Review
Oncology
Fabrizio Tabbo, Chiara Pisano, Julien Mazieres, Laura Mezquita, Ernest Nadal, David Planchard, Anne Pradines, David Santamaria, Aurelie Swalduz, Chiara Ambrogio, Silvia Novello, Sandra Ortiz-Cuaran
Summary: The emergence of high-throughput sequencing has allowed for a deeper understanding of the molecular characteristics of non-small cell lung cancer, providing better strategies for the treatment of specific BRAF-mutated lung cancers, but there remains a lack of targeted approaches for some patients.
CANCER TREATMENT REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Elisa Bonaldi, Chiara Gargiuli, Loris De Cecco, Arianna Micali, Maria Grazia Rizzetti, Angela Greco, Maria Grazia Borrello, Emanuela Minna
Summary: The study demonstrates that the BRAF inhibitors Vemurafenib and Dabrafenib induce antiproliferative and redifferentiative effects in thyroid cancer cells, while rewiring the MAPK pathway related to RAS signaling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Gianluca Mauri, Erica Bonazzina, Alessio Amatu, Federica Tosi, Katia Bencardino, Viviana Gori, Daniela Massihnia, Tiziana Cipani, Francesco Spina, Silvia Ghezzi, Salvatore Siena, Andrea Sartore-Bianchi
Summary: The BRAF(V600E) mutation is detected in 8-10% of patients with metastatic colorectal cancer (mCRC) and has a poor prognostic outlook, with median overall survival below 20 months. Treatment options include immune checkpoint inhibitors (CPIs) for those with concomitant MSI-H status, and a combination of cytotoxic chemotherapy + anti-VEGF or EGFR and BRAF inhibitors for first and second line treatment, respectively. However, acquired resistance limits the potential benefits and survival remains poor. Ongoing clinical trials are exploring various strategies to improve treatment outcomes for this subset of patients.
Article
Oncology
Khaled Saleh, Mai Al Sakhen, Sana Kanaan, Salem Yasin, Michael Hoepfner, Lubna Tahtamouni, Bernhard Biersack
Summary: The compound Briva showed selective activity against BRAFV600E-mutant colorectal carcinoma cells by targeting VEGFR2 tyrosine kinase and reducing cell adhesion and metastasis formation.
INVESTIGATIONAL NEW DRUGS
(2023)
Article
Biochemistry & Molecular Biology
Mesfer Al Shahrani, Mohammad Abohassan, Mohammad Y. Alshahrani, Abdulrahim R. Hakami, Prasanna Rajagopalan
Summary: CB-1, a novel and potent dual B-Raf/c-Raf inhibitor, was effective against colon cancer cells expressing wild-type and mutant variants of B-Raf. Experimental results showed that CB-1 can inhibit cell proliferation by reducing B-Raf expression and inducing apoptosis, making it a potential therapeutic drug for colon cancer.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Review
Oncology
Mariona Riudavets, Priscilla Cascetta, David Planchard
Summary: This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with BRAF mutations, emphasizing the importance of BRAF mutations in lung cancer patients and discussing the different types of BRAF mutations and current treatment approaches.
Article
Cell Biology
Avinashnarayan Venkatanarayan, Jason Liang, Ivana Yen, Frances Shanahan, Benjamin Haley, Lilian Phu, Erik Verschueren, Trent B. Hinkle, David Kan, Ehud Segal, Jason E. Long, Tony Lima, Nicholas P. D. Liau, Jawahar Sudhamsu, Jason Li, Christiaan Klijn, Robert Piskol, Melissa R. Junttila, Andrey S. Shaw, Mark Merchant, Matthew T. Chang, Donald S. Kirkpatrick, Shiva Malek
Summary: CRAF is necessary for the growth of KRAS mutant tumors and its dimerization plays a vital role. Lack of CRAF leads to sustained ERK activation and cell cycle arrest, and the CRAF-loss phenotype can be rescued by inhibiting MEK or ERK.
Article
Biochemistry & Molecular Biology
Ernesto Rossi, Giovanni Schinzari, Francesco Cellini, Mario Balducci, Mariangela Pasqualoni, Brigida Anna Maiorano, Bruno Fionda, Silvia Longo, Francesco Deodato, Alessandro Di Stefani, Ketty Peris, Maria Antonietta Gambacorta, Giampaolo Tortora
Summary: BRAF and MEK inhibitors have changed the clinical management of metastatic melanoma, but their combination with radiotherapy needs careful monitoring for potential toxicity. This study reports the successful use of fractionated radiotherapy in metastatic melanoma patients receiving BRAF and MEK inhibitors, without significant adverse events. These results suggest that interruption of targeted therapy during radiotherapy for oligoprogressive disease can be avoided.
Article
Multidisciplinary Sciences
Juliane Mooz, Kristina Riegel, P. S. Hari, Anguraj Sadanandam, Federico Marini, Matthias Klein, Ulrike Werner, Wilfried Roth, Annett Wilken-Schmitz, Irmgard Tegeder, Krishnaraj Rajalingam
Summary: The expression level of ARAF kinase is decreased in lung cancer and is associated with lymph node metastasis and poor patient survival. Depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells. ARAF suppresses ERBB3-AKT signaling and tumor metastasis by inhibiting ERBB3 expression.
Article
Oncology
Lisa Dinter, Paula C. Karitzky, Alexander Schulz, Alexander A. Wurm, Marie-Christin Mehnert, Mildred Sergon, Antje Tunger, Mathias Lesche, Rebekka Wehner, Anja Mueller, Theresa Kaeubler, Heike Niessner, Andreas Dahl, Stefan Beissert, Marc Schmitz, Friedegund Meier, Barbara Seliger, Dana Westphal
Summary: This study investigated the combined effects of MEK inhibitors (MEKi) and BRAF inhibitors (BRAFi) on sensitive NRAS-mutant melanoma cells, including their ability to inhibit proliferation, induce apoptosis, and alter the expression of immune modulatory molecules. The study found that BRAFi significantly enhanced the antiproliferative and proapoptotic activity of MEKi, and upregulated the expression of immune relevant molecules in melanoma cells.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Oncology
Yoshihiro Morimoto, Nami Yamashita, Haruka Hirose, Atsushi Fushimi, Naoki Haratake, Tatsuaki Daimon, Atrayee Bhattacharya, Rehan Ahmad, Yozo Suzuki, Hidekazu Takahashi, Donald W. Kufe
Summary: This study reveals that the BRAF(V600E) mutation in colorectal cancer (CRC) is associated with aggressive disease and resistance to BRAF inhibitors. The expression of MUC1-C protein is significantly upregulated in BRAF(V600E) CRCs. MUC1-C plays a crucial role in promoting cell proliferation and resistance to BRAF inhibitors in BRAF(V600E) CRC cells.
Article
Chemistry, Multidisciplinary
Charles W. Morgan, Ian L. Dale, Andrew P. Thomas, James Hunt, Jason W. Chin
Summary: In this study, bio-orthogonal ligand tethering (BOLT) was used to selectively target inhibitors to CRAF, showing that selective CRAF inhibition promotes paradoxical activation. This suggests that BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Oncology
Kevin Yao, Emily Zhou, Chao Cheng
Summary: In this study, a B-Raf signature score was defined using RNA-seq data, which could predict B-Raf mutation status and other aberrations. Patients dichotomized by the median B-Raf score showed more significant stratification compared to other metrics. High B-Raf score also predicted higher sensitivity to B-Raf inhibitors and drugs targeting other relevant oncogenic pathways.
Review
Oncology
Elisa Grassi, Jody Corbelli, Giorgio Papiani, Maria Aurelia Barbera, Federica Gazzaneo, Stefano Tamberi
Summary: 8-12% of patients with advanced colon rectal cancer present with BRAF alterations, particularly the V600E mutation, which is associated with poor prognosis. New therapeutic options, such as targeted therapy combinations, are emerging for this subgroup of patients. Treatment optimization for this subgroup is an important goal.
FRONTIERS IN ONCOLOGY
(2021)
Article
Endocrinology & Metabolism
Laura Boucai, Venkatraman Seshan, Michelle Williams, Jeffrey A. Knauf, Mahesh Saqcena, Ronald A. Ghossein, James A. Fagin
Summary: Two subtypes of BRAF-mutant PTCs (BRAF-TDShi and BRAF-TDSlo) show significant differences in demographic distribution, tumor size, lymph node involvement, and distant metastases, indicating distinct clinical characteristics and prognosis.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Review
Immunology
Katja Bieber, Jennifer E. Hundt, Xinhua Yu, Marc Ehlers, Frank Petersen, Christian M. Karsten, Jorg Koehl, Khalaf Kridin, Kathrin Kalies, Anika Kasprick, Stephanie Goletz, Jens Y. Humrich, Rudolf A. Manz, Axel Kuenstner, Christoph M. Hammers, Reza Akbarzadeh, Hauke Busch, Christian D. Sadik, Tanja Lange, Hanna Grasshoff, Alexander M. Hackel, Jeanette Erdmann, Inke Koenig, Walter Raasch, Mareike Becker, Anja Kerstein-Staehle, Peter Lamprecht, Gabriela Riemekasten, Enno Schmidt, Ralf J. Ludwig
Summary: Approximately 5% of the world-wide population is affected by autoimmune diseases, which are still difficult to treat and have a significant economic impact. The progression from harmless to inflammatory autoimmune disease conditions is a key factor. Biomarkers that can predict this progression would be highly impactful. Factors such as genetics, environment, and lifestyle choices may influence the progression from benign to inflammatory autoimmune conditions. Research is needed to define and modulate autoimmune predisease.
AUTOIMMUNITY REVIEWS
(2023)
Article
Endocrinology & Metabolism
Mostafa Al-Sharkawi, Veronica Calonga-Solis, Franz F. Dressler, Hauke Busch, Olaf Hiort, Ralf Werner
Summary: Research has shown that impaired virilisation may occur in certain 46,XY individuals with defects in androgen synthesis or action, despite normal testicular development. A recent case study of a patient with complete androgen insensitivity syndrome (CAIS) revealed abnormal expression of HSD17B3 in Sertoli cells (SCs) and not in Leydig cells (LCs), suggesting a defect in testicular development and function. This study investigates the impact of altered androgen signalling in the gonads of five individuals with defects in androgen synthesis or action.
EUROPEAN JOURNAL OF ENDOCRINOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Alya R. Alnuaimi, Justus Bottner, Vidhya A. Nair, Nival Ali, Razaz Alnakhli, Eva Dreyer, Iman M. Talaat, Hauke Busch, Sven Perner, Jutta Kirfel, Rifat Hamoudi, Wael M. Abdel-Rahman
Summary: Colorectal cancer is a deadly disease with increasing rates worldwide. Caldesmon (CaD) has emerged as a promising biomarker for diagnosis and therapy. It was found that l-CaD is overexpressed in colorectal cancer and associated with preinvasive stages, while h-CaD is expressed in smooth muscle cells but not in cancer cells or normal colon mucosal epithelial cells. These findings have significant implications for the management of colorectal cancer patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Ana Paula Francese-Santos, Jakob A. Meinel, Cristiane S. C. Piveta, Juliana G. R. Andrade, Beatriz A. Barros, Helena Fabbri-Scallet, Vera Lucia Gil-da-Silva-Lopes, Gil Guerra-Junior, Axel Kuenstner, Hauke Busch, Olaf Hiort, Maricilda P. de Mello, Ralf Werner, Andrea T. Maciel-Guerra
Summary: We report a girl with 46,XY partial gonadal dysgenesis who carries a 297 kb duplication at Xp21.2 upstream of the NR0B1 gene. This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis. The fine mapping of the breakpoints revealed a tandem duplication of TASL (CXorf21), GK, and partially TAB3.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Gastroenterology & Hepatology
Gajanan Kendre, Karthikeyan Murugesan, Tilman Brummer, Oreste Segatto, Anna Saborowski, Arndt Vogel
Summary: This study retrospectively analyzed the genomic data of 6,130 patients diagnosed with intrahepatic cholangiocarcinoma (iCCA), and identified seven oncogenic driver genes and their co-mutational patterns. The study also discovered genetic variations and genomic patterns associated with iCCA, which are important for developing effective treatment strategies and predicting mechanisms of resistance.
JOURNAL OF HEPATOLOGY
(2023)
Article
Biochemical Research Methods
Michael Olbrich, Axel Kuenstner, Hauke Busch
Summary: This study presents the development of a Microbiome Batch Effects Correction Suite, which integrates multiple batch effect correcting algorithms and evaluation metrics into a statistical computation software package R.
BMC BIOINFORMATICS
(2023)
Article
Oncology
Robert Zeiser
Summary: This study summarizes the treatment approach for chronic graft-versus-host disease (cGVHD) and finds that adding ibrutinib to first-line therapy is not recommended. Currently, glucocorticoid monotherapy remains the standard treatment for cGVHD.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Meeting Abstract
Oncology
Romain Sigaud, Anja Stefanski, Florian Selt, Thomas Hielscher, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Budenbender, Marc Remke, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Carolin Walter, Daniel Muenter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamel Mann, Augusto Faria Andrade, Nada Jabado, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl, Till Milde
Article
Hematology
Radu-Florian Gherman, Sophie Ewald, Gabriele Ihorst, Tim Strussmann, Robert Zeiser, Ralph Waesch, Hartmut Bertz, Daiana Stolz, Justus Duyster, Juergen Finke, Reinhard Marks, Monika Engelhardt, Jesus Duque-Afonso
Summary: This study retrospectively analyzed the outcomes of 396 patients undergoing autologous hematopoietic stem cell transplantation with BEAM or TEAM conditioning protocols. The results showed that BEAM conditioning was associated with worse survival outcomes in patients with impaired pulmonary function, while PD before transplantation was the only significant factor in patients treated with TEAM.
EUROPEAN JOURNAL OF HAEMATOLOGY
(2023)
Article
Genetics & Heredity
Paul-Martin Holterhus, Alexandra Kulle, Hauke Busch, Malte Spielmann
Summary: Critical genetic and hormonal switches are crucial in fetal sex development and determine gonadal sex as well as the differentiation of genital and somatic sex phenotype. Recent data show that these switches can have variable effects and lead to a broad spectrum of differences in biological sex development and diversity in genital and somatic sex phenotypes. SRY and testosterone are important upstream switches for gonadal and phenotypic sex determination, while AMH plays a key role in the inhibition of female genital development. Advances in technology, such as single-cell and spatial transcriptomics, will provide further insights into these molecular switches.
MEDIZINISCHE GENETIK
(2023)
Article
Multidisciplinary Sciences
Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Daniela Kocher, Carolin Walter, Daniel Muenter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria-Andrade, Nada Jabado, Martin U. Schuhmann, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl, Till Milde
Summary: The authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi in pediatric low-grade gliomas (pLGG) and validate their effectiveness using bulk and single-cell sequencing datasets. The MSSs successfully distinguish sensitive and non-sensitive cells and correlate with treatment response in independent datasets. These MSSs are important for patient stratification and should be validated in clinical trials.
NATURE COMMUNICATIONS
(2023)
Review
Immunology
Robert Zeiser, Olle Ringden, Behnam Sadeghi, Gil Gonen-Yaacovi, Oscar G. Segurado
Summary: Graft versus host disease (GVHD) is a common clinical complication that can occur at any period post allogeneic hematopoietic stem cell transplantation. There is currently no consensus on the management of steroid-refractory acute GVHD and the prognosis for these patients remains poor. Recent advancements in cell therapies, particularly the use of decidua stromal cells (DSCs), have shown promising results in the treatment of acute GVHD.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Manuel Lauinger, Daniel Christen, Rhena F. U. Klar, Carole Roubaty, Christoph E. Heilig, Michael Stumpe, Jennifer J. Knox, Nikolina Radulovich, Laura Tamblyn, Irene Y. Xie, Peter Horak, Andrea Forschner, Michael Bitzer, Uwe A. Wittel, Melanie Boerries, Claudia R. Ball, Christoph Heining, Hanno Glimm, Martina Froehlich, Daniel Huebschmann, Steven Gallinger, Ralph Fritsch, Stefan Froehling, Grainne M. O'Kane, Joern Dengjel, Tilman Brummer
Summary: This study functionally characterizes BRAF exon 12 deletions and compares them with other BRAF ss 3-alpha C mutants. It demonstrates that BRAF(Delta ss 3-alpha C) deletion mutants form stable dimers and multiprotein complexes, and their dimerization is necessary. Some mutants with aromatic amino acid insertions at the deletion junction exhibit resistance to monomer-favoring RAF inhibitors while being sensitive to dimer-favoring inhibitors.
Article
Oncology
Gila Mostufi-Zadeh-Haghighi, Pia Veratti, Kyra Zodel, Gabriele Greve, Miguel Waterhouse, Robert Zeiser, Michael L. Cleary, Michael Luebbert, Jesus Duque-Afonso
Summary: This study focused on the characterization of the TGF beta signaling pathway in B-acute lymphoblastic leukemia (ALL) and resistance to the multi-kinase inhibitor dasatinib. The results showed that TGF beta signaling negatively regulates cell growth in B-cell precursor-ALL and in dasatinib-resistant ALL cells. The upregulation of the TGF beta pathway was identified in dasatinib-resistant pre-BCR+/E2A-PBX1(+) ALL cells, and dasatinib partially blocked TGF beta-induced SMAD3 phosphorylation in B-cell precursor ALL cell lines and dasatinib-resistant pre-BCR+/E2A-PBX1(+) ALL cells.