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Drug resistance in melanoma

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https://www.readbyqxmd.com/read/28535666/ddx53-regulates-cancer-stem-cell-like-properties-by-binding-to-sox-2
#1
Youngmi Kim, Minjeong Yeon, Dooil Jeoung
This study investigated the role of cancer/testis antigen DDX53 in regulating cancer stem cell-like properties. DDX53 shows co-expression with CD133, a marker for cancer stem cells. DDX53 directly regulates the SOX-2 expression in anticancer drug-resistant Malme3MR cells. DDX53 and miR-200bwere found to be involved in the regulation of tumor spheroid forming potential of Malme3M and Malme3MR cells. Furthermore, the self-renewal activity and the tumorigenic potential of Malme3M(R)-CD133 (+) cells were also regulated by DDX53...
May 2, 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28527094/circulating-tumor-dna-measurement-by-picoliter-droplet-based-digital-pcr-and-vemurafenib-plasma-concentrations-in-patients-with-advanced-braf-mutated-melanoma
#2
Fanny Garlan, Benoit Blanchet, Nora Kramkimel, Alicja Puszkiel, Jean-Louis Golmard, Gaelle Noe, Nicolas Dupin, Pierre Laurent-Puig, Michel Vidal, Valerie Taly, Audrey Thomas-Schoemann
BACKGROUND: Circulating tumor DNA (ctDNA) has been reported as a prognostic marker in melanoma. In BRAF V600-mutant melanoma, a plasma under-exposure to vemurafenib could favor emerging resistance but no biological data are available to support this hypothesis. OBJECTIVE: We aimed to investigate the relationship between vemurafenib plasma concentrations and the ctDNA plasma concentration during follow-up of BRAF-mutated melanoma patients. PATIENTS AND METHODS: Eleven patients treated with single-agent vemurafenib for advanced BRAF V600-mutant melanoma were analyzed in an exploratory monocentric study...
May 19, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#3
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28514651/modeling-genomic-instability-and-selection-pressure-in-a-mouse-model-of-melanoma
#4
Lawrence N Kwong, Lihua Zou, Sharmeen Chagani, Chandra Sekhar Pedamallu, Mingguang Liu, Shan Jiang, Alexei Protopopov, Jianhua Zhang, Gad Getz, Lynda Chin
Tumor evolution is an iterative process of selection for pro-oncogenic aberrations. This process can be accelerated by genomic instability, but how it interacts with different selection bottlenecks to shape the evolving genomic landscape remains understudied. Here, we assessed tumor initiation and therapy resistance bottlenecks in mouse models of melanoma, with or without genomic instability. At the initiation bottleneck, whole-exome sequencing revealed that drug-naive tumors were genomically silent, and this was surprisingly unaffected when genomic instability was introduced via telomerase inactivation...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28512412/sudden-onset-of-brain-metastasis-despite-the-use-of-vemurafenib-for-another-metastatic-lesion-in-malignant-melanoma-patients
#5
Keisuke Imafuku, Koji Yoshino, Kei Yamaguchi, Satoshi Tsuboi, Kuniaki Ohara, Hiroo Hata
Vemurafenib is an inhibitor of the BRAF mutation and has been approved by the Food and Drug Administration as a treatment option for patients with unresectable melanoma without brain metastasis. In the literature, vemurafenib has been reported to be also effective against brain metastasis. We encountered 3 cases with brain metastasis on vemurafenib therapy. In these cases, vemurafenib was clinically effective against metastatic lesions other than those in the brain. The brain lesions developed after the metastatic lesion had occurred...
January 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28500236/identification-of-the-serine-biosynthesis-pathway-as-a-critical-component-of-braf-inhibitor-resistance-of-melanoma-pancreatic-and-non-small-cell-lung-cancer-cells
#6
Kayleigh C Ross, Andrew J Andrews, Christopher D Marion, Timothy J Yen, Vikram Bhattacharjee
Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFis). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28487385/immune-related-gene-expression-profiling-after-pd-1-blockade-in-non-small-cell-lung-carcinoma-head-and-neck-squamous-cell-carcinoma-and-melanoma
#7
Aleix Prat, Alejandro Navarro, Laia Paré, Noemí Reguart, Patricia Galvan, Tomás Pascual, Alex Martínez, Paolo Nuciforo, Laura Comerma, Llucia Alos, Nuria Pardo, Susana Cedrés, Cheng Fan, Joel S Parker, Lydia Gaba, Ivan Victoria, Nuria Viñolas, Ana Vivancos, Ana Arance, Enriqueta Felip
Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor speciments from 65 patients with melanoma, lung non-squamous, squamous cell lung or head and neck cancers who were treated with the approved PD1 targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS)...
May 9, 2017: Cancer Research
https://www.readbyqxmd.com/read/28483693/combined-delivery-of-a-tgf-%C3%AE-inhibitor-and-an-adenoviral-vector-expressing-interleukin-12-potentiates-cancer-immunotherapy
#8
Jiayu Jiang, Yuandong Zhang, Ke Peng, Qin Wang, Xiaoyu Hong, Hanmei Li, Gerui Fan, Zhirong Zhang, Tao Gong, Xun Sun
Cancer immunotherapy appears a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-β (TGF-β), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-β inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-β inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene...
May 5, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28450382/an-adaptive-signaling-network-in-melanoma-inflammatory-niches-confers-tolerance-to-mapk-signaling-inhibition
#9
Helen L Young, Emily J Rowling, Mattia Bugatti, Emanuele Giurisato, Nadia Luheshi, Imanol Arozarena, Juan-Carlos Acosta, Jivko Kamarashev, Dennie T Frederick, Zachary A Cooper, Alexandre Reuben, Jesus Gil, Keith T Flaherty, Jennifer A Wargo, William Vermi, Michael P Smith, Claudia Wellbrock, Adam Hurlstone
Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands...
April 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28445958/repressing-cd147-is-a-novel-therapeutic-strategy-for-malignant-melanoma
#10
REVIEW
Xing Hu, Juan Su, Youyou Zhou, Xiaoyun Xie, Cong Peng, Zhimin Yuan, Xiang Chen
CD147/basigin, a transmembrane protein, is a member of the immunoglobulin super family. Accumulating evidence has revealed the role of CD147 in the development and progression of various cancers, including malignant melanoma (MM). MM is a malignancy of pigment-producing cells that causes the greatest number of skin cancer-related deaths worldwide. CD147 is overexpressed in MM and plays an important role in cell viability, apoptosis, proliferation, invasion, and metastasis, probably by mediating vascular endothelial growth factor (VEGF) production, glycolysis, and multi-drug resistance (MDR)...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28442677/1-2-3-triazolyl-esterization-of-pak1-blocking-propolis-ingredients-artepillin-c-arc-and-caffeic-acid-ca-for-boosting-their-anti-cancer-anti-pak1-activities-along-with-cell-permeability
#11
Hideaki Takahashi, Binh Cao Quan Nguyen, Yoshihiro Uto, Md Shahinozzaman, Shinkichi Tawata, Hiroshi Maruta
Artepillin C (ARC) and caffeic acid (CA) are among the major anti-cancer ingredients of propolis, and block the oncogenic/melanogenic/ageing kinase PAK1. However, mainly due to their COOH moiety, cell-permeability of these herbal compounds is rather limited. Thus, in this study, in an attempt to increase their cell-permeability without any significant loss of their water-solubility, we have esterized both ARC and CA with the water-soluble 1,2,3-triazolyl alcohol through Click Chemistry. We found that this esterization boosts the anti-cancer activity of ARC and CA by 100 and over 400 folds, respectively, against the PAK-dependent growth of A549 lung cells, but show no effect on the PAK1-independent growth of B16F10 melanoma cells...
April 24, 2017: Drug Discoveries & Therapeutics
https://www.readbyqxmd.com/read/28436422/rational-design-of-non-resistant-targeted-cancer-therapies
#12
Francisco Martínez-Jiménez, John P Overington, Bissan Al-Lazikani, Marc A Marti-Renom
Drug resistance is one of the major problems in targeted cancer therapy. A major cause of resistance is changes in the amino acids that form the drug-target binding site. Despite of the numerous efforts made to individually understand and overcome these mutations, there is a lack of comprehensive analysis of the mutational landscape that can prospectively estimate drug-resistance mutations. Here we describe and computationally validate a framework that combines the cancer-specific likelihood with the resistance impact to enable the detection of single point mutations with the highest chance to be responsible of resistance to a particular targeted cancer therapy...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28435463/design-and-development-of-fluorescent-vemurafenib-analogs-for-in-vivo-imaging
#13
Hannes Mikula, Shawn Stapleton, Rainer H Kohler, Claudio Vinegoni, Ralph Weissleder
Herein we describe fluorescent derivatives of vemurafenib to probe therapeutic BRAF inhibition in live cells and in vivo. The compounds were evaluated and compared by determining target binding, inhibition of mutant BRAF melanoma cell lines and live cell imaging. We show that vemurafenib-BODIPY is a superior imaging drug to visualize the targets of vemurafenib in live cells and in vivo in non-resistant and resistant melanoma tumors.
2017: Theranostics
https://www.readbyqxmd.com/read/28423711/the-antitumor-activity-and-preliminary-modeling-on-the-potential-mechanism-of-action-of-human-peroxiredoxin-5
#14
Juanjuan Liu, Xiaozhou Feng, Yuanyuan Jin, Zhengyang Sun, Haoyi Meng, Zhifei Zhang, Laixing Hu, Zhaoyong Yang
Goat peroxiredoxin-5 (gPRDX5) was verified as a good anti-cancer bioactive peptide (ACBP) against different tumor cell lines. Considering the immunogenicity between species for further therapeutic application, it is necessary to similarly investigate the antitumor activity of human peroxiredoxin-5 (hPRDX5) with 89% similarity in sequence to gPRDX5. In order to evaluate its antitumor activity, the potential anti-neoplastic effect of hPRDX5 on a mouse model was observed directly. The results of its in vivo antitumor activity suggested that hPRDX5 could resist immunosuppression by promoting lymphocyte proliferation and up-regulating the levels of serum cytokines...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423208/combined-activity-of-temozolomide-and-the-mtor-inhibitor-temsirolimus-in-metastatic-melanoma-involves-dkk1
#15
Heike Niessner, Corinna Kosnopfel, Tobias Sinnberg, Daniela Beck, Kathrin Krieg, Ines Wanke, Konstantinos Lasithiotakis, Michael Bonin, Claus Garbe, Friedegund Meier
The BRAFV600E inhibitor vemurafenib achieves remarkable clinical responses in patients with BRAF-mutant melanoma, but its effects are limited by the onset of drug resistance. In the case of resistance, chemotherapy can still be applied as second line therapy. However, it yields low response rates and strategies are urgently needed to potentiate its effects. In a previous study, we showed that the inhibition of the PI3K-AKT-mTOR pathway significantly increases sensitivity of melanoma cells to chemotherapeutic drugs (1)...
April 19, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/28420878/synergistic-antimicrobial-effects-of-silver-transition-metal-combinatorial-treatments
#16
Javier A Garza-Cervantes, Arturo Chávez-Reyes, Elena C Castillo, Gerardo García-Rivas, Oscar Antonio Ortega-Rivera, Eva Salinas, Margarita Ortiz-Martínez, Sara Leticia Gómez-Flores, Jorge A Peña-Martínez, Alan Pepi-Molina, Mario T Treviño-González, Xristo Zarate, María Elena Cantú-Cárdenas, Carlos Enrique Escarcega-Gonzalez, J Rubén Morones-Ramírez
Due to the emergence of multi-drug resistant strains, development of novel antibiotics has become a critical issue. One promising approach is the use of transition metals, since they exhibit rapid and significant toxicity, at low concentrations, in prokaryotic cells. Nevertheless, one main drawback of transition metals is their toxicity in eukaryotic cells. Here, we show that the barriers to use them as therapeutic agents could be mitigated by combining them with silver. We demonstrate that synergism of combinatorial treatments (Silver/transition metals, including Zn, Co, Cd, Ni, and Cu) increases up to 8-fold their antimicrobial effect, when compared to their individual effects, against E...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28418845/preclinical-development-of-g1t38-a-novel-potent-and-selective-inhibitor-of-cyclin-dependent-kinases-4-6-for-use-as-an-oral-antineoplastic-in-patients-with-cdk4-6-sensitive-tumors
#17
John E Bisi, Jessica A Sorrentino, Jamie L Jordan, David D Darr, Patrick J Roberts, Francis X Tavares, Jay C Strum
Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414587/non-melanoma-skin-cancer-new-and-future-synthetic-drug-treatments
#18
Teresa Amaral, Claus Garbe
Non-melanoma skin cancers (NMSC) mainly comprise two different entities: basal cell carcinoma (BCC) and squamous cell carcinoma (SCC); beneath these two entities, Merkel cell carcinoma, adnexal tumors, dermatofibrosarcoma protuberans, angiosarcoma, and cutaneous lymphoma belong to NMSC. These rare skin tumors are not the topic of this review. BCC and SCC are the most common cancers diagnosed in humans. The preferred treatment is surgery, which in most cases is curative. Although a high recurrence rate is seen, these cancers rarely metastasize...
May 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28413965/small-molecule-drugs-and-targeted-therapy-for-melanoma-current-strategies-and-future-directions
#19
Carmen Cerchia, Antonio Lavecchia
Malignant melanoma is the most aggressive and life-threatening skin cancer. Melanoma develops in melanocytes and is characterized by a very high tendency to spread to other parts of the body. Its pathogenesis depends on DNA mutations leading to the activation of oncogenes or to the inactivation of suppressor genes. The identification of misregulations in intracellular signal transduction pathways has provided an opportunity for development of mutation-specific inhibitors, which specifically target the mutated signaling cascades...
April 14, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28408301/impact-of-braf-kinase-inhibitors-on-the-mirnomes-and-transcriptomes-of-melanoma-cells
#20
Ines Kozar, Giulia Cesi, Christiane Margue, Demetra Philippidou, Stephanie Kreis
BACKGROUND: Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. METHODS: To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory...
April 10, 2017: Biochimica et Biophysica Acta
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