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Drug resistance in melanoma

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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29333049/marine-derived-fungi-extracts-enhance-the-cytotoxic-activity-of-doxorubicin-in-nonsmall-cell-lung-cancer-cells-a459
#2
Bruno Castro-Carvalho, Alice A Ramos, Maria Prata-Sena, Fernanda Malhão, Márcia Moreira, Daniela Gargiulo, Tida Dethoup, Suradet Buttachon, Anake Kijjoa, Eduardo Rocha
Background: Drug resistance is a major concern in the current chemotherapeutic approaches and the combination with natural compounds may enhance the cytotoxic effects of the anticancer drugs. Therefore, this study evaluated the cytotoxicity of crude ethyl extracts of six marine-derived fungi - Neosartorya tsunodae KUFC 9213 (E1), Neosartorya laciniosa KUFC 7896 (E2), Neosartorya fischeri KUFC 6344 (E3), Aspergillus similanensis KUFA 0013 (E4), Neosartorya paulistensis KUFC 7894 (E5), and Talaromyces trachyspermum KUFC 0021 (E6) - when combined with doxorubicin (Dox), in seven human cancer cell lines...
December 2017: Pharmacognosy Research
https://www.readbyqxmd.com/read/29330434/targeting-melanoma-stem-cells-with-the-vitamin-e-derivative-%C3%AE-tocotrienol
#3
Monica Marzagalli, Roberta Manuela Moretti, Elio Messi, Marina Montagnani Marelli, Fabrizio Fontana, Alessia Anastasia, Maria Rosa Bani, Giangiacomo Beretta, Patrizia Limonta
The prognosis of metastatic melanoma is very poor, due to the development of drug resistance. Cancer stem cells (CSCs) may play a crucial role in this mechanism, contributing to disease relapse. We first characterized CSCs in melanoma cell lines. We observed that A375 (but not BLM) cells are able to form melanospheres and show CSCs traits: expression of the pluripotency markers SOX2 and KLF4, higher invasiveness and tumor formation capability in vivo with respect to parental adherent cells. We also showed that a subpopulation of autofluorescent cells expressing the ABCG2 stem cell marker is present in the A375 spheroid culture...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29317343/nanoliposomal-delivery-of-cytosolic-phospholipase-a2-inhibitor-arachidonyl-trimethyl-ketone-for-melanoma-treatment
#4
Raghavendra Gowda, Saketh S Dinavahi, Soumya Iyer, Shubhadeep Banerjee, Rogerio I Neves, Colette R Pameijer, Gavin P Robertson
Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs in melanoma therapy. Nanotechnology can decrease drug resistance by improving drug delivery, with limited toxicity. This study details the development of nanoparticles containing arachidonyl trifluoromethyl ketone (ATK), a cytosolic phospholipase A2 inhibitor, which can inhibit multiple key pathways responsible for the development of recurrent resistant disease. Free ATK is toxic, limiting its efficacy as a therapeutic agent...
January 6, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29308322/impaired-nk-cell-recognition-of-vemurafenib-treated-melanoma-cells-is-overcome-by-simultaneous-application-of-histone-deacetylase-inhibitors
#5
Sheila López-Cobo, Natalia Pieper, Carmen Campos-Silva, Eva M García-Cuesta, Hugh T Reyburn, Annette Paschen, Mar Valés-Gómez
Therapy of metastatic melanoma advanced recently with the clinical implementation of signalling pathway inhibitors, such as vemurafenib, specifically targeting mutant BRAFV600E. In general, patients experience remarkable clinical responses under BRAF inhibitor (BRAFi) treatment but eventually progress within 6-8 months due to resistance development. Responding metastases show an increased immune cell infiltrate, including also NK cells, that, however, is no longer detectable in BRAFi-resistant lesions, suggesting NK cell activity should be exploited to prevent disease progression...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29299138/new-role-of-id3-in-melanoma-adaptive-drug-resistance
#6
Sachindra, Lionel Larribère, Daniel Novak, Huizi Wu, Laura Hüser, Karol Granados, Elias Orouji, Jochen Utikal
Adaptive resistance to targeted therapy such as BRAF inhibitors represents in melanoma a major drawback to this otherwise powerful treatment. Some of the underlying molecular mechanisms have recently been described: hyperactivation of the BRAF-MAPK pathway, of the AKT pathway, of the TGFβ/EGFR/PDGFRB pathway, or the low MITF/AXL ratio. Nevertheless, the phenomenon of early resistance is still not clearly understood. In this report, we show that knockdown of neural crest-associated gene ID3 increases the melanoma sensitivity to vemurafenib short-term treatment...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29289977/anti-pd-1-induced-high-grade-hepatitis-associated-with-corticosteroid-resistant-t-cells-a-case-report
#7
Helen M McGuire, Elena Shklovskaya, Jarem Edwards, Paul R Trevillian, Geoffrey W McCaughan, Patrick Bertolino, Catriona McKenzie, Ralph Gourlay, Stuart J Gallagher, Barbara Fazekas de St Groth, Peter Hersey
Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control...
December 30, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29282298/%C3%AE-catenin-mrna-silencing-and-mek-inhibition-display-synergistic-efficacy-in-preclinical-tumor-models
#8
Shanthi Ganesh, Xue Shui, Kevin Craig, Martin Koser, Girish R Chopda, Wendy A Cyr, Chengjung Lai, Henryk Dudek, Weimin Wang, Bob Brown, Marc Abrams
Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents...
December 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29273566/nutritional-shortage-augments-cisplatin-effects-on-murine-melanoma-cells
#9
F Antunes, G J Pereira, M G Jasiuliones, C Bincoletto, S S Smaili
Melanoma incidence increases every year worldwide and is responsible for 80% of skin cancer deaths. Due to its metastatic potential and resistance to almost any treatments such as chemo, radio, immune and target-therapy, the patients still have a poor prognosis, especially at metastatic stage. Considering that, it is crucial to find new therapeutic approaches to overcome melanoma resistance. Here we investigated the effect of cisplatin (CDDP), one of the chemotherapeutic agents used for melanoma treatment, in association with nutritional deprivation in murine melanoma cell lines...
December 19, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29243224/palbociclib-synergizes-with-braf-and-mek-inhibitors-in-treatment-na%C3%A3-ve-melanoma-but-not-after-the-development-of-braf-inhibitor-resistance
#10
Claire A Martin, Carleen Cullinane, Laura Kirby, Shatha Abuhammad, Emily J Lelliott, Kelly Waldeck, Richard J Young, Natalie Brajanovski, Donald P Cameron, Rachael Walker, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Richard B Pearson, Rodney J Hicks, Grant A McArthur, Karen E Sheppard
Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination were assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors...
December 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29242354/moving-synergistically-acting-drug-combinations-to-the-clinic-by-comparing-sequential-versus-simultaneous-drug-administrations
#11
Saketh S Dinavahi, Mohammed A Noory, Raghavendra Gowda, Joseph J Drabick, Rogerio I Neves, Arthur Berg, Gavin P Robertson
Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. AKT is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 seems to have potential to make AKT based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine them sequentially, enabling the use of existing phase-I clinical trial toxicity data...
December 14, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29235562/targeting-the-raf-kinases-in-human-cancer-the-raf-dimer-dilemma
#12
David E Durrant, Deborah K Morrison
The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29233008/non-polar-compounds-of-persian-gulf-sea-cucumber-holothuria-parva-selectively-induce-toxicity-on-skin-mitochondria-isolated-from-animal-model-of-melanoma
#13
Yalda Arast, Nina Seyed Razi, Melika Nazemi, Enayatollah Seydi, Jalal Pourahmad
PURPOSE: Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melonama. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling. MATERIALS AND METHODS: In the present study, selective toxicity and apoptotic effect of three extracts of Holothuria parva (H...
December 12, 2017: Cutaneous and Ocular Toxicology
https://www.readbyqxmd.com/read/29229836/single-cell-analysis-resolves-the-cell-state-transition-and-signaling-dynamics-associated-with-melanoma-drug-induced-resistance
#14
Yapeng Su, Wei Wei, Lidia Robert, Min Xue, Jennifer Tsoi, Angel Garcia-Diaz, Blanca Homet Moreno, Jungwoo Kim, Rachel H Ng, Jihoon W Lee, Richard C Koya, Begonya Comin-Anduix, Thomas G Graeber, Antoni Ribas, James R Heath
Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-derived BRAFV600 -mutant melanoma cell lines. A subset of plastic cell lines, which followed a trajectory covering multiple known cell state transitions, provided models for more detailed biophysical investigations...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29229605/mir-204-5p-and-mir-211-5p-contribute-to-braf-inhibitor-resistance-in-melanoma
#15
Marta Díaz-Martínez, Lucía Benito-Jardón, Lola Alonso, Lisa Koetz-Ploch, Eva Hernando, Joaquin Teixido
Melanoma treatment with the BRAF V600E inhibitor vemurafenib (VMF) provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to VMF with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response. Their expression was rapidly affected by VMF treatment through RNA stabilization...
December 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29227308/medical-bioinformatics-in-melanoma
#16
Phil F Cheng
PURPOSE OF REVIEW: Bioinformatic insights from next-generation sequencing has been integral in understanding melanoma biology, resistance to treatment and provided new avenues for melanoma treatment. Whole-genome sequencing, whole-exome sequencing and RNA sequencing has redefined the molecular classification of melanoma, revealed distinct genetic aberrations that define clinical subtypes of melanoma and uncovered the diverse heterogeneity that resides in an individual tumor. RECENT FINDINGS: In this review, we will summarize the recent whole-genome study that catalogs the genomic landscape across many melanoma subtypes, the single-cell RNA sequencing studies that interrogates tumor heterogeneity and the personalized vaccine approaches to melanoma treatment...
December 8, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29222604/model-based-analysis-of-the-heterogeneity-in-the-tumour-size-dynamics-differentiates-vemurafenib-dabrafenib-and-trametinib-in-metastatic-melanoma
#17
Hitesh B Mistry, David Orrell, Raluca Eftimie
PURPOSE: Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data. METHODS: Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data. RESULTS: The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates...
December 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29221137/ev20-sap-a-novel-anti-her-3-antibody-drug-conjugate-displays-promising-antitumor-activity-in-melanoma
#18
Emily Capone, Francesco Giansanti, Sara Ponziani, Alessia Lamolinara, Manuela Iezzi, Annamaria Cimini, Francesco Angelucci, Rossana La Sorda, Vincenzo De Laurenzi, Pier Giorgio Natali, Rodolfo Ippoliti, Stefano Iacobelli, Gianluca Sala
Melanoma is the most biologically aggressive skin cancer of well established constitutive and induced resistance to pharmacological treatment. Despite the recent progresses in immunotherapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective drugs. HER-3 - one of the four member of the tyrosin kinase epidermal growth factor receptors (EGFRs) family- is frequently overexpressed in solid tumors, including melanoma...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29218872/diffusion-mapping-of-drug-targets-on-disease-signaling-network-elements-reveals-drug-combination-strategies
#19
Jielin Xu, Kelly Regan-Fendt, Siyuan Deng, William E Carson, Philip R O Payne, Fuhai Li
The emergence of drug resistance to traditional chemotherapy and newer targeted therapies in cancer patients is a major clinical challenge. Reactivation of the same or compensatory signaling pathways is a common class of drug resistance mechanisms. Employing drug combinations that inhibit multiple modules of reactivated signaling pathways is a promising strategy to overcome and prevent the onset of drug resistance. However, with thousands of available FDA-approved and investigational compounds, it is infeasible to experimentally screen millions of possible drug combinations with limited resources...
2018: Pacific Symposium on Biocomputing
https://www.readbyqxmd.com/read/29212027/melanoma-therapeutic-strategies-that-select-against-resistance-by-exploiting-myc-driven-evolutionary-convergence
#20
Katherine R Singleton, Lorin Crawford, Elizabeth Tsui, Haley E Manchester, Ophelia Maertens, Xiaojing Liu, Maria V Liberti, Anniefer N Magpusao, Elizabeth M Stein, Jennifer P Tingley, Dennie T Frederick, Genevieve M Boland, Keith T Flaherty, Shannon J McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J Adams, Jason W Locasale, Karen Cichowski, Sayan Mukherjee, Kris C Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression...
December 5, 2017: Cell Reports
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