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  • 1
    Publication Date: 2015-09-12
    Description: Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Allen, Eliezer M -- Miao, Diana -- Schilling, Bastian -- Shukla, Sachet A -- Blank, Christian -- Zimmer, Lisa -- Sucker, Antje -- Hillen, Uwe -- Foppen, Marnix H Geukes -- Goldinger, Simone M -- Utikal, Jochen -- Hassel, Jessica C -- Weide, Benjamin -- Kaehler, Katharina C -- Loquai, Carmen -- Mohr, Peter -- Gutzmer, Ralf -- Dummer, Reinhard -- Gabriel, Stacey -- Wu, Catherine J -- Schadendorf, Dirk -- Garraway, Levi A -- U54 HG003067/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):207-11. doi: 10.1126/science.aad0095. Epub 2015 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium(DKTK), 69121 Heidelberg, Germany. ; Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland. ; Skin Cancer Unit, German Cancer Research Center(DKTK), 69121 Heidelberg, Germany. Skin Cancer Unit, German Cancer Research Center(DKTK), 69121 Heidelberg, Germany. Department of Dermatology, Venerology, and Allergology, University Medical Center, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany. ; Department of Dermatology, University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany. ; Department of Dermatology, University Hospital Tubingen, 72076 Tubingen, Germany. ; Department of Dermatology, University Hospital Kiel, 24105 Kiel, Germany. ; Department of Dermatology, University Medical Center, 55131 Mainz, Germany. ; Department of Dermatology, Elbe-Kliniken, 21614 Buxtehude, Germany. ; Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium(DKTK), 69121 Heidelberg, Germany. levi_garraway@dfci.harvard.edu dirk.schadendorf@uk-essen.de. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. levi_garraway@dfci.harvard.edu dirk.schadendorf@uk-essen.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26359337" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/*pharmacology/therapeutic use ; Antigens, Neoplasm/*genetics ; *Biomarkers, Pharmacological ; CTLA-4 Antigen/*antagonists & inhibitors ; Cell Cycle Checkpoints/genetics/immunology ; Cohort Studies ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Exome ; Female ; Genomics ; HLA Antigens/genetics ; Humans ; Male ; Melanoma/*drug therapy/*genetics/secondary ; Middle Aged ; Mutation ; Skin Neoplasms/*drug therapy/*genetics/pathology ; Tumor Microenvironment/drug effects/immunology ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-01-11
    Description: Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with 〉/=50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)--〉MEK--〉ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930354/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930354/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das Thakur, Meghna -- Salangsang, Fernando -- Landman, Allison S -- Sellers, William R -- Pryer, Nancy K -- Levesque, Mitchell P -- Dummer, Reinhard -- McMahon, Martin -- Stuart, Darrin D -- R01 CA176839/CA/NCI NIH HHS/ -- R01-CA176839/CA/NCI NIH HHS/ -- T32 HL007185/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Feb 14;494(7436):251-5. doi: 10.1038/nature11814. Epub 2013 Jan 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23302800" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Administration Schedule ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Indoles/*administration & dosage/*adverse effects/pharmacology ; MAP Kinase Signaling System/drug effects ; Melanoma/*drug therapy/genetics/*pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mutation ; Neoplasm Transplantation ; Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism ; Subcutaneous Tissue ; Sulfonamides/*administration & dosage/*adverse effects/pharmacology ; Time Factors ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Keywords: SURVIVAL ; COMBINATION ; evaluation ; Germany ; THERAPY ; FOLLOW-UP ; SURGERY ; TIME ; PATIENT ; primary ; CYCLE ; treatment ; ALPHA ; TRIAL ; DIFFERENCE ; METASTASIS ; chemotherapy ; MELANOMA ; PROGNOSTIC-FACTORS ; HIGH-RISK ; PROGNOSTIC FACTORS ; IMMUNOTHERAPY ; FOLLOW-UP TIME ; MALIGNANT-MELANOMA ; INTERFERON ; CENTERS ; MELANOMA PATIENTS ; CUTANEOUS MELANOMA ; RANDOMIZED TRIAL ; ADJUVANT ; DACARBAZINE ; DOSE BOLUS INTERLEUKIN-2 ; IL-2 ; PROGNOSTIC FACTOR ; RANDOMIZED-TRIAL ; RECOMBINANT INTERLEUKIN-2 ; relapse
    Abstract: Purpose: Low-dose interferon alfa (IFNalpha) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients. Patients and Methods: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose 1FNalpha2b (3 million international units [MU]/m(2)/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m(2)/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval. Results: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFNalpha2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFNalpha2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P = .93). Conclusion: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFNalpha2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival
    Type of Publication: Journal article published
    PubMed ID: 12885805
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  • 5
    Keywords: CELLS ; INVASION ; IRRADIATION ; SURVIVAL ; tumor ; BLOOD ; CELL ; Germany ; CLASSIFICATION ; DIAGNOSIS ; FOLLOW-UP ; imaging ; EXPOSURE ; SITE ; PROTEIN ; DIFFERENTIATION ; TUMORS ; MARKER ; primary ; prognosis ; LYMPH-NODES ; SKIN ; SUFFICIENT ; FREQUENCY ; FREQUENCIES ; STAGE ; IDENTIFICATION ; LESIONS ; NUMBER ; METASTASIS ; metastases ; MELANOMA ; PROGNOSTIC-FACTORS ; SURVEILLANCE ; BETA ; PARAMETERS ; PROGNOSTIC FACTORS ; BODY ; FACTOR-I ; PROGNOSTIC FACTOR ; SONOGRAPHY ; BIOPSY ; staging ; DIFFERENTIAL-DIAGNOSIS ; GUIDELINES ; BODIES ; FEATURES ; ONCOLOGY ; RE ; PROGNOSTIC-FACTOR ; PRIMARY TUMORS ; AMERICAN JOINT COMMITTEE ; CANCER STAGING SYSTEM ; LEVEL ; INTERVAL ; CUTANEOUS MALIGNANT-MELANOMA ; USA ; lymph node metastases ; LYMPH-NODE ; RISK-FACTOR ; EXTENT ; THICKNESS ; BIOPSIES ; MEDICINE ; interdisciplinary ; German ; MELANOMAS ; ULTRAVIOLET-IRRADIATION ; A-B-C-D rule ; ABCD RULE ; DERMATOLOGICAL-SOCIETY ; dermoscopy ; differential diagnosis ; EPILUMINESCENCE MICROSCOPY ; evidence ; I MELANOMA ; LACTATE-DEHYDROGENASE ; MELANOCYTIC SKIN-LESIONS ; melanoma diagnosis ; sentinel lymph node ; tumor node metastasis classification
    Abstract: Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1 -mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100 beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually
    Type of Publication: Journal article published
    PubMed ID: 17992123
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    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; SURVIVAL ; CELL ; CELL-PROLIFERATION ; Germany ; IN-VIVO ; VIVO ; microarray ; RNA ; ADHESION MOLECULES ; MOLECULES ; TISSUE ; SUPPRESSION ; BREAST-CANCER ; TARGET ; CELL-SURVIVAL ; PROGRESSION ; METASTASIS ; MELANOMA ; ADHESION ; MIGRATION ; EPITHELIAL-CELLS ; L1 ; MALIGNANT-MELANOMA ; TARGETS ; CELL-ADHESION MOLECULE ; OVEREXPRESSION ; DIFFERENTIAL EXPRESSION ; AMYLOID PRECURSOR PROTEIN ; chemoresistance ; CELL-GROWTH ; E-cadherin ; development ; tissue microarray ; ALPHA-SECRETASE
    Abstract: ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our Study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo Immunohistochemical analysis oil tissue microarrays indicated that ADAM-10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM-10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM-10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, Our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas
    Type of Publication: Journal article published
    PubMed ID: 19865098
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  • 10
    Keywords: SURVIVAL ; SAMPLES ; TUMORS ; T-CELLS ; MUTATIONS ; CANCER-IMMUNOTHERAPY ; IPILIMUMAB PLUS DACARBAZINE ; UNTREATED MELANOMA ; PD-1 BLOCKADE ; NEO-ANTIGENS
    Abstract: Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield significant clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
    Type of Publication: Journal article published
    PubMed ID: 26359337
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