Article
Oncology
Rachel S. Goodman, Lorenza Di Guardo, Andrea Maurichi, Brendan Kirwin, Adnan Khattak, Vito Vanella, Joanna Lee, Aleigha Lawless, Juliane Czapla, Andrea Spagnoletti, Margherita Ambrosini, Elisabeth Livingstone, Georgina V. Long, Ryan J. Sullivan, Matteo S. Carlino, Victoria Atkinson, Claudia Trojanello, Paolo A. Ascierto, Dirk Schadendorf, Lydia Warburton, Alexander M. Menzies, Mario Santinami, Douglas B. Johnson
Summary: This retrospective multicenter cohort study evaluated patients who received BRAF/MEK inhibitors and had a progression-free survival of 4 years or more, and found that over 75% of patients still had durable antitumor responses after nearly 8 years of median follow-up. Similar results were observed in patients who discontinued therapy. Long-term toxicities were uncommon and low-grade.
EUROPEAN JOURNAL OF CANCER
(2023)
Review
Oncology
Jonathan N. Priantti, Maysa Vilbert, Thiago Madeira, Francisco Cezar A. Moraes, Erica C. Koch Hein, Anwaar Saeed, Ludimila Cavalcante
Summary: Approximately 50% of melanoma patients with a specific mutation can receive targeted therapy with BRAF/MEK inhibitors. However, many develop resistance and experience disease progression. Rechallenging these patients with the inhibitors has been found to improve outcomes in terms of survival and response. This systematic review and meta-analysis evaluated the efficacy and safety of rechallenging advanced melanoma patients with BRAF/MEK inhibitors. The results showed improvement in progression-free survival and overall survival rates, with no unexpected safety concerns.
Article
Oncology
Francesco Spagnolo, Bruna Dalmasso, Enrica Tanda, Miriam Potrony, Susana Puig, Remco van Doorn, Ellen Kapiteijn, Paola Queirolo, Hildur Helgadottir, Paola Ghiorzo
Summary: The study retrospectively collected data of patients with germline CDKN2A pathogenic variants who received targeted therapy for advanced melanoma across four European centers. The results support treatment with targeted therapy in this subset of patients, showing that the clinical activity of BRAF+/-MEK inhibitors in patients with germline CDKN2A pathogenic variants was not inferior to that of clinical trials and real-world studies.
Review
Oncology
Lucia Musacchio, Anna Amela Valsecchi, Vanda Salutari, Giorgio Valabrega, Floriana Camarda, Valentina Tuninetti, Gaia Giannone, Michele Bartoletti, Claudia Marchetti, Sandro Pignata, Anna Fagotti, Giovanni Scambia, Massimo Di Maio, Domenica Lorusso
Summary: The systematic review and meta-analysis showed that MEK inhibitors have some activity in the treatment of low grade serous carcinoma of the ovary and peritoneum, but their effect on progression-free survival is not significant.
CANCER TREATMENT REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Emmanuelle M. Ruiz, Solomon A. Alhassan, Youssef Errami, Zakaria Y. Abd Elmageed, Jennifer S. Fang, Guangdi Wang, Margaret A. Brooks, Joe A. Abi-Rached, Emad Kandil, Mourad Zerfaoui
Summary: A 13-gene panel was identified to accurately predict resistance to BRAF/MEK inhibitor therapy in melanoma patients. Dysregulation of HMOX1, ICAM, MMP2, and SPARC defined a treatment-resistant landscape, and HMOX1-mediated mitochondrial stress response was identified as a potential key driver of resistance. These findings highlight the importance of these genes in predicting treatment outcomes and targeting underlying mechanisms to reduce resistance development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Thomas Jung, Maximilian Haist, Michael Kuske, Stephan Grabbe, Matthias Bros
Summary: The advent of MAPK inhibitors and ICI has greatly improved the treatment of metastatic melanoma, with BRAF/MEK inhibitors used for BRAF mutation patients, showing immunomodulatory functions in addition to their antiproliferative effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Signe Caksa, Usman Baqai, Andrew E. Aplin
Summary: Melanoma, a growing cancer, is currently treated with targeted inhibitors in the MAPK pathway, but drug resistance limits its effectiveness. However, new applications and combinations with other therapies may provide hope for melanoma treatment.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Dermatology
Dimitrios C. Ziogas, Frosso Konstantinou, Spyros Bouros, Maria Theochari, Helen Gogas
Summary: The management and prognosis of BRAF-mutant metastatic melanoma have undergone significant changes with the introduction of immune checkpoint inhibitors and molecularly targeted agents. Combining BRAF/MEK inhibitors with immune checkpoint inhibitors is thought to improve sensitivity to immunotherapy, with ongoing clinical trials exploring optimal timing and eligible patient subsets for these regimens.
AMERICAN JOURNAL OF CLINICAL DERMATOLOGY
(2021)
Article
Medicine, Research & Experimental
Shini Liu, Qiong Zou, Jie-Ping Chen, Xiaosai Yao, Peiyong Guan, Weiting Liang, Peng Deng, Xiaowei Lai, Jiaxin Yin, Jinghong Chen, Rui Chen, Zhaoliang Yu, Rong Xiao, Yichen Sun, Jing Han Hong, Hui Liu, Huaiwu Lu, Jianfeng Chen, Jin-Xin Bei, Joanna Koh, Jason Yongsheng Chan, Baohua Wang, Tiebang Kang, Qiang Yu, Bin-Tean Teh, Jihong Liu, Ying Xiong, Jing Tan
Summary: A study found that resistance to the MEK inhibitor trametinib in ovarian cancer patients was associated with enhancer reprogramming, leading to downregulation of negative regulators of the MAPK pathway and subsequent ERK activation. Additionally, HDAC inhibitors were shown to alter enhancer reprogramming, upregulate MAPK negative regulators, and reverse trametinib resistance. The combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Oncology
Martin Salzmann, Johannes Pawlowski, Carmen Loquai, David A. Rafei-Shamsabadi, Frank Meiss, Selma Ugurel, Dirk Schadendorf, Friedegund Meier, Alexander H. Enk, Jessica C. Hassel
Summary: This retrospective, multi-centre study evaluated the clinical course of patients with advanced NRAS-mutated melanoma treated with MEK inhibitors (MEKi) in German cancer centres. The results showed that MEKi can stabilize the disease course but expectations regarding ongoing tumor response should be tempered.
EUROPEAN JOURNAL OF CANCER
(2022)
Article
Oncology
Maximilian Haist, Henner Stege, Ronja Ebner, Maria Isabel Fleischer, Carmen Loquai, Stephan Grabbe
Summary: Sequential treatment with front-line CPI is associated with favorable tumor control and overall survival in untreated BRAF-mutant metastatic melanoma patients.
Article
Biochemistry & Molecular Biology
Svenja Mergener, Jens T. Siveke, Samuel Pena-Llopis
Summary: The study found that monosomy of chromosome 3 (M3) and mutations in BAP1 are associated with higher resistance to MEK inhibitors in uveal melanoma. Reconstitution of BAP1 was unable to restore sensitivity to MEK inhibition. Comparison of UM tumors with mutations in BAP1 and wild-type BAP1 from TCGA showed clear differentiation in overall and progression-free survival.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
A. Marani, H. Gioacchini, M. Paolinelli, A. Offidani, A. Campanati
Summary: This review provides a comprehensive analysis of the drug-drug interactions of MEK inhibitors used in the treatment of patients with BRAF-mutated advanced melanoma. The review discusses the impact of these interactions on efficacy and safety of the treatments and differentiates between interactions supported by pharmacokinetic or pharmacodynamic mechanisms, those encountered in clinical practice, and those observed in preclinical studies.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
(2023)
Article
Oncology
Daan Jan Willem Rauwerdink, Remco van Doorn, Jos van der Hage, Alfonsus J. M. Van den Eertwegh, John B. A. G. Haanen, Maureen Aarts, Franchette Berkmortel, Christian U. Blank, Marye J. Boers-Sonderen, Jan Willem B. De Groot, Geke A. P. Hospers, Melissa de Meza, Djura Piersma, Rozemarijn S. Van Rijn, Marion Stevense, Astrid Van der Veldt, Gerard Vreugdenhil, Michel W. J. M. Wouters, Karijn Suijkerbuijk, Monique van der Kooij, Ellen Kapiteijn
Summary: This study aimed to compare the efficacy of immunotherapy and BRAF/MEK inhibitors in metastatic nodular melanoma and metastatic superficial spreading melanoma. The results showed no difference in efficacy between the two treatments for patients with either type of melanoma. However, patients with nodular melanoma had shorter distant metastasis-free survival and worse overall survival, suggesting that the poorer overall survival of nodular melanoma is mainly due to the propensity for metastatic spread after the primary diagnosis.
Article
Dermatology
Mario Mandala, Giuseppe Palmieri, Vienna Ludovini, Sara Baglivo, Francesca Marasciulo, Francesca Castiglione, Alessio Gili, Simona Osella Abate, Marco Rubatto, Rebecca Senetta, Gianluca Avallone, Simone Ribero, Luca Romano, Nicola Pimpinelli, Vincenzo de Giorgi, Fausto Roila, Marina Pisano, Milena Casula, Antonella Manca, Maria Cristina Sini, Daniela Massi, Pietro Quaglino
Summary: The prognostic impact of variant allele frequency (VAF) on clinical outcome in metastatic melanoma patients receiving BRAF and MEK inhibitors is still unclear. This study found that high VAF is an independent poor prognostic factor in these patients.
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
(2023)
Article
Medicine, General & Internal
Robert A. Heaton, Simon Heales, Khalid Rahman, Darren W. Sexton, Iain Hargreaves
JOURNAL OF CLINICAL MEDICINE
(2020)
Article
Developmental Biology
Abdulmajeed Fahad Alrefaei, Andrea E. Munsterberg, Grant N. Wheeler
Summary: Frizzled receptors, transducing signals through Wnts, are crucial for neural tube development. Specific expression profiles of FZD receptors offer basis for future functional studies, showing interactions of Wnts-FZDs during spinal cord neurogenesis.
GENE EXPRESSION PATTERNS
(2021)
Review
Oncology
Nancy M. Y. Teng, Christopher A. Price, Alastair M. McKee, Lindsay J. Hall, Stephen D. Robinson
Summary: The microbiota plays a key role in cancer outcomes and responses, although breast cancer has been relatively understudied compared to other types of cancer. Environmental factors like diet and antibiotics can impact the microbiota and influence breast cancer outcomes. In-depth studies on the microbiota-Breast Cancer relationship and the underlying mechanisms are still needed to fully understand these complex interactions.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Article
Multidisciplinary Sciences
Gi Fay Mok, Leighton Folkes, Shannon A. Weldon, Eirini Maniou, Victor Martinez-Heredia, Alice M. Godden, Ruth M. Williams, Tatjana Sauka-Spengler, Grant N. Wheeler, Simon Moxon, Andrea E. Muensterberg
Summary: This study used ATAC-seq and RNA-seq to analyze the spatiotemporal dynamics along the chick embryonic axis, identifying differential binding site coverage for key transcription factors and connecting accessible chromatin with nearby expressed genes. The authors determined cis-regulatory elements for TCF15 and MEOX1, investigated their spatiotemporal activity and evolutionary conservation, and disrupted their expression through epigenome silencing to recapitulate phenotypic abnormalities of anterior-posterior axis extension. This integrated approach allows for dissection of paraxial mesoderm regulatory circuits in vivo and has implications for investigating gene regulatory networks.
NATURE COMMUNICATIONS
(2021)
Editorial Material
Microbiology
Lindsay J. Hall, Stephen D. Robinson
Summary: Bifidobacterium bifidum is enriched in the gut microbiome of patients who respond to cancer treatment, but only specific strains of commercial B. bifidum synergistically reduced tumor burden in a mouse model.
NATURE MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Christopher J. Benwell, James A. G. E. Taylor, Stephen D. Robinson
Summary: NRP2 plays a crucial role in promoting EC adhesion and migration, contributing to vascular formation. Further research is needed to fully understand its specific functions in angiogenesis.
Article
Multidisciplinary Sciences
Alastair M. McKee, Benjamin M. Kirkup, Matthew Madgwick, Wesley J. Fowler, Christopher A. Price, Sally A. Dreger, Rebecca Ansorge, Kate A. Makin, Shabhonam Caim, Gwenaelle Le Gall, Jack Paveley, Charlotte Leclaire, Matthew Dalby, Cristina Alcon-Giner, Anna Andrusaite, Tzu-Yu Feng, Martina Di Modica, Tiziana Triulzi, Elda Tagliabue, Simon W. F. Milling, Katherine N. Weilbaecher, Melanie R. Rutkowski, Tamas Korcsmaros, Lindsay J. Hall, Stephen D. Robinson
Summary: Antibiotic-induced perturbation of gut microbiota significantly increases breast cancer tumor progression in mouse models, while Faecalibaculum rodentium helps to slow tumor growth. Increased abundance of mast cells in tumors can be mitigated by a mast cell stabilizer to reduce tumor growth.
Review
Biochemistry & Molecular Biology
Marco Antonaci, Grant N. Wheeler
Summary: This article explores the importance of the neural crest in neurocristopathies and introduces the potential role of non-coding gene miRNA in neural crest development and pathology.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Article
Developmental Biology
Alice M. Godden, Marco Antonaci, Nicole J. Ward, Michael van der Lee, Anita Abu-Daya, Matthew Guille, Grant N. Wheeler
Summary: Researchers used CRISPR-Cas9 knockout methods to study the role of miRNAs in the development of Xenopus neural crest. They designed a new approach to effectively 'drop out' miRNAs and studied their functions and effects through phenotype validation and gene analysis.
DEVELOPMENTAL BIOLOGY
(2022)
Meeting Abstract
Toxicology
S. E. Wyville, G. N. Wheeler
TOXICOLOGY LETTERS
(2022)
Article
Oncology
Tzu-Yu Feng, Francesca N. Azar, Sally A. Dreger, Claire Buchta Rosean, Mitchell T. McGinty, Audrey M. Putelo, Sree H. Kolli, Maureen A. Carey, Stephanie Greenfield, Wesley J. Fowler, Stephen D. Robinson, Melanie R. Rutkowski
Summary: Establishing commensal dysbiosis before breast tumor initiation enhances early dissemination of hormone receptor-positive (HR+) mammary tumor cells. Dysbiosis increases both the frequency and profibrogenicity of mast cells in normal mammary tissues, which can persist after tumor implantation. Enhanced collagen levels in tumor-adjacent mammary tissue positively correlate with mast cell abundance and HR+ breast cancer recurrence.
CANCER IMMUNOLOGY RESEARCH
(2022)
Article
Multidisciplinary Sciences
Eudald Pascual-Carreras, Marta Marin-Barba, Sergio Castillo-Lara, Pablo Coronel-Cordoba, Marta Silvia Magri, Grant N. Wheeler, Jose Luis Gomez-Skarmeta, Josep F. Abril, Emili Salo, Teresa Adell
Summary: Any planarian fragment can regenerate the missing head and tail properly by activating the Wnt/beta-catenin signaling pathway, which changes the chromatin accessibility of the wound cells. The determination of missing tissue identity relies on pre-existing tissue. Planarians are perfect organisms for studying this mechanism, as the same group of cells can regenerate a head or a tail depending on the injured body part. The differential activation of the Wnt/beta-catenin signal after amputation specifies anterior or posterior identity. The chromatin accessibility of wound cells shifts according to the polarity of pre-existing tissue in a Wnt/beta-catenin-dependent manner within 12 hours.
NATURE COMMUNICATIONS
(2023)
Article
Microbiology
Raymond Kiu, Alexander G. Shaw, Kathleen Sim, Antia Acuna-Gonzalez, Christopher A. Price, Harley Bedwell, Sally A. Dreger, Wesley J. Fowler, Emma Cornwell, Derek Pickard, Gusztav Belteki, Jennifer Malsom, Sarah Phillips, Gregory R. Young, Zoe Schofield, Cristina Alcon-Giner, Janet E. Berrington, Christopher J. Stewart, Gordon Dougan, Paul Clarke, Gillian Douce, Stephen D. Robinson, J. Simon Kroll, Lindsay J. Hall
Summary: Genomic and phenotypic analyses of 272 infant-associated Clostridium perfringens isolates suggest that pfoA is an important toxin gene in C. perfringens linked with preterm infant intestinal diseases. The gene encoding toxin perfringolysin O, pfoA, was largely deficient in a human-derived hypovirulent lineage, as well as certain colonization factors, in contrast to typical pfoA-encoding virulent lineages. These findings suggest both the importance of pfoA(+)C. perfringens as a gut pathogen in preterm infants and areas for further investigation, including potential intervention and therapeutic strategies.
NATURE MICROBIOLOGY
(2023)
Article
Microbiology
Nancy M. Y. Teng, Raymond Kiu, Rhiannon Evans, David J. Baker, Christian Zenner, Stephen D. Robinson, Lindsay J. Hall
Summary: Two novel bacterial isolates were obtained from faecal samples of patients attending the Breast Care clinic at the Norwich and Norfolk University Hospital. Strain LH1062T was predicted to be a potential novel genus most closely related to Coprobacillus, whilst LH1063T was predicted to be a novel species belonging to Coprobacter. The strains were characterized using various methods, including genetic analysis and phenotypic testing.
INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY
(2023)
Article
Oncology
Christopher J. Benwell, Robert T. Johnson, James A. G. E. Taylor, Christopher A. Price, Stephen D. Robinson
Summary: The expression of neuropilin (NRP) is associated with poor outcomes in various types of cancer. As known coreceptors for VEGFRs, which are key drivers of angiogenesis, previous studies have suggested that NRP1 and NRP2 play a functional role in promoting tumorigenesis by facilitating invasive vessel growth. However, it is still unclear whether NRP1 and NRP2 act synergistically to enhance pathological angiogenesis. This study used mouse models to demonstrate that simultaneous targeting of endothelial NRP1 and NRP2 leads to maximum inhibition of primary tumor development and angiogenesis. Metastasis and secondary site angiogenesis were also significantly reduced. Mechanistic studies revealed that depleting both NRP1 and NRP2 in mouse-microvascular endothelial cells promoted the rapid degradation of VEGFR-2. These findings highlight the importance of targeting both NRP1 and NRP2 to modulate tumor angiogenesis.
CANCER RESEARCH COMMUNICATIONS
(2022)