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Drug resistance in melanoma

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https://www.readbyqxmd.com/read/28749946/genome-wide-association-analysis-identifies-genetic-correlates-of-immune-infiltrates-in-solid-tumors
#1
Nathan O Siemers, James L Holloway, Han Chang, Scott D Chasalow, Petra B Ross-MacDonald, Charles F Voliva, Joseph D Szustakowski
Therapeutic options for the treatment of an increasing variety of cancers have been expanded by the introduction of a new class of drugs, commonly referred to as checkpoint blocking agents, that target the host immune system to positively modulate anti-tumor immune response. Although efficacy of these agents has been linked to a pre-existing level of tumor immune infiltrate, it remains unclear why some patients exhibit deep and durable responses to these agents while others do not benefit. To examine the influence of tumor genetics on tumor immune state, we interrogated the relationship between somatic mutation and copy number alteration with infiltration levels of 7 immune cell types across 40 tumor cohorts in The Cancer Genome Atlas...
2017: PloS One
https://www.readbyqxmd.com/read/28740606/structure-guided-strategy-for-the-development-of-potent-bivalent-erk-inhibitors
#2
Bernhard C Lechtenberg, Peter D Mace, E Hampton Sessions, Robert Williamson, Romain Stalder, Yann Wallez, Gregory P Roth, Stefan J Riedl, Elena B Pasquale
ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28738256/p53-and-mitf-bcl-2-identified-as-key-pathways-in-the-acquired-resistance-of-nras-mutant-melanoma-to-mek-inhibition
#3
Ahmad Najem, Mohammad Krayem, François Salès, Nader Hussein, Bassam Badran, Caroline Robert, Ahmad Awada, Fabrice Journe, Ghanem E Ghanem
Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors...
July 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28722539/an-autophagy-driven-pathway-of-atp-secretion-supports-the-aggressive-phenotype-of-braf-v600e-inhibitor-resistant-metastatic-melanoma-cells
#4
Shaun Martin, Aleksandra M Dudek-Peric, Abhishek D Garg, Heleen Roose, Seyma Demirsoy, Sofie Van Eygen, Freya Mertens, Peter Vangheluwe, Hugo Vankelecom, Patrizia Agostinis
The ingrained capacity of melanoma cells to rapidly evolve towards an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF(V600E). Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF(V600E) inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP...
July 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28721808/molecular-tests-for-the-choice-of-cancer-therapy
#5
Anna P Sokolenko, Evgeny N Imyanitov
There are over a dozen of approved cancer drugs, whose administration is tailored to predictive laboratory tests. The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy, HER2 assessment for the administration of HER2-targeting agents, EGFR and ALK gene testing for lung cancer treatment, BRAF analysis in melanoma, etc. While first predictive tests relied on relatively easy laboratory procedures, more recent developments require rather sophisticated assays...
July 19, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28718799/zebrafish-as-a-model-organism-for-the-development-of-drugs-for-skin-cancer
#6
REVIEW
Fatemeh Bootorabi, Hamed Manouchehri, Reza Changizi, Harlan Barker, Elisabetta Palazzo, Annalisa Saltari, Mataleena Parikka, Carlo Pincelli, Ashok Aspatwar
Skin cancer, which includes melanoma and squamous cell carcinoma, represents the most common type of cutaneous malignancy worldwide, and its incidence is expected to rise in the near future. This condition derives from acquired genetic dysregulation of signaling pathways involved in the proliferation and apoptosis of skin cells. The development of animal models has allowed a better understanding of these pathomechanisms, with the possibility of carrying out toxicological screening and drug development. In particular, the zebrafish (Danio rerio) has been established as one of the most important model organisms for cancer research...
July 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28715002/cationic-folate-mediated-liposomal-delivery-of-bis-arylidene-oxindole-induces-efficient-melanoma-tumor-regression
#7
Chandra Kumar Elechalawar, Kathyayani Sridharan, Abhishek Pal, Mohammed Tanveer Ahmed, Mohammed Yousuf, Susanta Sekhar Adhikari, Rajkumar Banerjee
The folate receptor (FR) is a well-validated and common target for cancer due to its high over-expression in many different cancer cells. Herein, we developed a new FR-targeting ligand (FA8) by conjugating folic acid and a cationic lipid. Owing to its favorable structural property FA8 as a ligand could be accommodated at an unusually higher molar ratio for a ligand-targeted liposome. We then encapsulated a drug-like molecule, bis-arylidene oxindole (NME2), in the targeted liposome. The resulting formulation induced potent caspase-8 up-regulation even in FR-moderately expressing melanoma cells...
July 17, 2017: Biomaterials Science
https://www.readbyqxmd.com/read/28710962/discovery-of-potent-molecular-chimera-cm358-to-treat-human-metastatic-melanoma
#8
Y Gilad, H Tuchinsky, G Ben-David, R Minnes, A Gancz, H Senderowitz, G Luboshits, M A Firer, G Gellerman
The resistance of cancer cells to chemotherapeutic agents, whether through intrinsic mechanisms or developed resistance, motivates the search for new chemotherapeutic strategies. In the present report, we demonstrate a facile synthetic strategy towards the discovery of new anti-cancer substances. This strategy is based on simple covalent coupling between known anti-cancer drugs, which results in novel 'chimeric' small molecules. One of these novel compounds, CM358, is the product of an amide bond formation between the known Topoisomerase II (Topo II) inhibitor amonafide (AM) and the known DNA mustard alkylator chlorambucil (CLB)...
June 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28708099/role-played-by-signalling-pathways-in-overcoming-braf-inhibitor-resistance-in-melanoma
#9
REVIEW
Xian Yang Chan, Alamdeep Singh, Narin Osman, Terrence J Piva
The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28702658/overcoming-multidrug-resistance-using-folate-receptor-targeted-and-ph-responsive-polymeric-nanogels-containing-covalently-entrapped-doxorubicin
#10
Y Chen, O Tezcan, D Li, N Beztsinna, B Lou, T Etrych, K Ulbrich, J M Metselaar, T Lammers, W E Hennink
Multidrug resistance (MDR) contributes to failure of chemotherapy. We here show that biodegradable polymeric nanogels are able to overcome MDR via folic acid targeting. The nanogels are based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) (p(HEMAm-co-AzEMAm)-Gly-HEMAm), covalently loaded with the chemotherapeutic drug doxorubicin (DOX) and subsequently decorated with a folic acid-PEG conjugate via copper-free click chemistry. pH-Responsive drug release is achieved via the acid-labile hydrazone bond between DOX and the methacrylamide polymeric network...
July 27, 2017: Nanoscale
https://www.readbyqxmd.com/read/28699904/the-anti-apoptotic-bag3-protein-is-involved-in-braf-inhibitor-resistance-in-melanoma-cells
#11
Luana Guerriero, Giuseppe Palmieri, Margot De Marco, Antonio Cossu, Paolo Remondelli, Mario Capunzo, Maria Caterina Turco, Alessandra Rosati
BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-γ levels, allowing a sustained activation of NF-κB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas...
June 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28699537/recent-advances-in-polymeric-nanosystems-for-treating-cutaneous-melanoma-and-its-metastasis
#12
Yi-Ping Chou, Yin-Ku Lin, Chun-Han Chen, Jia-You Fang
Melanoma shows a high possibility of mortality after it metastasizes because of its aggressive nature. Although there are several options for anti-melanoma therapy, this skin malignancy is resistant to some therapies. Chemotherapy, biochemotherapy, immunotherapy, and adoptive cell therapy have failed to exhibit a significant amelioration in overall survival. Nanomedicine provides an opportunity to improve the efficiency of the anti-melanoma regimen. Nanoparticles for treating melanoma provide the advantages over conventional therapies such as drug solubility increment, drug stability enhancement, epithelium permeability and bioavailability amelioration, half-life prolonging, tumor targeting, and side effect minimization...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28688365/albumin-nanoparticles-with-synergistic-antitumor-efficacy-against-metastatic-lung-cancers
#13
Bomi Kim, Bohyung Seo, Sanghyun Park, Changkyu Lee, Jong Oh Kim, Kyung Taek Oh, Eun Seong Lee, Han-Gon Choi, Yu Seok Youn
Albumin nanoparticles are well-known as effective drug carriers used to deliver hydrophobic chemotherapeutic agents. Albumin nanoparticles encapsulating curcumin and doxorubicin were fabricated using slightly modified nanoparticle albumin-bound (nab™) technology, and the synergistic effects of these two drugs were examined. Albumin nanoparticles encapsulating curcumin, doxorubicin, and both curcumin and doxorubicin were prepared using a high pressure homogenizer. The sizes of albumin nanoparticles were ∼130nm, which was considered to be suitable for the EPR (enhanced permeability and retention) effect...
June 27, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28685959/targeting-cholesterol-transport-in-circulating-melanoma-cells-to-inhibit-metastasis
#14
Yu-Chi Chen, Raghavendra Gowda, Raymond K Newswanger, Patrick Leibich, Barry Fell, Gerson Rosenberg, Gavin P Robertson
Despite recent break throughs in targeted- and immune-based therapies, rapid development of drug resistance remains a hurdle for the long-term treatment of melanoma patients. Targeting metastatically spreading circulating tumor cells (CTCs) may provide an additional approach to manage melanoma. This study investigates whether targeting cholesterol transport in melanoma CTCs can retard metastasis development. Nanolipolee-007, the liposomal form of leelamine, reduced melanoma metastasis in both a novel in vitro flow system mimicking the circulating system and in experimental as well as spontaneous animal metastasis models, irrespective of the BRAF mutational status of the CTCs...
July 7, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28684402/braf-v600-inhibition-alters-the-microrna-cargo-in-the-vesicular-secretome-of-malignant-melanoma-cells
#15
Taral R Lunavat, Lesley Cheng, Berglind O Einarsdottir, Roger Olofsson Bagge, Somsundar Veppil Muralidharan, Robyn A Sharples, Cecilia Lässer, Yong Song Gho, Andrew F Hill, Jonas A Nilsson, Jan Lötvall
The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF(V600) mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment...
July 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28677730/chemotherapy-oxaliplatin-sensitizes-prostate-cancer-to-immune-checkpoint-blockade-therapies-via-stimulating-tumor-immunogenicity
#16
Jin Zhou, Tuo Yang, Lipeng Liu, Bingxin Lu
Even though standard treatment options are available for prostate cancer patients, prostate cancer is still a leading cause of death in many Western countries due to drug resistance and recurrence. Immune checkpoint blockade therapy has been proved to be very effective in some melanoma patients, which might dependent on the preconditioned immune system. Here we explored the effect of chemotherapy (oxaliplatin) in combination with immune checkpoint blockade therapy (anti‑PD‑1 treatment) in prostate cancer cell lines and pre‑clinical animal models...
September 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28677036/%C3%AE-np73-regulates-the-expression-of-the-multidrug-resistance-genes-abcb1-and-abcb5-in-breast-cancer-and-melanoma-cells-a-short-report
#17
Habib A M Sakil, Marina Stantic, Johanna Wolfsberger, Suzanne Egyhazi Brage, Johan Hansson, Margareta T Wilhelm
PURPOSE: Multidrug resistance (MDR) is a major cause of treatment failure. In cancer cells, MDR is often caused by an increased efflux of therapeutic drugs mediated by an up-regulation of ATP binding cassette (ABC) transporters. It has previously been shown that oncogenic ΔNp73 plays an important role in chemo-resistance. Here we aimed at unraveling the role of ΔNp73 in regulating multidrug resistance in breast cancer and melanoma cells. METHODS: KEGG pathway analysis was used to identify pathways enriched in breast cancer samples with a high ΔNp73 expression...
July 4, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28671620/epithelial-to-mesenchymal-transition-in-the-pathogenesis-and-therapy-of-head-and-neck-cancer
#18
REVIEW
Julia Thierauf, Johannes Adrian Veit, Jochen Hess
Head and neck cancer (HNC) is one of the most prevalent human malignancies worldwide, with a high morbidity and mortality. Implementation of interdisciplinary treatment modalities has improved the quality of life, but only minor changes in overall survival have been achieved over the past decades. Main causes for treatment failure are an aggressive and invasive tumor growth in combination with a high degree of intrinsic or acquired treatment resistance. A subset of tumor cells gain these properties during malignant progression by reactivating a complex program of epithelia-to-mesenchymal transition (EMT), which is integral in embryonic development, wound healing, and stem cell behavior...
July 3, 2017: Cancers
https://www.readbyqxmd.com/read/28646617/melanoma-associated-grm3-variants-dysregulate-melanosome-trafficking-and-camp-signaling
#19
Ana Neto, Craig J Ceol
Large-scale sequencing studies have revealed several genes that are recurrently mutated in melanomas. To annotate the melanoma genome we have expressed tumor-associated variants of these genes in zebrafish and characterized their effects on melanocyte development and function. Here, we describe expression of tumor-associated variants of the recurrently-mutated metabotropic glutamate receptor 3 (GRM3) gene. Unlike wild-type GRM3, tumor-associated GRM3 variants disrupted trafficking of melanosomes, causing their aggregation in the cell body...
June 24, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28645859/discovery-of-a-novel-pan-raf-inhibitor-with-potent-anti-tumor-activity-in-preclinical-models-of-braf-v600e-mutant-cancer
#20
Sung Pyo Hong, Soon Kil Ahn
AIMS: BRAF mutations, especially BRAF V600E, are a frequent occurrence in malignant melanomas. The BRAF inhibitors are used as the care standard for BRAF-mutant metastatic melanomas. However, melanomas rapidly develop resistance to BRAF inhibitors after a median response duration of 6months, and the subsequent rapid development of cutaneous toxicity is enhanced by the paradoxical activation of CRAF. In this study, we discovered a potent and selective pan-RAF inhibitor: INU-152. The goal of this study was to investigate whether the inhibition of pan-RAF with INU-152 completely disrupts the MAPK pathway in cancer cells bearing BRAF or RAS mutations...
June 20, 2017: Life Sciences
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