Browsing by Subject "Melanoma"
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Item Open Access Adjuvant autologous melanoma vaccine for macroscopic stage III disease: survival, biomarkers, and improved response to CTLA-4 blockade(Hindawi Limited, 2016) Lotem, M.; Merims, S.; Frank, S.; Hamburger, T.; Nissan, A.; Kadouri, L.; Cohen, J.; Straussman, R.; Eisenberg, G.; Frankenburg, S.; Carmon, E.; Alaiyan, B.; Shneibaum, S.; Ayyildiz, Z. O.; Isbilen, M.; Senses, K. M.; Ron, I.; Steinberg, H.; Smith, Y.; Shiloni, E.; Gure, A. O.; Peretz, T.Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p = 0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.Item Open Access Ankaferd Hemostat affects etoposide resistance of the malignant melanoma cells(Akademi Doktorlar Yayınevi, 2020) Ghasemi, M.; Okay, M.; Malkan, Ü. Y.; Türk, S.; Jabbar, Javaid; Hocaoğlu, H.; Haznedaroğlu, İ. C.The development of resistance towards chemotherapeutic drugs has become an obstacle in treatment of cancer. Ankaferd Hemostat [ABS] has shown to suppress the proliferation of melanoma cells, but little is known about its’ mechanism. In this study, we demon¬strate that ABS can make some melanoma cell lines such as A2058 more sensitive towards etoposide by altering the genes involved in oxidative phosphorylation [OXPHOS] pathway. ABS treatment has shown to increase the sensitivity of A2058 towards etoposide and showed no effect for SK-MEL-5. Previously known to be more resistant to etoposide, SK-MEL-30 showed least amount of sen¬sitivity to ABS. We found mitochondrion cluster to be the most relevant to genes altered by ABS. To validate our claim, we compared two sets of melanoma cell lines; A375 with A2058 and A375 with SK-MEL-2. The clusters that we obtained from A375 and A2058 comparison did contain mitochondrial related clusters, their corresponding p value was not significant. Whereas, the clusters from A375 and SK-MEL-2 comparison contain 72 genes in ‘oxidoreductase’ cluster with enrichment score of 2.52. To get insight of the oxidoreductase cluster, we put the genes in that cluster to Enrichr. We found that majority of the genes among oxidoreductase cluster participate in oxidative phosphorylation and electron transport chain. Our study suggests that the use of ABS prior to etoposide treat¬ment can increase the response of melanoma cell lines because of the alteration of OXPHOS genes.Item Open Access Cancer testis gene expression as a biomarker of one-carbon metabolic activity, drug sensitivity and phenotypic heterogeneity in non-small cell lung cancer and malignant melanoma(2016-09) Şenses, Kerem MertExpression of cancer-testis (CT) genes on X chromosome (CT-X) is restricted to tumors, with very low or no expression in normal adult tissues. CT-X gene expression is one of the factors contributing to tumor heterogeneity and is variably observed in various types of cancers including non-small cell lung cancer (NSCLC) and malignant melanoma. Regulation of CT-X gene expression has been strongly linked to DNA methylation of promoter regions, however, mechanisms leading to re-expression of these genes in tumors, driven by promoter hypomethylation, is remained unsolved. Although tumors expressing CT-X genes are shown to be associated with higher tumor stage, larger tumors and aggressiveness, differential drug sensitivity of CT-X positive and negative tumors have not been investigated. In this thesis, we aimed to find the association between one-carbon pathway polymorphisms and CT-X gene expression. Moreover, we tested various tools and methods to find effective drugs for tumors in different phenotypic subgroups determined by CT-X gene expression or by other factors.Item Open Access Phenotype-based variation as a biomarker of sensitivity to molecularly targeted therapy in melanoma(Royal Society of Chemistry, 2017) Senses, K. M.; Ghasemi M.; Akbar, M. W.; Isbilen, M.; Fallacara, A. L.; Frankenburg, S.; Schenone, S.; Lotem, M.; Botta, M.; Gure, A. O.Transcriptomic phenotypes defined for melanoma have been reported to correlate with sensitivity to various drugs. In this study, we aimed to define a minimal signature that could be used to distinguish melanoma sub-types in vitro, and to determine suitable drugs by which these sub-types can be targeted. By using primary melanoma cell lines, as well as commercially available melanoma cell lines, we find that the evaluation of MLANA and INHBA expression is as capable as one based on a combined analysis performed with genes for stemness, EMT and invasion/proliferation, in identifying melanoma subtypes that differ in their sensitivity to molecularly targeted drugs. Using this approach, we find that 75% of melanoma cell lines can be treated with either the MEK inhibitor AZD6244 or the HSP90 inhibitor 17AAG.Item Open Access Predictive gene signature for pyrazolopyrimidine derivative c-Src inhibitor 10a sensitivity in melanoma cells(American Chemical Society, 2020-02) Kücükkaraduman, Barış; Türk, C.; Fallacara, A. L.; Şenses, K. M.; Ayyıldız, Z. O.; Akbar, Muhammad W.; Lotem, Michal; Botta, M.; İşbilen, M.; Güre, Ali O.Melanoma is a highly aggressive cancer with poor prognosis. Although more than 80% of melanomas harbor an activating mutation in genes within the MAPK pathway, which are mutually exclusive, usefulness of therapies targeting MAPK pathway are impeded by innate and/or acquired resistance in most patients. In this study, using melanoma cells, we report the efficacy of a recently developed pyrazolo[3,4-d]pyrimidine derived c-Src inhibitor 10a and identify a molecular signature which is predictive of 10a chemosensitivity. We show that the expression of TMED7, PLOD2, XRCC5, and NSUN5 are candidate biomarkers for 10a sensitivity. Although an undifferentiated/mesenchymal/invasive status of melanoma cells is associated with resistance to 10a, we show here for the first time that melanoma cells can be sensitized to 10a via treatment with valproic acid, a histone deacetylase inhibitor.