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Cancer Discovery Nov 2023Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic...
UNLABELLED
Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study.
SIGNIFICANCE
PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Synthetic Lethal Mutations; Lung Neoplasms; Enzyme Inhibitors; Protein-Arginine N-Methyltransferases
PubMed: 37552839
DOI: 10.1158/2159-8290.CD-23-0669 -
Breathe (Sheffield, England) Dec 2023Malignant pleural disease represents a growing healthcare burden. Malignant pleural effusion affects approximately 1 million people globally per year, causes disabling... (Review)
Review
Malignant pleural disease represents a growing healthcare burden. Malignant pleural effusion affects approximately 1 million people globally per year, causes disabling breathlessness and indicates a shortened life expectancy. Timely diagnosis is imperative to relieve symptoms and optimise quality of life, and should give consideration to individual patient factors. This review aims to provide an overview of epidemiology, pathogenesis and suggested diagnostic pathways in malignant pleural disease, to outline management options for malignant pleural effusion and malignant pleural mesothelioma, highlighting the need for a holistic approach, and to discuss potential challenges including non-expandable lung and septated effusions.
PubMed: 38351947
DOI: 10.1183/20734735.0145-2023 -
Archives of Pathology & Laboratory... Apr 2024Mesothelioma is an uncommon tumor that can be difficult to diagnose.
CONTEXT.—
Mesothelioma is an uncommon tumor that can be difficult to diagnose.
OBJECTIVE.—
To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma.
DATA SOURCES.—
Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks.
CONCLUSIONS.—
There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.
PubMed: 38586983
DOI: 10.5858/arpa.2023-0304-RA -
The British Journal of Radiology Aug 2023Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in both sexes combined. Recent years have seen major advances in the diagnostic... (Review)
Review
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in both sexes combined. Recent years have seen major advances in the diagnostic and treatment options for patients with non-small-cell lung cancer (NSCLC), including the routine use of 2-deoxy-2[F]-fluoro-D-glucose positron emission tomography/computed tomography (F-FDG PET/CT) in staging and response evaluation, minimally invasive endoscopic biopsy, targeted radiotherapy, minimally invasive surgery, and molecular and immunotherapies. In this review, the central roles of CT and F-FDG PET/CT in staging and response in both NSCLC and malignant pleural mesothelioma (MPM) are critically assessed. The Tumour Node Metastases (TNM-8) staging systems for NSCLC and MPM are presented with critical appraisal of the strengths and pitfalls of imaging. Overviews of the Response Evaluation Criteria in Solid Tumours (RECIST 1.1) for NSCLC and the modified RECIST criteria for MPM are provided, together with discussion of the benefits and limitations of these anatomical-based tools. Metabolic response assessment (not evaluated by RECIST 1.1) will be explored. We introduce the Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST 1.0) to include its advantages and challenges. The limitations of both anatomical and metabolic assessment criteria when applied to NSCLC treated with immunotherapy and the important concept of pseudoprogression are addressed with reference to immune RECIST (iRECIST). Separate consideration is given to the diagnosis and follow up of solitary pulmonary nodules with reference to the British Thoracic Society guidelines and Fleischner guidelines and use of the Brock (CT-based) and Herder (addition of F-FDG PET/CT) models for assessing malignant potential. We discuss how these models inform decisions by the multidisciplinary team, including referral of suspicious nodules for non-surgical management in patients unsuitable for surgery. We briefly outline current lung screening systems being used in the UK, Europe and North America. Emerging roles for MRI in lung cancer imaging are reviewed. The use of whole-body MRI in diagnosing and staging NSCLC is discussed with reference to the recent multicentre trial. The potential use of diffusion-weighted MRI to distinguish tumour from radiotherapy-induced lung toxicity is discussed. We briefly summarise the new PET-CT radiotracers being developed to evaluate specific aspects of cancer biology, other than glucose uptake. Finally, we describe how CT, MRI and F-FDG PET/CT are moving from primarily diagnostic tools for lung cancer towards having utility in prognostication and personalised medicine with the agency of artificial intelligence.
Topics: Male; Female; Humans; Lung Neoplasms; Positron Emission Tomography Computed Tomography; Carcinoma, Non-Small-Cell Lung; Fluorodeoxyglucose F18; Artificial Intelligence; Radiopharmaceuticals; Positron-Emission Tomography; Magnetic Resonance Imaging; Neoplasm Staging
PubMed: 37097296
DOI: 10.1259/bjr.20220339