Article
Oncology
Oren Yakovian, Julia Sajman, Rand Arafeh, Yair Neve-Oz, Michal Alon, Yardena Samuels, Eilon Sherman
Summary: The study reveals the nanoscale organization and signal coupling of NRas and BRAF in melanoma cells, showing that mutant NRas exhibits more pronounced self-clustering and increased association with BRAF. The findings suggest a new regulatory mechanism for NRas signaling and potential therapeutic targets for MEK inhibitors in melanoma.
Article
Pharmacology & Pharmacy
Yahong Liu, Ying Cheng, Gongchao Huang, Xiangying Xia, Xingkai Wang, Hongqi Tian
Summary: Tunlametinib is a novel MEK inhibitor with higher selectivity and anti-proliferation activity compared to current MEK inhibitors. It exhibits significant tumor suppression and cell cycle regulation in vivo. Furthermore, combination therapy of tunlametinib with other inhibitors or chemotherapeutic agents enhances the treatment response.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ming-Ju Hsieh, Hsin-Yu Ho, Yu-Sheng Lo, Chia-Chieh Lin, Yi-Ching Chuang, Mosleh Mohammad Abomughaid, Ming-Chang Hsieh, Mu-Kuan Chen
Summary: The study investigates the anticancer activities of a natural compound called semilicoisoflavone B (SFB) in oral squamous cell carcinoma (OSCC). Results show that SFB reduces cell viability by targeting the cell cycle and inducing apoptosis. It also inhibits several signaling pathways and downregulates survivin expression. Overall, the study suggests that SFB has potential as a therapeutic agent for human OSCC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Kavita Y. Sarin, John Kincaid, Brittney Sell, Jahanbanoo Shahryari, Matthew A. J. Duncton, Elaine Morefield, Wenchao Sun, Karol Prieto, Omar Chavez-Chiang, Carlos de Moran Segura, Jonathan Nguyen, Roderick T. Bronson, Scott R. Plotkin, Gerd G. Kochendoerfer, Peter Fenn, Michael A. Wootton, Christopher Powala, Mark P. de Souza, Kenneth Y. Tsai
Summary: This study developed a metabolically labile MEK inhibitor, NFX-179, which effectively suppresses the development of cSCC when applied topically, without observed toxicities. NFX-179 inhibits the growth of cSCC cells by blocking MAPK signaling.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Yanlin Song, Zhenfei Bi, Yu Liu, Furong Qin, Yuquan Wei, Xiawei Wei
Summary: Molecular target inhibitors have been approved for tumor treatment and mainly target cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway plays essential roles in cell functions and abnormal activation of this pathway leads to tumor development. In this review, the development and potential combinations of inhibitors targeting this pathway are discussed.
Article
Pharmacology & Pharmacy
Aoli Wang, Juan Liu, Xixiang Li, Fengming Zou, Ziping Qi, Shuang Qi, Qingwang Liu, Zuowei Wang, Jiangyan Cao, Zongru Jiang, Beilei Wang, Juan Ge, Li Wang, Wenchao Wang, Jing Liu, Qingsong Liu
Summary: In this study, a highly potent pan-RAF inhibitor, IHMT-RAF-128, was developed, which demonstrated strong anti-tumor efficacy against cancer cells harboring RAF or RAS mutations, especially the KRAS-G12C secondary mutations resistant to AMG510. IHMT-RAF-128 also exhibited excellent pharmacokinetic profile and dose-dependent anti-tumor efficacy in xenograft mouse tumor models without obvious toxicities. These findings support further investigation of IHMT-RAF-128 as a potential clinical drug candidate for cancer patients with RAF or RAS mutations.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Qian Zhao, Teng Wang, Huanhuan Wang, Cheng Cui, Wen Zhong, Diyi Fu, Wanlin Xi, Lu Si, Jun Guo, Ying Cheng, Hongqi Tian, Pei Hu
Summary: This study investigated the pharmacokinetics of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma. The results showed that tunlametinib was rapidly absorbed and eliminated at a medium speed after drug withdrawal. There was a general dose-proportional increase in pharmacokinetic body exposure. Slight accumulation was found after multiple oral doses. The findings provide guidance for the dosing regimen of tunlametinib.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Yunli Huang, Yongqi Zhen, Yanmei Chen, Shaoguang Sui, Lan Zhang
Summary: This article provides a comprehensive review of the interplay between the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their application in cancer therapy. The impact of small molecule inhibitors targeting this pathway on autophagy is discussed, and the advantages and limitations of combining these inhibitors with autophagy inhibitors are explored.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jakob Fleischmann, Andreas Feichtner, Louis DeFalco, Valentina Kugler, Selina Schwaighofer, Roland G. Huber, Eduard Stefan
Summary: Mutations in the MAPK signaling pathway can lead to abnormal activation of protein kinases, with targeted MEK inhibition causing qualitative changes in carcinogenic MAPK signals. By phosphorylating MEK1 at specific sites, RAF kinases trigger conformational changes that enable substrate phosphorylation. Allosterically acting MEK inhibitors can reverse the conformational changes induced by phosphorylation, indicating their potential efficacy in cancer therapy.
Article
Fisheries
Linlin Zhang, Lu Chen, Meng Qi, Fuchang Yu, Xiaotong Ni, Haozheng Hong, Haotian Xu, Shiwen Xu
Summary: Glyphosate exposure induces autophagy in hepatic L8824 cells by activating nitric oxide (NO), regulating energy metabolism, and activating the RAS/RAF/MEK/ERK signaling pathway. This study provides insight into the mechanism of glyphosate toxicity and its effects on cellular processes.
FISH & SHELLFISH IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Peng Zhao, Linghang Zhuang, Xiangzhu Wang, Song Huang, Heping Wu, Yu Zhou, Yuna Yan, Fan Zhang, Ru Shen, Jing Li, Suxing Liu, Rumin Zhang, Ping Dong, Yuchang Mao, Yuanmin Fan, Chunyong He, Jiakang Sun, Lei Zhang, Qiyue Hu, Hong Wan, Jun Feng, Chang Bai, Feng He, Weikang Tao
Summary: A molecule called SHR902275 (or molecule 33) has been discovered with significantly improved potency and solubility, which shows potential for targeting cancers with mutant RAS and wild type RAF activity. In vivo experiments have demonstrated dose dependent efficacy of molecule 33.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Shumei Kato, Robert Porter, Ryosuke Okamura, Suzanna Lee, Ori Zelichov, Gabi Tarcic, Michael Vidne, Razelle Kurzrock
Summary: The study found that patients with tumors harboring RAS alterations with high MAPK activity had significantly longer median progression-free survival (PFS) and overall survival when treated with MEK inhibitors. This correlation between RAS-mutant cancers with greater MAPK signaling and PFS suggests potential clinical benefit of MEK inhibitor treatment.
EUROPEAN JOURNAL OF CANCER
(2021)
Review
Oncology
Jing Han, Yang Liu, Sen Yang, Xuan Wu, Hongle Li, Qiming Wang
Summary: BRAF and KRAS mutations play a significant role in NSCLC by activating the RAS/RAF/MEK/ERK signaling pathway. Current approved therapies include BRAF and MEK inhibitors, while combination with other drugs may enhance therapeutic effects. Further research is needed to explore optimal drug combinations for treating lung cancer patients.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Oncology
Sara J. Hamis, Yury Kapelyukh, Aileen McLaren, Colin J. Henderson, C. Roland Wolf, Mark A. J. Chaplain
Summary: The study developed a mechanistic mathematical model to describe the synergistic action of dabrafenib and trametinib on ERK activity in BRAFV600E-mutant melanoma cells, elucidating the molecular mechanism underlying vertical inhibition of the BRAF-MEK-ERK cascade.
BRITISH JOURNAL OF CANCER
(2021)
Article
Virology
Chengyuan Wu, Guangyan Zhu, Fang Qiu, Fuli Ren, Binbin Lin, Dingyu Zhang, Qingyu Yang, Chaolin Huang
Summary: EV71 is a serious threat to human health and there is currently no effective drug for its treatment. PLX8394, a RAF inhibitor, has been found to have high antiviral activity against EV71 in vitro and also exhibits broad-spectrum antiviral activity against enteroviruses. In a mouse model, PLX8394 provided significant protection against EV71 infection by reducing viral load and relieving inflammation through inhibiting the RAF/MEK/ERK signaling pathway.
Article
Oncology
J. L. Perez-Gracia, N. Penel, E. Calvo, A. Awada, H. T. Arkenau, T. Amaral, V. Gruenwald, M. F. Sanmamed, L. Castelo-Branco, G. Bodoky, M. P. Lolkema, M. Di Nicola, P. Casali, R. Giuliani, G. Pentheroudakis
Summary: In recent years, the burden of bureaucracy in clinical research has significantly increased, negatively impacting investigators and clinical research teams. While compliance with regulations and guidelines is important, the overinterpretation and substitution by sponsors and CROs have increased administrative burden. A survey among 940 investigators confirmed excessive administrative burden and bureaucracy as obstacles to clinical research.
ANNALS OF ONCOLOGY
(2023)
Review
Oncology
D. Araujo, A. Greystoke, S. Bates, A. Bayle, E. Calvo, L. Castelo-Branco, J. de Bono, A. Drilon, E. Garralda, P. Ivy, O. Kholmanskikh, I. Melero, G. Pentheroudakis, J. Petrie, R. Plummer, S. Ponce, S. Postel-Vinay, L. Siu, A. Spreafico, A. Stathis, N. Steeghs, C. Yap, T. A. Yap, M. Ratain, L. Seymour
Summary: In 2021, the FDA Oncology Center of Excellence launched Project Optimus to optimize dosage for oncology drugs. The MDICT Taskforce reviewed and discussed dosage optimization for oncology trials, providing recommendations for trial design and a practical guide for phase I trials. The aim is to improve dosage selection in early clinical trials of new anticancer treatments and ultimately enhance patient outcomes.
ANNALS OF ONCOLOGY
(2023)
Article
Urology & Nephrology
Francois Lannes, Michael Baboudjian, Alain Ruffion, Mathieu Rouy, Francesco Giammarile, Thierry Rousseau, Francoise Kraeber-Bodere, Caroline Rousseau, Daniela Rusu, Mathilde Colombie, Isabelle Brenot-Rossi, Dominique Rossi, Nicolas Mottet, Cyrille Bastide
Summary: The aim of this study was to evaluate the diagnostic accuracy of sentinel lymph node biopsy-guided lymph node dissection compared to extended pelvic lymph node dissection in intermediate- or high-risk prostate cancer patients. The results showed that sentinel lymph node biopsy is a very effective and sensitive method for pelvic lymph node staging in patients with intermediate- or high-risk localized prostate cancer.
JOURNAL OF UROLOGY
(2023)
Letter
Oncology
J. L. Perez-Gracia, N. Penel, E. Calvo, H. T. Arkenau, T. Amaral, V. Gruenwald, M. F. Sanmamed
ANNALS OF ONCOLOGY
(2023)
Article
Oncology
Anthony B. B. El-Khoueiry, James Clarke, Tobias Neff, Tim Crossman, Nirav Ratia, Chetan Rathi, Paul Noto, Aarti Tarkar, Ignacio Garrido-Laguna, Emiliano Calvo, Jordi Rodon, Ben Tran, Peter J. J. O'Dwyer, Adam Cuker, Albiruni R. Abdul R. Razak
Summary: GSK3368715, a reversible inhibitor of type I protein methyltransferases, showed anticancer activity in preclinical studies. This Phase 1 study evaluated its safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced solid tumors. However, due to a higher-than-expected incidence of thromboembolic events, the study was terminated.
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Drew W. W. Rasco, Theresa Medina, Pippa Corrie, Anna C. C. Pavlick, Mark R. R. Middleton, Paul Lorigan, Chris Hebert, Ruth Plummer, James Larkin, Sanjiv S. S. Agarwala, Adil I. I. Daud, Jiaheng Qiu, Viviana Bozon, Michelle Kneissl, Elly Barry, Anthony J. J. Olszanski
Summary: This study investigated the safety and antitumor activity of tovorafenib, a drug for treating solid tumors, and found that it has good antitumor activity in BRAF-mutated melanoma, particularly in patients who have not received RAF and MEK inhibitors. The study evaluated the safety and pharmacokinetic characteristics of two dosing schedules and identified the recommended dose as 200 mg or 600 mg administered once every other day or once weekly.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2023)
Article
Oncology
Fabienne Desmots, Delphine Rossille, Mikael Roussel, Celine Pangault, Laetitia Louarn, Mylene De Saint Jore, Steven Le Gouill, Krimo Bouabdallah, Vincent Delwail, Remy Gressin, Jerome Cornillon, Gandhi Damaj, Herve Maisonneuve, Diane Damotte, Francoise Kraeber-Bodere, Thierry Lamy, Marie-Cecile Parrens, Noel Milpied, Thierry Fest
Summary: The study aimed to investigate the relationship between the intensity of initial treatment and the baseline cell-free DNA (cfDNA) levels of DLBCL patients, and their impact on long-term survival. The results showed that a high cfDNA concentration at diagnosis was associated with poor clinical prognostic factors and independently predicted worse overall survival. High-cfDNA R-CHOP patients had worse overall survival compared to high-cfDNA R-HDT patients, but salvage therapy and transplantation improved survival in patients with high cfDNA levels.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
James Larkin, Michele Del Vecchio, Mario Mandala, Helen Gogas, Ana M. Arance Fernandez, Stephane Dalle, Charles Lance Cowey, Michael Schenker, Jean -Jacques Grob, Vanna Chiarion-Sileni, Ivan Marquez-Rodas, Marcus O. Butler, Anna Maria Di Giacomo, Mark R. Middleton, Jose Lutzky, Luis de la Cruz-Merino, Petr Arenberger, Victoria Atkinson, Andrew G. Hill, Leslie A. Fecher, Michael Millward, Paul D. Nathan, Nikhil I. Khushalani, Paola Queirolo, Corey Ritchings, Maurice Lobo, Margarita Askelson, Hao Tang, Sonia Dolfi, Paolo A. Ascierto, Jeffrey Weber
Summary: The study demonstrates that adjuvant nivolumab significantly improves recurrence-free survival and distant metastasis-free survival in high-risk melanoma patients who have undergone surgical resection, with sustained long-term benefits. Biomarkers such as tumor mutational burden, tumor PD-L1, intratumoral CD8+ T cells and IFNy-associated gene expression signature are associated with improved treatment outcomes, but their predictive value is limited.
CLINICAL CANCER RESEARCH
(2023)
Editorial Material
Radiology, Nuclear Medicine & Medical Imaging
Bastien Jamet, Caroline Bodet-Milin, Philippe Moreau, Francoise Kraeber-Bodere, Cyrille Touzeau
Summary: T-cell-redirecting bispecific antibodies are now the standard of care for triple-class refractory myeloma patients. A 61-year-old woman with relapsed myeloma underwent 2-[F-18]FDG PET/CT imaging to assess the metabolic response to talquetamab, a GPRC5DxCD3 bispecific antibody. At day 28, the patient showed very good partial response based on monoclonal component assessment, but early bone flare-up was observed through 2-[F-18]FDG PET/CT imaging. By day 84, complete response was confirmed through bone marrow aspirate, M-component assessment, and 2-[F-18]FDG PET/CT, supporting the early flare-up hypothesis.
CLINICAL NUCLEAR MEDICINE
(2023)
Article
Oncology
Reinhard Dummer, Pippa Corrie, Ralf Gutzmer, Tarek M. Meniawy, Michele Del Vecchio, Celeste Lebbe, Michele Guida, Caroline Dutriaux, Brigitte Dreno, Nicolas Meyer, Pier Francesco Ferrucci, Stephane Dalle, Muhammad Adnan Khattak, Jean-Jacques Grob, Karen Briscoe, James Larkin, Sandrine Mansard, Thierry Lesimple, Massimo Guidoboni, Silvia Sabatini, Erika Richtig, Rudolf Herbst, Maurice Lobo, Margarita Askelson, Paolo A. Ascierto, Michele Maio
Summary: The study aimed to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in patients with advanced melanoma. It found that the treatment was tolerable and had similar efficacy in all treated population with various subgroups, but reduced efficacy in patients with specific characteristics, indicating a need for novel treatment options.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Hematology
Cristina Nanni, Carsten Kobe, Bettina Baessler, Christian Baues, Ronald Boellaard, Peter Borchmann, Andreas Buck, Irene Buvat, Bjoern Chapuy, Bruce D. Cheson, Robert Chrzan, Ann-Segolene Cottereau, Ulrich Duhrsen, Live Eikenes, Martin Hutchings, Wojciech Jurczak, Francoise Kraeber-Bodere, Egesta Lopci, Stefano Luminari, Steven MacLennan, N. George Mikhaeel, Marcel Nijland, Paula Rodriguez-Otero, Giorgio Treglia, Nadia Withofs, Elena Zamagni, Pier Luigi Zinzani, Josee M. Zijlstra, Ken Hermaann, Jolanta Kunikowska
Summary: Given the lack of high-certainty evidence and differences in opinion on the use of nuclear medicine for hematological malignancies, a consensus process involving key experts was conducted to provide interim guidance. A three-stage consensus process was used, including a literature review, statement generation, and panel scoring. After two rounds of voting, consensus was reached on most statements, with further studies needed for multiple myeloma and the introduction of new technologies.
LANCET HAEMATOLOGY
(2023)
Article
Oncology
Simona Manacorda, Maria De Toro Carmena, Ciara Malone, Ha Mo Linh Le, Andrew J. S. Furness, James Larkin, Andreas M. Schmitt
Summary: This study investigated the efficacy of PD-1-directed antibody-based therapy in patients with symptomatic melanoma brain metastases (MBM) and concurrent treatment with corticosteroids. The findings showed that patients only derived modest benefit from the treatment, but those with disease response had the potential to derive long-term benefit, justifying the use of this therapy in this group in the absence of other more effective treatment options.
EUROPEAN JOURNAL OF CANCER
(2023)
Editorial Material
Radiology, Nuclear Medicine & Medical Imaging
Valentina Ambrosini, Sofia Carrilho Vaz, Niloefar Ahmadi Bidakhvidi, Marion Chanchou, Matthijs C. F. Cysouw, Francesca Serani, Conrad-Amadeus Voltin, Francoise Kraeber-Bodere, Christophe M. Deroose, Lioe-Fee De Geus-Oei, Matthias Eiber, Gopinath Gnanasegaran, Martin Gotthardt, Carsten Kobe, Mark W. Konijnenberg, Cristina Nanni, Daniela E. Oprea Lager, Kambiz Rahbar, David Taieb, Felix M. Mottaghy, Karolien Goffin, Ken Herrmann
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
(2023)
Article
Oncology
Adi Diab, Helen Gogas, Shahneen Sandhu, Georgina V. Long, Paolo A. Ascierto, James Larkin, Mario Sznol, Fabio Franke, Tudor E. Ciuleanu, Caio Pereira, Eva Munoz Couselo, Fernanda Bronzon Damian, Michael Schenker, Aldo Perfetti, Celeste Lebbe, Gaelle Quereux, Friedegund Meier, Brendan D. Curti, Carlos Rojas, Yull Arriaga, Haisu Yang, Ming Zhou, Shruthi Ravimohan, Paul Statkevich, Mary A. Tagliaferri, Nikhil I. Khushalani
Summary: Despite the efficacy of Bempegaldesleukin (BEMPEG) in the treatment of melanoma, the PIVOT IO 001 study did not meet its primary end points, with increased toxicity observed with the combination of BEMPEG plus NIVO.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Tatiana Hernandez Guerrero, Natalia Banos, Laura del Puerto Nevado, Ignacio Mahillo-Fernandez, Bernard Doger De-Speville, Emiliano Calvo, Michael Wick, Jesus Garcia-Foncillas, Victor Moreno
Summary: This study aimed to determine the factors that may predict better engraftment rates in patient-derived xenografts (PDXs). The use of systemic antibiotics and steroids by patients prior to sampling were found to impact the likelihood of success in PDX development. Furthermore, certain clinical, pathological, and molecular factors such as lactate dehydrogenase levels, grade of differentiation, Ki67 levels, presence of lymphovascular invasion, and mismatch repair status were correlated with engraftment success in PDXs.