Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting

Improving Melanoma Classification by Integrating Genetic and Morphologic Features

Boris Bastian and colleagues present a refined morphological classification of primary melanomas that can be used to improve existing melanoma classifications by defining genetically homogeneous subgroups

Melanoma: What are the gaps in our knowledge?

Jonathan Rees outlines a number of puzzling gaps that remain in our knowledge of the etiology of non-acral melanomas

Space mission design ontology : extraction of domain-specific entities and concepts similarity analysis

Expert Systems, computer programs able to capture human expertise and mimic experts’ reasoning, can support the design of future space missions by assimilating and facilitating access to accumulated knowledge. To organise these data, the virtual assistant needs to understand the concepts characterising space systems engineering. In other words, it needs an ontology of space systems. Unfortunately, there is currently no official European space systems ontology. Developing an ontology is a lengthy and tedious process, involving several human domain experts, and therefore prone to human error and subjectivity. Could the foundations of an ontology be instead semi-automatically extracted from unstructured data related to space systems engineering? This paper presents an implementation of the first layers of the Ontology Learning Layer Cake, an approach to semi-automatically generate an ontology. Candidate entities and synonyms are extracted from three corpora: a set of 56 feasibility reports provided by the European Space Agency, 40 books on space mission design publicly available and a collection of 273 Wikipedia pages. Lexica of relevant space systems entities are semi-automatically generated based on three different methods: a frequency analysis, a term frequency-inverse document frequency analysis, and a Weirdness Index filtering. The frequency-based lexicon of the combined corpora is then fed to a word embedding method, word2vec, to learn the context of each entity. With a cosine similarity analysis, concepts with similar contexts are matched

High-rate, high-resolution single photon X-ray imaging: Medipix4, a large 4-side buttable pixel readout chip with high granularity and spectroscopic capabilities

The Medipix4 chip is the latest member in the Medipix/Timepix family of hybrid pixel detector chips aimed at high-rate spectroscopic X-ray imaging using high-Z materials. It can be tiled on all 4 sides making it ideal for constructing large-area detectors with minimal dead area. The chip is designed to read out a sensor of 320 x 320 pixels with dimensions of 75 {\mu}m x 75 {\mu}m or 160 x 160 pixels with dimensions of 150 {\mu}m x 150 {\mu}m. The readout architecture features energy binning of the single photons, which includes charge sharing correction for hits with energy spread over adjacent pixels. This paper presents the specifications, architecture, and circuit implementation of the chip, along with the first electrical measurements

A phase 2 trial of complete resection for stage IV melanoma

BACKGROUND: On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting. METHODS: Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death. RESULTS: Seventy‐seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow‐up of 5 years, the median relapse‐free survival was 5 months (95% CI, 3‐7 months) whereas median overall survival was 21 months (95% CI, 16‐34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively. CONCLUSIONS: In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse‐free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy. Cancer 2011;. © 2011 American Cancer Society. One of the only prospective analyses of surgery for metastatic disease in patients with stage IV disease, this article reports on a multicenter cooperative group trial with enrollment of patients from 18 different institutions. Incorporating consistent monitoring is a hallmark of cooperative group trials.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86987/1/26111_ftp.pd

Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma.

BACKGROUND: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. METHODS: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. RESULTS: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. CONCLUSION: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments

A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo

The microphthalmia-associated transcription factor (MITF) is the “master melanocyte transcription factor” with a complex role in melanoma. MITF protein levels vary between and within clinical specimens, and amplifications and gain- and loss-of-function mutations have been identified in melanoma. How MITF functions in melanoma development and the effects of targeting MITF in vivo are unknown because MITF levels have not been directly tested in a genetic animal model. Here, we use a temperature-sensitive mitf zebrafish mutant to conditionally control endogenous MITF activity. We show that low levels of endogenous MITF activity are oncogenic with BRAFV600E to promote melanoma that reflects the pathology of the human disease. Remarkably, abrogating MITF activity in BRAFV600Emitf melanoma leads to dramatic tumor regression marked by melanophage infiltration and increased apoptosis. These studies are significant because they show that targeting MITF activity is a potent antitumor mechanism, but also show that caution is required because low levels of wild-type MITF activity are oncogenic