Among more than 200
-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a
mutant allele developed one or more malignancies during their lifetime, mostly uveal ...and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic
mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover,
has emerged as a key regulator of gene-environment interaction.
.
Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from ...developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high‐resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1‐asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.
Commentary: A chess game for mesothelioma treatment: Not checkmate yet Pass, Harvey I.
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
January 2023, 2023-01-00, 20230101, Letnik:
165, Številka:
1
Journal Article
Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung ...adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.
Display omitted
► Exome and genome characterization of somatic alterations in 183 lung adenocarcinomas ► U2AF1, RBM10, and ARID1A are among newly identified recurrently mutated genes ► Structural variants include activating in-frame fusion of EGFR ► Epigenetic and RNA deregulation proposed as a potential lung adenocarcinoma hallmark
Whole-exome and whole-genome sequencing of 183 lung adenocarcinoma tumor/normal DNA pairs reveals new candidate genes as attractive targets for biological characterization and therapeutic targeting of lung cancer.
MARS, although provocative, forced mesothelioma surgeons to question the role of extrapleural pneumonectomy in trimodality management of pleural mesothelioma, and concluded that extrapleural ...pneumonectomy within trimodal therapy offers no benefit and possibly harms patients. ...any subsequent trial should be examined carefully with regard to the MARS conclusion. The implication is that comparing two trials of induction therapy before extrapleural pneumonectomy, one with preoperative hemithoracic radiotherapy and one with standard-of-care preoperative neoadjuvant therapy, there was a 9 month overall survival increase with preoperative radiotherapy. ...in the phase 2 part of the SAKK trial, wherein 27 patients were randomly assigned to receive postoperative radiotherapy after neoadjuvant chemotherapy and surgery, the disease-free survival was 12·2 months (95% CI 9·5–14·8) from registration compared with 18·0 months (12·6–21·7) from registration in the SMART trial.4 How do we account for these supposed differences in survival? Combining this radiotherapy protocol with CTLA-4 blockade provided better results than radiotherapy alone.5 They have also reported the first data regarding changes in the human mesothelioma tumour microenvironment after SMART treatment, not only revealing different effects on immune phenotypes comparing epithelial with nonepithelial tumours but also that SMART survival was associated with CD8 tumour infiltrating lymphocytes.6,7 The role of neoantigen release and the timing of checkpoint inhibitor therapies with preoperative radiotherapy is another focus of their work.
Approximately 30% of human lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which controls oxidative homeostasis. Here, we ...show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival and metastasis in lung cancer patients. We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
Display omitted
•Keap1 loss and Nrf2 activation induce metastasis in LUAD by accumulating Bach1•Nrf2 inhibits the Fbxo22-mediated degradation of Bach1 in a Ho1-dependent manner•Bach1 signature is associated with metastasis and shortened survival in LUAD patients•Ho1 inhibitors reduce LUAD metastasis in a Fbxo22- and Bach1-dependent manner
Stabilization of the transcription factor Bach1 drives metastasis of lung adenocarcinoma and this can be counteracted by the pharmacological inhibition of heme oxygenase.
Commentary: Thoracic research funding: Staying power is only one issue Pass, Harvey I.
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
March 2022, 2022-03-00, 20220301, Letnik:
163, Številka:
3
Journal Article
Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a ...novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.
Commentary: Pulmonary metastasectomy efficacy: A game of clones? Pass, Harvey I.
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
February 2022, 2022-02-00, 20220201, Letnik:
163, Številka:
2
Journal Article
HMGB1 as a therapeutic target in disease Xue, Jiaming; Suarez, Joelle S.; Minaai, Michael ...
Journal of cellular physiology,
20/May , Letnik:
236, Številka:
5
Journal Article
Recenzirano
Odprti dostop
High‐mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription. HMGB1 has since been ...reevaluated to be a prototypical damage‐associated molecular pattern (DAMP) protein, and together with its exogenous counterpart, pathogen‐associated molecular pattern (PAMP), completes the body's alarmin system against disturbances in homeostasis. HMGB1 can be released into the extracellular matrix (ECM) by either granulocytes or necrotic cells to serve as a chemotaxis/cytokine during infection, endotoxemia, hypoxia, ischemia–reperfusion events, and cancer. Different isoforms of HMGB1 present with distinctive physiological functions in ECM—fully‐reduced HMGB1 (all thiol) acts as the initial damage signal to recruit circulating myeloid cells, disulfide HMGB1 behaves as a cytokine to activate macrophages and neutrophils, and both signals are turned off when HMGB1 is terminally oxidized into the final sulfonate form. Targeting HMGB1 constitutes a favorable therapeutic strategy for inflammation and inflammatory diseases. Antagonists such as ethyl pyruvate inhibit HMGB1 by interfering with its cytoplasmic exportation, while others such as glycyrrhizin directly bind to HMGB1 and render it unavailable for its receptors. The fact that a mixture of different HMGB1 isoforms is present in the ECM poses a challenge in pinpointing the exact role of an individual antagonist. A more discriminative probe for HMGB1 may be necessary to advance our knowledge of HMGB1, HMGB1 antagonists, and inflammatory‐related diseases.
Graphical
High‐mobility group box 1 (HMGB1) has captured much attention as a prototypical damage‐associated molecular pattern molecule that actively participates in inflammation, inflammatory diseases, and cancer. Targeting HMGB1 has been proven successful in treating inflammation and inflammatory diseases, especially in sepsis, sterile inflammation, autoimmune diseases, and cancer. Continued efforts in the field of HMGB1 can help to fill the gaps in our knowledge and bring HMGB1 antagonists closer to the next step of targeted clinical use.
PDF
