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)
Article
Chemistry, Medicinal
Yuqi Jiang, Jie Xu, Kairui Yue, Chao Huang, Mengting Qin, Dongyu Chi, Qixin Yu, Yue Zhu, Xiaohan Hou, Tongqiang Xu, Min Li, C. James Chou, Xiaoyang Li
Summary: The study focused on modifying HDAC inhibitors to deactivate the Michael reaction in order to improve their potency. Compound 11h showed significant improvements in both HDAC inhibitory activity and cell-based antitumor assay, demonstrating potential for clinical application and efficacy against AML.
JOURNAL OF MEDICINAL CHEMISTRY
(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)
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
Silvia Mezi, Andrea Botticelli, Simone Scagnoli, Giulia Pomati, Giulia Fiscon, Federica De Galitiis, Francesca Romana Di Pietro, Sofia Verkhovskaia, Sasan Amirhassankhani, Simona Pisegna, Giovanna Gentile, Maurizio Simmaco, Bjoern Gohlke, Robert Preissner, Paolo Marchetti
Summary: Drug-drug interactions (DDIs) are significantly associated with treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.
Review
Oncology
Thomas Yul Avery, Natalie Koehler, Robert Zeiser, Tilman Brummer, Dietrich Alexander Ruess
Summary: Hyperactivation of the RAS-RAF-MEK-ERK cascade plays a significant role in the oncogenesis of various tumors. It mediates the crosstalk between tumor, tumor microenvironment, and the immune system, leading to immune escape mechanisms and establishment of a tumor-supporting environment. Pharmacological interruption of this pathway disrupts tumor cells and modifies the tumor microenvironment, as well as anti-tumor immunomodulation. MEK inhibition has shown promise in modulating immune responses. However, the durable efficacy, therapy resistance, and toxicity still pose challenges for the clinical application of therapeutic agents targeting RAS-RAF-MEK-ERK hyperactivation.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Kun Zhao, Qiong Dai, Junli Wu, Zhang Wei, Yi Duan, Bo Chen
Summary: This study found that morusin can enhance the inhibitory effect of MAPK pathway inhibitors on BRAF mutant melanoma cells by inhibiting the feedback activation of the STAT3/SOX2 pathway. The combination of morusin and MAPK pathway inhibitors shows greater efficacy in inhibiting BRAF-mutant melanoma and drug-resistant melanoma compared to the use of MAPK pathway inhibitors alone.
EUROPEAN JOURNAL OF CANCER
(2022)
Article
Oncology
Mattia Garutti, Melissa Bergnach, Jerry Polesel, Lorenza Palmero, Maria Antonietta Pizzichetta, Fabio Puglisi
Summary: To date, the combination of BRAF and MEK inhibitors is commonly used for the treatment of mutated BRAF metastatic melanoma. However, there is no evidence to support the superiority of one combination over others, and safety data is limited. In this meta-analysis, we evaluated the adverse events associated with each treatment combination to provide clinicians with information for tailored patient treatment.
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
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
Hussein Akil, Mercedes Quintana, Jeremy H. Raymond, Tommy Billoux, Valentin Benboubker, Sophie Besse, Philippe Auzeloux, Veronique Delmas, Valerie Petit, Lionel Larue, Michel D'Incan, Francoise Degoul, Jacques Rouanet
Summary: Targeted radionuclide therapy (TRT) combined with MAPK/ERK inhibitors shows additive efficiency in BRAF and NRAS mutant melanoma cells. TRT has a significant therapeutic effect on NRAS(Q61K) mutated melanoma and reduces metastasis capacity.
Review
Immunology
Gita Manzari Tavakoli, Mohammad Hossein Mirzapour, Sepideh Razi, Nima Rezaei
Summary: Melanoma, the most aggressive form of skin cancer, has been extensively studied for the development of efficient treatments. Surgical resection, targeted therapies, and immune checkpoint inhibitors are the best approaches for treating early and advanced/metastatic melanoma. Ferroptosis, an iron-dependent cell death pathway, and its inducers have shown potential in overcoming resistance to conventional therapies in advanced/metastatic melanoma. This review discusses the mechanisms of ferroptosis, its environmental triggers, and its implications for the treatment of melanoma.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ahlem Jebali, Maxime Battistella, Celeste Lebbe, Nicolas Dumaz
Summary: The network involving PI3K, AKT, and mTOR is important in melanoma oncogenesis, with RICTOR overexpression associated with poor prognosis. RICTOR enhances melanoma-initiating cells with stemness properties and contributes to resistance to BRAF inhibitors. An interaction between RICTOR and STAT3 in resistant cells, as well as a connection between RAS and RICTOR in resistant melanoma, were identified, suggesting RICTOR as a valuable therapeutic target in melanoma.
Review
Pharmacology & Pharmacy
Meran Keshawa Ediriweera
Summary: Histone acetylation is a crucial epigenetic event and continues to be an area of great interest in biochemical research. The balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs) is disrupted in various human cancers. Histone deacetylase inhibitors (HDACi) have shown promising results in restoring dysregulated histone acetylation profiles and are considered as potential anti-cancer therapeutics. Recent studies have identified odd-chain fatty acids as novel HDACi, further expanding the understanding of fatty acids in cancer therapy.
DRUG DISCOVERY TODAY
(2023)
Article
Gastroenterology & Hepatology
Franck Carbonnel, Emilie Routier, Thierry Lazure, Charlotte Mussini, Christophe Bellanger, Carine Merklen, Bakhtiar Bejou, Anthony Buisson, Aurelien Amiot, Antoine Meyer, Catherine Dong, Caroline Robert
Summary: This study provides the first systematic description of colitis caused by dual blockade of BRAF and MEK kinases in the treatment of melanoma. The study found that severe colitis characterized by ulcerations of the right colon can occur, leading to symptoms such as diarrhea, rectal bleeding, abdominal pain, and intestinal obstruction. In some cases, the colitis was associated with ischemic changes and inflammation.
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Peripheral Vascular Disease
Katherine J. Perschbacher, Guorui Deng, Jeremy A. Sandgren, John W. Walsh, Phillip C. Witcher, Sarah A. Sapouckey, Caitlyn E. Owens, Shao Yang Zhang, Sabrina M. Scroggins, Nicole A. Pearson, Eric J. Devor, Julien A. Sebag, Gary L. Pierce, Rory A. Fisher, Anne E. Kwitek, Donna A. Santillan, Katherine N. Gibson-Corley, Curt D. Sigmund, Mark K. Santillan, Justin L. Grobe
Article
Clinical Neurology
Marshall T. Holland, Scott C. Seaman, Royce W. Woodroffe, Douglas C. Fredericks, Christopher K. Kovach, Katherine N. Gibson-Corley, George T. Gillies, Matthew A. Howard
WORLD NEUROSURGERY
(2020)
Article
Physiology
Sarah A. Sapouckey, Lisa L. Morselli, Guorui Deng, Chetan N. Patil, Kirthikaa Balapattabi, Vanessa Oliveira, Kristin E. Claflin, Javier Gomez, Nicole A. Pearson, Matthew J. Potthoff, Katherine N. Gibson-Corley, Curt D. Sigmund, Justin L. Grobe
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Kelly C. Falls-Hubert, Aimee L. Butler, Kai Gui, Michael Anderson, Mengshi Li, Jeffrey M. Stolwijk, Samuel N. Rodman, Shane R. Solst, Ann Tomanek-Chalkley, Charles C. Searby, Val C. Sheffield, Vanessa Sandfort, Hartmut Schmidt, Michael L. McCormick, Brian R. Wels, Bryan G. Allen, Garry R. Buettner, Michael K. Schultz, Douglas R. Spitz
FREE RADICAL BIOLOGY AND MEDICINE
(2020)
Article
Oncology
Charles A. Kunos, David A. Mankoff, Michael K. Schultz, Stephen A. Graves, Daniel A. Pryma
Summary: Radiation oncologists and nuclear medicine physicians have observed a resurgence in the clinical use of radiopharmaceuticals for cancer treatment. The United States National Cancer Institute has adapted its clinical trial enterprise to facilitate the discovery and development of new targeted radiopharmaceutical treatments, viewing investigational radiopharmaceuticals as drugs with maximum tolerable doses determined by normal organ toxicity frequency. This shift in perspective has led to the emergence of alpha-particle and beta-particle emitters as a significant approach to cancer treatment, with resources allocated to biomarkers of molecular pathophysiology now used to select treatment or evaluate clinical performance of radiopharmaceuticals.
SEMINARS IN RADIATION ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mahboubeh Varmazyad, Mira M. Modi, Amanda L. Kalen, Ehab H. Sarsour, Brett Wagner, Juan Du, Michael K. Schultz, Garry R. Buettner, F. Christopher Pigge, Prabhat C. Goswami
Summary: The study showed that TPVP-DHA treatments resulted in dose-dependent toxicity of human melanoma and pancreatic cancer cells, while normal human fibroblasts were resistant to this treatment. TPVP-DHA treatments led to a G(1) delay in the cancer cell cycle, along with significant inhibition of the mTOR-metabolic and ERK1/2-proliferative signaling pathways.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Letter
Clinical Neurology
Lucy P. Evans, Katherine N. Gibson-Corley, Robert F. Mullins, Budd A. Tucker, Amy Trent, Edwin M. Stone, Karra A. Jones
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
(2021)
Article
Multidisciplinary Sciences
Samantha N. Jensen, Nicole M. Cady, Shailesh K. Shahi, Stephanie R. Peterson, Arnav Gupta, Katherine N. Gibson-Corley, Ashutosh K. Mangalam
Summary: The study demonstrates that altering the composition of the gut microbiota through dietary interventions can alleviate the severity of multiple sclerosis and may play a role in the pathogenesis of the disease.
Article
Oncology
Mengshi Li, Dijie Liu, Dongyoul Lee, Yinwen Cheng, Nicholas J. Baumhover, Brenna M. Marks, Edwin A. Sagastume, Zuhair K. Ballas, Frances L. Johnson, Zachary S. Morris, Michael K. Schultz
Summary: The study demonstrated the feasibility of delivering alpha-particle radiation to murine melanoma tumors using a radiolabeled peptide that targets the melanocortin 1 receptor. The combination of targeted alpha-particle radionuclide therapy and immune checkpoint inhibitors showed significant anti-tumor cooperation in preclinical models of melanoma, mediated by induction of tumor-specific immunity.
Article
Infectious Diseases
Breanna M. Scorza, Kurayi G. Mahachi, Arin C. Cox, Angela J. Toepp, Adam Leal-Lima, Anurag Kumar Kushwaha, Patrick Kelly, Claudio Meneses, Geneva Wilson, Katherine N. Gibson-Corley, Lyric Bartholomay, Shaden Kamhawi, Christine A. Petersen
Summary: Vertically infected dogs are capable of transmitting parasites to sand flies, with dogs having mild to moderate clinical disease showing higher transmission rates. The skin parasite burden has a significant correlation with sand fly parasite uptake.
PLOS NEGLECTED TROPICAL DISEASES
(2021)
Article
Multidisciplinary Sciences
Kyle J. Kinney, Sharon S. Tang, Xiao-Jun Wu, Phuong M. Tran, Nikhila S. Bharadwaj, Katherine N. Gibson-Corley, Ana N. Forsythe, Katarina Kulhankova, Jenny E. Gumperz, Wilmara Salgado-Pabon
Summary: The superantigen staphylococcal enterotoxin C (SEC) is critical for Staphylococcus aureus infective endocarditis (SAIE) in rabbits. Superantigenicity alone cannot account for SAIE, and the antiangiogenic effects of SEC may play an important role.
Editorial Material
Radiology, Nuclear Medicine & Medical Imaging
Dirk Mueller, Hendrik Herrmann, Michael K. Schultz, Christoph Solbach, Thomas Ettrich, Vikas Prasad
Summary: In a patient with end-stage midgut neuroendocrine tumor, various imaging techniques were used to assess the feasibility of Pb-212-VMT-alpha-NET therapy. The results of planar, 22 hours SPECT/CT, and Ga-68-HA-DOTATATE PET/CT images showed high uptake of Pb-203-VMT-alpha-NET in liver metastases.
CLINICAL NUCLEAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Kelly D. Orcutt, Kelly E. Henry, Christine Habjan, Keryn Palmer, Jack Heimann, Julie M. Cupido, Vijay Gottumukkala, Derek D. Cissell, Morgan C. Lyon, Amira Hussein, Dijie Liu, Mengshi Li, Frances L. Johnson, Michael K. Schultz
Summary: The goal of this study is to estimate the human dosimetry for [Pb-212]VMT01 and the impact of free Tl-208 in the injectate on human tissue absorbed doses. The results indicate that the dose-limiting tissues for [Pb-212]VMT01 are the red marrow and the kidneys, while absorbed doses from free Tl-208 in the injectate have a minimal increase.
Article
Radiology, Nuclear Medicine & Medical Imaging
Bryce J. B. Nelson, John Wilson, Michael K. Schultz, Jan D. Andersson, Frank Wuest
Summary: This study developed a high-yield solid target cyclotron production route for 203Pb using isotopically enriched 205Tl target material and the 205Tl(p,3n)203Pb reaction as an alternative to lower energy production. The produced 203Pb showed high radionuclidic and elemental purity, making it suitable for clinical applications.
NUCLEAR MEDICINE AND BIOLOGY
(2023)
Article
Immunology
Kelsey Voss, Allison E. Sewell, Evan S. Krystofiak, Katherine N. Gibson-Corley, Arissa C. Young, Jacob H. Basham, Ayaka Sugiura, Emily N. Arner, William N. Beavers, Dillon E. Kunkle, Megan E. Dickson, Gabriel A. Needle, Eric P. Skaar, W. Kimryn Rathmell, Michelle J. Ormseth, Amy S. Major, Jeffrey C. Rathmell
Summary: T cells in systemic lupus erythematosus (SLE) exhibit metabolic abnormalities, with excess iron playing a potential role in SLE pathogenesis. The transferrin receptor (CD71) is critical for T(H)1 cells and inhibitory for induced regulatory T cells (iT(regs)). Increased CD71 expression and iron uptake were observed in activated T cells, particularly in SLE-prone T cells. Blocking CD71 reduced intracellular iron, mTORC1 signaling, and the production of T(H)1 and T(H)17 cells, while enhancing iT(regs) and IL-10 secretion. In vivo treatment targeting CD71 reduced kidney pathology in SLE-prone mice. CD71 expression on T(H)17 cells correlated with disease severity in SLE patients. Thus, T cell iron uptake via CD71 contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.
SCIENCE IMMUNOLOGY
(2023)
