Two-fluid and magnetohydrodynamic modelling of magnetic reconnection in the MAST spherical tokamak and the solar corona

Twisted magnetic flux ropes are ubiquitous in space and laboratory plasmas, and the merging of such flux ropes through magnetic reconnection is an important mechanism for restructuring magnetic fields and releasing free magnetic energy. The merging-compression scenario is one possible start up scheme for spherical tokamaks, which has been used on the Mega Amp Spherical Tokamak MAST. Two current-carrying plasma rings, or flux ropes, approach each other through the mutual attraction of their like currents, and merge, through magnetic reconnection, into a single plasma torus, with substantial plasma heating. 2D resistive MHD and Hall MHD simulations of this process are reported, and new results for the temperature distribution of ions and electrons are presented. A model of the based on relaxation theory is also described, which is now extended to tight aspect ratio geometry. This model allows prediction of the final merged state and the heating. The implications of the relaxation model for heating of the solar corona are also discussed, and a model of the merger of two or more twisted coronal flux ropes is presented, allowing for different senses of twist

The impact of targeting TRAF2 and NCK-interacting protein kinase (TNIK) on anti-tumor effect in small cell lung cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1056/thumbnail.jp

Validating DLL3-targeting CAR T in small cell lung cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1022/thumbnail.jp

Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer

PURPOSE: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. EXPERIMENTAL DESIGN: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. RESULTS: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. CONCLUSIONS: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models

Anti-Tumor Activity of Cetuximab Plus Avelumab in Non-Small Cell Lung Cancer Patients Involves Innate Immunity Activation: Findings From the CAVE-Lung Trial

BACKGROUND: We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab. METHODS: We report long-term clinical follow-up and additional findings on the anti-tumor activity and on the immune effects of cetuximab plus avelumab treatment for these 3 patients. RESULTS: As of November 30, 2021, 2/3 patients were alive. One patient was still on treatment from 34 months, while the other two patients had progression free survival (PFS) of 15 and 19 months, respectively. Analysis of serially collected peripheral blood mononuclear cells (PBMC) revealed long-term activation of NK cell-mediated ADCC. Comprehensive genomic profile analysis found somatic mutations and germline rare variants in DNA damage response (DDR) genes. Furthermore, by transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset we found that DDR mutant NSCLC displayed high STING pathway gene expression. In NSCLC patient-derived three-dimensional in vitro spheroid cultures, cetuximab plus avelumab treatment induced additive cancer cell growth inhibition as compared to single agent treatment. This effect was partially blocked by treatment with an anti-CD16 mAb, suggesting a direct involvement of NK cell activation. Furthermore, cetuximab plus avelumab treatment induced 10-, 20-, and 20-fold increase, respectively, in the gene expression of CCL5 and CXCL10, two STING downstream effector cytokines, and of interferon β, as compared to untreated control samples. CONCLUSIONS: DDR mutations may contribute to DDR-induced STING pathway with sustained innate immunity activation following cetuximab plus avelumab combination in previously treated, PD-1 inhibitor responsive NSCLC patients

Triple Blockade of Ido-1, PD-L1 and MEK as a Potential Therapeutic Strategy in NSCLC

BACKGROUND: Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and PD-L1 thus representing a potential escape mechanism to this combination. METHODS: We analyzed transcriptomic profile of NSCLC lung adenocarcinoma cohort of TCGA (The Cancer Genome Atlas), stratifying tumors based on EMT (Epithelial mesenchymal Transition) score; in parallel, we investigated the activation of Ido-1 pathway and modulation of immune cytokines productions both in NSCLC cells lines, in peripheral blood mononuclear cells (PBMCs) and in ex-vivo NSCLC spheroids induced by triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor. RESULTS: In NSCLC lung adenocarcinoma patient cohort (from TCGA) Ido-1 gene expression was significantly higher in samples classified as mesenchymal according EMT score. Similarly, on a selected panel of NSCLC cell lines higher expression of MEK and Ido-1 related genes was detected in cells with mesenchymal phenotype according EMT score, thus suggesting a potential correlation of co-activation of these two pathways in the context of EMT, with cancer cells sustaining an immune-suppressive microenvironment. While exerting an antitumor activity, the dual blockade of MEK and PD-L1 enhances the secretion of pro-inflammatory cytokines (IFNγ, TNFα, IL-12 and IL-6) and, consequently, the expression of new immune checkpoints such as Ido-1. The triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor demonstrated significant antiproliferative and proapoptotic activity on ex-vivo NSCLC samples; at the same time the triple combination kept increased the levels of pro-inflammatory cytokines produced by both PBMCs and tumor spheroids in order to sustain the immune response and simultaneously decreased the expression of other checkpoint (such as CTLA-4, Ido-1 and TIM-3) thus promoting an immune-reactive and inflamed micro-environment. CONCLUSIONS: We show that Ido-1 activation is a possible escape mechanism to immune-mediated cell death induced by combination of PD-L1 and MEK inhibitors: also, we show that triple combination of anti-PD-L1, anti-MEK and anti-Ido-1 drugs may overcome this negative feedback and restore anti-tumor immune response in NSCLC patients\u27 derived three dimensional cultures

A murine preclinical syngeneic transplantation model for breast cancer precision medicine

We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments

DNA Damage Response Signatures Are Associated With Frontline Chemotherapy Response and Routes of Tumor Evolution in Extensive Stage Small Cell Lung Cancer

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes. Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy. Results: Using multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased inflamed biomarkers, both within and across SCLC subtypes. Clinical analyses demonstrated treatment naive DDR status was associated with different responses to frontline chemotherapy. Using longitudinal liquid biopsies, we found that DDR Intermediate and High tumors exhibited subtype switching and coincident emergence of heterogenous phenotypes following frontline treatment. Conclusions: We establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes and may be associated with different chemotherapy responses and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes

Reverse Phase Protein Arrays elucidate mechanisms-of-action and phenotypic response in 2D and 3D models

The development of new 2D and 3D phenotypic screening assays combined with high-throughput genomic and proteomic technologies are well placed to advance a new era of molecular pathway informed Phenotypic Drug Discovery. We describe the application of Reverse Phase Protein Array (RPPA) technology to elucidate the mechanism-of-action of small molecules at the post-translational pathway level. We propose that profiling of phenotypic hits and lead molecules in increasingly more complex 3D in vitro and ex vivo models at the post-translational pathway network level represents an effective strategy to both triage and progress the preclinical development of phenotypic screening hits