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Browsing by Subject "melanoma"

Now showing 1 - 3 of 3
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    Hi-511 Inhibits Both BRAF and AURKB To Overcome Malignant Melanoma Drug Resistance and Metastasis
    (2020-05) Chang, Xiaoyu
    Melanoma is an aggressive tumor of the skin. Although BRAF V600E inhibitors have been developed to treat melanoma, drug resistance and metastasis are still the major problems in melanoma therapy. Novel targets and effective agents to overcome drug resistant melanoma and reduce metastasis are urgently needed in clinical therapy. In this study, AURKB was defined as the target for melanoma therapy in an effort to overcome drug resistance. Notably, HI-511, a novel dual-target inhibitor for AURKB and BRAF V600E, inhibits development of both drug-sensitive and drug-resistant melanoma. We analyzed the Gene Expression Omnibus (GEO) database, utilized gene editing, and a xenograft mouse model to show AURKB is crucial for development of both drug-sensitive and drug-resistant melanoma. Inhibition of AURKB suppresses the cell growth and the rate of induced apoptosis in melanoma. Knocking down expression of AURKB decreased activation of the BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Notably, a novel AURKB and BRAF V600E dual-target inhibitor HI-511 was developed. HI-511 strongly suppresses development of vemurafenib-sensitive and vemurafenib-resistant melanoma in vitro and in vivo, which is evidenced by in vitro kinase assays, cell base studies, xenograft mouse models and the BRAF V600E/PTEN-loss melanoma mouse model. Moreover, we also analysis the metastatic melanoma database and utilized the wound healing assay and a luciferase-linked xenograft mouse model to demonstrate HI-511 could reduce melanoma metastasis. Overall, AURKB could be a potential target for melanoma treatment and could overcome the resistance to BRAF V600E inhibitor and reduce melanoma metastasis. HI-511 is a novel dual-target inhibitor for both AURKB and BRAF V600E and could achieve durable suppression of melanoma, even drug-resistant melanoma and metastatic melanoma.
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    Melanoma displays an evolutionarily conserved resistance to modulation of phagocytic signals
    (2017-08) Anderson, Katie
    Therapeutic activation of macrophage phagocytosis has the ability to restrain tumor growth through phagocytic clearance of tumor cells and activation of the adaptive immune response. The objective of this thesis was to evaluate the effects of modulating pro- and anti-phagocytic pathways in malignant melanoma. We observed that melanoma cells from mice, humans, and dogs displayed an unexpected resistance to phagocytosis that could not be fully mitigated by blockade of the “don’t eat me” signal CD47 or by chemotherapeutic enhancement of known “eat me” signals. In addition, combination doxorubicin chemotherapy and CD47 blockade did not consistently promote an anti-tumor adaptive immune response. Phagocytosis of melanoma cells was not enhanced by inhibition of secretory pathways, and phagocytosis of sensitive lymphoma tumor cells was not impaired in the presence of melanoma culture supernatants, indicating that soluble factors did not mediate phagocytosis resistance. siRNA mediated knockdown of 47 candidate “don’t eat me” signals similarly did not enhance melanoma cell phagocytosis, suggesting that these proteins do not disable macrophage phagocytosis. We conclude melanoma cells possess a mechanism of resistance to phagocytosis. Further investigation will be needed to define this mechanism and to develop strategies to overcome melanoma cell resistance to the innate immune response.
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    Role of coat color genotypes in risk and severity of melanoma in gray Quarter Horses
    (2013-06) Teixeira, Raffaella
    Both graying and melanoma formation in horses have recently been linked to a duplication in the syntaxin-17 (STX17) gene. This duplication, as well as a mutation in the agouti signaling protein (ASIP) gene that increases melanocortin-1-receptor (MC1R) pathway signaling, affect melanoma risk and severity in gray horses. We hypothesized that melanoma susceptibility in gray Quarter Horses (QH) is lower than gray horses from other breeds, and that this might be due to decreased MC1R signaling resulting from a high incidence of the MC1R chestnut coat color allele in the QH population. Blood or hair root samples were collected from 335 gray QH with and without dermal melanomas, for DNA extraction and genotyping for STX17, ASIP and MC1R genes. Age, gender and external melanoma presence and grade were recorded. The effect of age and genotype on melanoma presence and severity was evaluated by candidate gene association study. The melanoma prevalence and grade in this QH cohort were lower than in other breeds. Age was significantly associated with melanoma prevalence and severity. No significant effect of MC1R genotype on melanoma prevalence or severity was identified. In contrast to prior reports, an effect of ASIP genotype on both melanoma prevalence and grade was not detected. Homozygosity of STX17 was low and precluded evaluation of the gray allele effect on melanoma presence and severity. Melanoma prevalence and severity appears to be lower in gray QH than in other breeds. This could be due to infrequent STX17 homozygosity, a mitigating effect of the MC1R mutation on ASIP potentiation of melanoma, other genes in the MC1R signaling pathway, or differences in breed genetic background.