The landscape of m6A regulators in small cell lung cancer: molecular characteristics, immuno-oncology features, and clinical relevance.
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ABSTRACT:
SUBMITTER: Zhang C
PROVIDER: S-EPMC8474928 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung cancer continues to be the leading cause of cancer death worldwide. Recently, immunotherapy for non-small cell lung cancer (NSCLC) has emerged as a powerful treatment option for advanced lung cancer. The relative success of programmed death 1 (PD-1) and/or programmed death ligand 1 (PD-L1) antibodies in metastatic disease have increased interest in expanding their use to earlier stage NSCLC. The complex and diverse nature of stage III disease also invites the incorporation of immunotherapy into treatment plans in both the neoadjuvant and consolidation settings. Currently available data of anti-PD-(L)1 therapies in stage III NSCLC are limited. However, interim results from two studies are encouraging: a phase II neoadjuvant nivolumab trial demonstrated early signals of efficacy, and the phase III PACIFIC trial of durvalumab recently showed significant improvement in progression-free survival (PFS). Preliminary results for the phase II DETERRED trial of durvalumab have also been reported. Many studies are testing anti-PD-(L)1 therapies in the neoadjuvant and consolidation settings for stage III NSCLC, and will be discussed. As these studies mature they may provide further treatment options in management of stage III NSCLC.
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Project description:Systemic therapy is an essential part of treatment for all patients with small-cell lung cancer (sclc) and for most patients with non-small-cell lung cancer (nsclc). Standards of care have evolved dramatically since 2009, especially in the setting of incurable or advanced nsclc. Part of that evolution has been the incorporation of immuno-oncology drugs, especially immune checkpoint inhibitors (icis) into multiple therapeutic scenarios. In the present review, we discuss the role of the immune system in lung cancer and the previous failures of immunotherapy for patients with lung cancer. We then provide an overview of the existing evidence for the use of icis in patients with advanced nsclc that is either treatment-naïve or pretreated, for consolidative treatment after chemoradiotherapy in stage iii nsclc, and for palliative therapy in patients with sclc. Finally, we discuss duration of treatment, special populations, and the future of immuno-oncology for patients with lung cancer. Overall, we provide an evidence-based snapshot of immuno-oncology agents in the treatment of lung cancer up to early 2019.
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Project description:Bone is among the main sites of metastasis in breast, prostate and other major cancers. Bone metastases remain incurable causing high mortality, severe skeletal-related effects and decreased quality of life. Despite the success of immunotherapies in oncology, no immunotherapies are approved for bone metastasis and no clear benefit has been observed with approved immunotherapies in treatment of bone metastatic disease. Therefore, it is crucial to consider unique features of tumor microenvironment in bone metastasis when developing novel therapies. The vicious cycle of bone metastasis, referring to crosstalk between tumor and bone cells that enables the tumor cells to grow in the bone microenvironment, is a well-established concept. Very recently, a novel osteoimmuno-oncology (OIO) concept was introduced to the scientific community. OIO emphasizes the significance of interactions between tumor, immune and bone cells in promoting tumor growth in bone metastasis, and it can be used to reveal the most promising targets for bone metastasis. In order to provide an insight into the current immuno-oncology drug development landscape, we used 1stOncology database, a cancer drug development resource to identify novel immunotherapies in preclinical or clinical development for breast and prostate cancer bone metastasis. Based on the database search, 24 immunotherapies were identified in preclinical or clinical development that included evaluation of effects on bone metastasis. This review provides an insight to novel immuno-oncology drug development in the context of bone metastasis. Bone metastases can be approached using different modalities, and tumor microenvironment in bone provides many potential targets for bone metastasis. Noting current increasing interest in the field of OIO, more therapeutic opportunities that primarily target bone metastasis are expected in the future.
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Project description:ObjectiveTo assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC).MethodsThis retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months.ResultsQualitative (r = - 0.41-0.40, p < 0.042) and quantitative (r = - 0.52-0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41-0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = - 0.48-0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76-0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098-0929).ConclusionsMRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation.Key points• MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma. • Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.
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Project description:To inhibitors for ADAR1 and a strong rationale for the development of ADAR1 p150 inhibitors for cancer immunotherapy Here, we describe AVA-ADR-001, a potential first-in-class small molecule inhibitor of ADAR1 p150 targeting the Z alpha domain. AVA-ADR-001 binds specifically to the Z alpha domain of ADAR1 p150 as confirmed by fluorescence spectroscopy and showed significant interferon induction in THP1 macrophages, which have high ADAR1 p150 expression compared with monocytes. Proteomics and transcriptomics analysis revealed significant upregulation of interferon signaling upon treatment with AVA-ADR -001. Interestingly, activation of interferon signaling resulted in AVA-ADR-001 induced cell killing in ADAR1-independent cell lines. In addition, treatment with AVA-ADR -001 resulted in significant activation of PKR, which may explain the decreased cell proliferation. Finally, AVA-ADR-001 showed superior anti-tumor efficacy compared to anti-PD1 in an in vivo tumor efficacy study and has a moderately synergistic effect when combined. Overall, this study reveals that ADAR1 p150 inhibition by AVA-ADR-001 exerts a multipronged impact on anti-tumor efficacy mediated by immune cells, accumulation of interferons and activation of PKR, resulting in protein translation inhibition and cell proliferation arrest.
2023-04-17 | GSE229503 | GEO
Project description:BackgroundThe quantity of skeletal muscles has recently been reported to have prognostic value in patients with non-small-cell lung cancer (NSCLC) treated with second-line immunotherapy. However, the prognostic role of skeletal muscle assessment in NSCLC patients undergoing first-line immuno-oncology (IO) combinatorial treatment (IO-chemotherapy) has not been elucidated.MethodsWe retrospectively reviewed 36 patients with NSCLC undergoing first-line IO-chemotherapy between April 2018 and June 2021 in our hospital. The cross-sectional area of the erector spinae muscle (ESMCSA ) was evaluated by manual tracing on computed tomography scans at the level of the 12th thoracic vertebra before initiating IO-chemotherapy. To minimize deviation due to physique, the ESMCSA was adjusted by body surface area (BSA) (ESMCSA to BSA ratio: ESMCSA /BSA). A survival time analysis was performed using the Kaplan-Meier method and log-rank test. A multivariate analysis with Cox proportional hazards model was conducted to investigate the prognostic value of the ESMCSA /BSA and inflammatory and nutritional indices.ResultsThe median progression-free survival (PFS) and overall survival (OS) were 6.5 and 16.6 months, respectively. Intergroup comparison by the log-rank test revealed that there was no significant difference in the median PFS, but the median OS was significantly long in the high ESMCSA /BSA (>19 cm2/ m2 ) (high ESMCSA /BSA group, p = 0.0373). The multivariate analysis showed that ESMCSA /BSA was an independent prognostic factor for OS (hazard ratio 0.79, p = 0.044).ConclusionsThe results of this study indicate that the pretreatment ESMCSA /BSA may be a potential prognostic factor in NSCLC patients receiving first-line IO-chemotherapy.
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