Stroncek, DF, Mozzillo, N, Marincola, FM, Ascierto, PA, De Maio, E, Bertuzzi, S, Palmieri, G, Halaban, R, Hendrix, M, Kashani-sabet, M, Ferrone, S, Wang, E, Cochran, A, Rivoltini, L, Lee, PP, Fox, BA, Kirkwood, JM, Ullmann, CD, Lehmann, FF, Sznol, M, Schwartzentruber, DJ, Maio, M, Flaherty, K, Galon, J, Ribas, A, Yang, J, Stroncek, DF, Mozzillo, N, and Marincola, FM

Abstract

Progress in understanding the molecular basis of melanoma has made possible the identification of molecular targets with important implications in clinical practice. In fact, new therapeutic approaches are emerging from basic science and it will be important to implement their rapid translation into clinical practice by active clinical investigation. The first meeting of Melanoma Research: a bridge Naples-USA, organized by Paolo A. Ascierto (INT, Naples, Italy) and Francesco Marincola (NIH, Bethesda, USA) took place in Naples, on 6-7 December 2010. This international congress gathered more than 30 international and Italian faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive discussion across Institutions belonging to Government, Academy and Pharmaceutical Industry, in order to stimulate new approaches in basic, translational and clinical research. Four topics of discussion were identified: New pathways in Melanoma, Biomarkers, Clinical Trials and New Molecules and Strategies.© 2011 Ascierto et al; licensee BioMed Central Ltd.

Published
2011

28. Genome-wide screen of promoter methylation identifies novel markers in melanoma

Author

Koga, Y, Pelizzola, M, Cheng, E, Krauthammer, M, Sznol, M, Ariyan, S, Narayan, D, Molinaro, A, Halaban, R, Weissman, S, Molinaro, AM, Weissman, SM, Koga, Y, Pelizzola, M, Cheng, E, Krauthammer, M, Sznol, M, Ariyan, S, Narayan, D, Molinaro, A, Halaban, R, Weissman, S, Molinaro, AM, and Weissman, SM

Abstract

DNA methylation is an important component of epigenetic modifications, which influences the transcriptional machinery aberrant in many human diseases. In this study we present the first genome-wide integrative analysis of promoter methylation and gene expression for the identification of methylation markers in melanoma. Genome-wide promoter methylation and gene expression of eight early-passage human melanoma cell strains were compared with newborn and adult melanocytes. We used linear mixed effect models (LME) in combination with a series of filters based on the localization of promoter methylation relative to the transcription start site, overall promoter CpG content, and differential gene expression to discover DNA methylation markers. This approach identified 76 markers, of which 68 were hyper- and eight hypomethylated (LME, P < 0.05). Promoter methylation and differential gene expression of five markers (COL1A2, NPM2, HSPB6, DDIT4L, MT1G) were validated by sequencing of bisulfite-modified DNA and real-time reverse transcriptase PCR, respectively. Importantly, the incidence of promoter methylation of the validated markers increased moderately in early and significantly in advanced-stage melanomas, using early-passage cell strains and snap-frozen tissues (n = 18 and n = 24, respectively) compared with normal melanocytes and nevi (n = 11 and n = 9, respectively). Our approach allows robust identification of methylation markers that can be applied to other studies involving genome-wide promoter methylation. In conclusion, this study represents the first unbiased systematic effort to determine methylation markers in melanoma and revealed several novel genes regulated by promoter methylation that were not described in cancer cells before.

Published
2009

31. A Variant in a MicroRNA complementary site in the 3′ UTR of the KIT oncogene increases risk of acral melanoma

Author

Godshalk, S E, primary, Paranjape, T, additional, Nallur, S, additional, Speed, W, additional, Chan, E, additional, Molinaro, A M, additional, Bacchiocchi, A, additional, Hoyt, K, additional, Tworkoski, K, additional, Stern, D F, additional, Sznol, M, additional, Ariyan, S, additional, Lazova, R, additional, Halaban, R, additional, Kidd, K K, additional, Weidhaas, J B, additional, and Slack, F J, additional

Published
2010
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32. Expression profiling reveals novel pathways in the transformation of Melanocytes to Melanomas.

Author

Hoek, K., primary, Rimm, D., additional, Williams, K., additional, Zhao, H., additional, Ariyan, S., additional, Lin, A., additional, Kluger, H., additional, Berger, A., additional, Cheng, E., additional, Trombetta, E. S., additional, Wu, T., additional, Halaban, R., additional, Niinobe, M., additional, Yoshikawa, K., additional, and Hannigan, G. E., additional

Published
2004
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42. Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes.

Author

Halaban, R, Halaban, R, Langdon, R, Birchall, N, Cuono, C, Baird, A, Scott, G, Moellmann, G, McGuire, J, Halaban, R, Halaban, R, Langdon, R, Birchall, N, Cuono, C, Baird, A, Scott, G, Moellmann, G, and McGuire, J

Abstract

To survive and proliferate in pure culture, human melanocytes require basic fibroblast growth factor (bFGF) and cAMP. Without these factors, even in the presence of serum, the cells die. Melanocytes cultured in the presence of keratinocytes, however, survive for weeks without added bFGF and cAMP. We show here that the growth factor for melanocytes produced by human keratinocytes is bFGF because its activity can be abolished by neutralizing antibodies to bFGF and by a bFGF synthetic peptide that inhibits the binding of the growth factor to its receptor. The melanocyte mitogen in keratinocytes is cell associated and increases after irradiation with ultraviolet B. Northern blots reveal bFGF gene transcripts in keratinocytes but not melanocytes. These studies demonstrate that bFGF elaborated by keratinocytes in vitro sustains melanocyte growth and survival, and they suggest that keratinocyte-derived bFGF is the natural growth factor for normal human melanocytes in vivo.

Published
1988

44. Release of cell cycle constraints in mouse melanocytes by overexpressed mutant E2F1E132, but not by deletion of p16INK4A or p21WAF1/CIP1.

Author

Halaban, R, Cheng, E, Zhang, Y, Mandigo, C E, and Miglarese, M R

Subjects
CELL cycle, MICE, MELANOCYTES, CELL lines, TUMOR proteins
Abstract

Compared to normal melanocytes, melanoma cell lines exhibit overexpression of hyperphosphorylated retinoblastoma tumor suppressor protein (Rb) or a marked decrease in, or lack of, expression of Rb. Hyperphosphorylation of Rb results in increased E2F-mediated transactivation of target genes and cell cycle progression. Using a combination of gene disruption and ectopic expression in growth factor-dependent mouse melanocytes, we studied the roles of E2F1 and the p16INK4A and p21WAF1/CIP1 CKIs (cyclin dependent kinase inhibitors) in the acquisition of TPA (12-O-tetradecanoyl phorbol-13-acetate)-independent growth in culture, a hallmark of melanomas. Surprisingly, melanocytes from p16INK4A- or p21WAF1/CIP1-null mice remained TPA-dependent, and disruption of p21WAF1/CIP1 accelerated cell death in the absence of this mitogen. Disruption of E2F1 had the most profound effect on melanocyte growth, resulting in a fourfold decrease in growth rate in the presence of TPA. Furthermore, enforced overexpression of the DNA-binding-defective E2F1E132 mutant conferred TPA-independence upon melanocytes and was associated with sequestration of Rb and constitutive expression of E2F1 target genes, including p21WAF1/CIP1. We conclude that neutralization of Rb by E2F1E132, but not the disruption of p16INK4A or p21WAF1/CIP1, resulted in the accumulation of free E2F and cell cycle progression. Thus, mechanisms other than the loss of p16INK4A or p21WAF1/CIP1 that activate E2F may play an important role in melanomas. [ABSTRACT FROM AUTHOR]

Published
1998
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46. Transformation of murine melanocytes by basic fibroblast growth factor cDNA and oncogenes and selective suppression of the transformed phenotype in a reconstituted cutaneous environment.

Author

Dotto, G P, Moellmann, G, Ghosh, S, Edwards, M, and Halaban, R

Abstract

Constitutive expression of basic fibroblast growth factor (bFGF), a common characteristic of metastatic melanomas, was reproduced in vitro by infection of normal murine melanocytes with a recombinant retrovirus carrying a cDNA for bFGF. Expression of bFGF in these cells conferred autonomous growth in culture and extinguished differentiated functions, such as the synthesis of melanin and formation of dendrites. Independence from exogenous bFGF and loss of differentiated functions in vitro were induced also by transformation of melanocytes with the oncogenes myc, Ela, ras, and neu, although bFGF was not expressed by the respective transformants. As shown in skin reconstitution experiments onto syngeneic mice and subcutaneous injections into nude mice, the various transformants differed in their behavior in vivo. The bFGF transformants did not form tumors. They reverted to having a normal, melanotic phenotype and restricted growth. Myc and Ela transformants grew as tumors in nude mice but not in syngeneic, immunocompetent animals. Ras-transformed melanocytes were always tumorigenic, whereas the formation of tumors by neu transformants was suppressed by the concomitant grafting of keratinocytes in reconstituted skin of syngeneic mice. These data show that melanocytes genetically manipulated to produce bFGF acquire properties in vitro similar to those of metastatic melanoma cells or those induced by various oncogenes but that constitutive production of bFGF by itself is insufficient to make melanocytes tumorigenic. The experiments also show that melanocytes transformed by the selected oncogenes respond differentially to various environments in vivo.

Published
1989
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47. Melanoma cells resistant to inhibition of growth by melanocyte stimulating hormone.

Author

Pawelek, J, Sansone, M, Koch, N, Christie, G, Halaban, R, Hendee, J, Lerner, A B, and Varga, J M

Abstract

Melanocyte stimulating hormone (MSH) enhances melanization but inhibits proliferation of Cloudman S91 melanoma cells in culture. We have isolated variants of these cells that can grow in the presence of MSH. The conclusions we have reached from analyses of these cells are the following: (1) Basal tyrosinase activity (monophenol monooxygenase; monophenol, dihydroxyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1), i.e., the activity that is present in the absence of added MSH, is related through a common biochemical pathway to MSH-mediated control of growth. (2) MSH-inducible tyrosinase activity does not appear to be related to MSH control of growth. (3) The morphological changes that occur following the addition of MSH or cAMP are related to controls of growth and not to those of melanization.

Published
1975
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48. VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells.

Author

Cohen, T, Gitay-Goren, H, Sharon, R, Shibuya, M, Halaban, R, Levi, B Z, and Neufeld, G

Abstract

Four vascular endothelial growth factor (VEGF) splice variants containing 121, 165, 189, and 206 amino acids are produced from a single human gene as a result of alternative splicing. VEGF121 is not a heparin-binding protein, while the other VEGF species possess heparin binding ability. YU-ZAZ6 human melanoma cells expressed the mRNA encoding the VEGF receptor flt-1, but not the mRNA encoding the VEGF receptor KDR/flk-1. Both VEGF121 and VEGF165 bound to the VEGF receptors of these cells. Unexpectedly, heparin inhibited the binding of VEGF121 as well as the binding of VEGF165 to the VEGF receptors of the melanoma cells. Digestion of the cells with heparinase also inhibited the binding of both VEGF variants. The VEGF165 binding ability of heparinase-digested cells could be partially restored by the addition of exogenous heparin to the binding reaction. In contrast, the addition of heparin to heparinase-digested cells did not restore VEGF121 binding. These results suggest that cell-surface heparan sulfates may regulate the binding ability of the VEGF receptors of the melanoma cells. They also indicate that heparin is not able to fully substitute for cell surface-associated heparan sulfates since VEGF121 binding to the VEGF receptors of heparinase-treated cells is not restored by heparin. These data suggest that changes in the composition of cell-surface heparin-like molecules may differentially affect the interaction of various VEGF isoforms with VEGF receptors.

Published
1995

49. Isolation and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus.

Author

Kwon, B S, Haq, A K, Pomerantz, S H, and Halaban, R

Abstract

Screening of a lambda gt11 human melanocyte cDNA library with antibodies against hamster tyrosinase (monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1) resulted in the isolation of 16 clones. The cDNA inserts from 13 of the 16 clones cross-hybridized with each other, indicating that they were from related mRNA species. One of the cDNA clones, Pmel34, detected one mRNA species with an approximate length of 2.4 kilobases that was expressed preferentially in normal and malignant melanocytes but not in other cell types. The amino acid sequence deduced from the nucleotide sequence showed that the putative human tyrosinase is composed of 548 amino acids with a molecular weight of 62,610. The deduced protein contains glycosylation sites and histidine-rich sites that could be used for copper binding. Southern blot analysis of DNA derived from newborn mice carrying lethal albino deletion mutations revealed that Pmel34 maps near or at the c-albino locus, the position of the structural gene for tyrosinase.

Published
1987
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50. Tyrosinases of murine melanocytes with mutations at the albino locus.

Author

Halaban, R, Moellmann, G, Tamura, A, Kwon, B S, Kuklinska, E, Pomerantz, S H, and Lerner, A B

Abstract

Tyrosinase (monophenol monooxygenase; monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1) is a key enzyme in the synthesis of melanin. Reduced levels of tyrosinase play an important role in albinism. The data described here show differences in the expression and characteristics of tyrosinase in cutaneous murine melanocytes grown in culture from normal wild-type strains (C/C); from three albino locus mutants: himalayan (ch/ch), chinchilla (cch/cch), and albino (c/c); and from the double-mutant heterozygous pink-eyed chinchilla (cchp/cp). Our results suggest that the diminished pigmentation in all mutants is due to abnormal posttranslational modification of the enzyme: the levels of mRNA for tyrosinase in wild-type, himalayan, and pink-eyed chinchilla melanocytes are similar; the himalayan mutation confers a deficiency in N-linked glycosylation, which results in an extremely unstable enzyme that is also temperature sensitive; the chinchilla and albino mutations confer susceptibility to proteolytic cleavage; the pink-eye dilution confers a reduction in the levels of immunoprecipitable tyrosinase, and what little enzyme there is fails to be translocated from the trans-Golgi network to melanosomes. The kinetics of activation and inhibition of the enzyme by the cofactor dopa are unique for the mutants tested and differ from those of tyrosinase from wild-type melanocytes. The findings support the conclusion that the albino locus in mice encodes the structural gene of tyrosinase.

Published
1988
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