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Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation
Abstract Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether ‘differentiation therapy’ is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.
TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors.
Many patients with cancer do not benefit from currently approved immune checkpoint inhibitors (ICIs), suggesting that additional immunomodulation of the immunosuppressive tumor microenvironment (TME) is required. MTL-CCAAT enhancer-binding protein alpha (CEBPA) specifically upregulates the expression of the master myeloid transcription factor, CEBPA, relieving myeloid-driven immunosuppression. Here, we report the safety, tolerability, pharmacokinetics, and efficacy of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumors that typically show ICI resistance. Multimodal exploratory analyses of paired patient biopsies demonstrate biological changes associated with the combination treatment of MTL-CEBPA and pembrolizumab, including increased infiltration of T cell and antigen-presenting cells supporting conversion from an immune-desert toward a more immune-inflamed TME. Patients with disease stabilization demonstrate reductions in immunosuppressive myeloid cells post treatment. Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335).
Interventions delivered in secondary or tertiary medical care settings to improve routine vaccination uptake in children and young people: a scoping review.
OBJECTIVE: To identify and analyse the interventions delivered opportunistically in secondary or tertiary medical settings, focused on improving routine vaccination uptake in children and young people. DESIGN: Scoping review. SEARCH STRATEGY: We searched CINAHL, Web of Science, Medline, Embase and Cochrane Database of Systematic Reviews for studies in English published between 1989 and 2021 detailing interventions delivered in secondary or tertiary care that aimed to improve childhood vaccination coverage. Title, abstract and full-text screening were performed by two independent reviewers. RESULTS: After deduplication, the search returned 3456 titles. Following screening and discussion between reviewers, 53 studies were included in the review. Most papers were single-centre studies from high-income countries and varied considerably in terms of their study design, population, target vaccination, clinical setting and intervention delivered. To present and analyse the study findings, and to depict the complexity of vaccination interventions in hospital settings, findings were presented and described as a sequential pathway to opportunistic vaccination in secondary and tertiary care comprising the following stages: (1) identify patients eligible for vaccination; (2) take consent and offer immunisations; (3) order/prescribe vaccine; (4) dispense vaccine; (5) administer vaccine; (6) communicate with primary care; and (7) ongoing benefits of vaccination. CONCLUSIONS: Most published studies report improved vaccination coverage associated with opportunistic vaccination interventions in secondary and tertiary care. Children attending hospital appear to have lower baseline vaccination coverage and are likely to benefit from vaccination interventions in these settings. Checking immunisation status is challenging, however, and electronic immunisation registers are required to enable this to be done quickly and accurately in hospital settings. Further research is required in this area, particularly multicentre studies and cost-effectiveness analysis of interventions.
Molecular profiling in MPN: who should have it and why?
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers that result from somatic mutations in hematopoietic stem cells, causing constitutive activation of JAK-STAT signaling pathways with consequent overproduction of 1 or more myeloid lineages. The initiating event in MPN pathogenesis is a genetic mutation, and consequently molecular profiling is central to the diagnosis, risk stratification, and, increasingly, monitoring of therapy response in persons with MPN. In this review we summarize current approaches to molecular profiling of classical MPNs (essential thrombocythemia, polycythemia vera, and myelofibrosis), using illustrative clinical case histories to demonstrate how genetic analysis is already fully integrated into MPN diagnostic classification and prognostic risk stratification. Molecular profiling can also be used in MPN to measure response to therapy both in clinical trials and increasingly in routine clinical practice. Taking a forward look, we discuss how molecular profiling in MPN might be used in the future to select specific molecularly targeted therapies and the role of additional genetic methodologies beyond mutation analysis.
A qualitative exploration of digital medicines information usage: Insights from an evaluation of the BNF
Objectives:: To explore the driving and resisting forces to the use of digital medicines information in the context of the British National Formulary (BNF) and British National Formulary for Children (BNFc). Methods:: Qualitative semi-structured interviews were carried out with 25 doctors, pharmacists and nurses. Data were analysed via thematic analysis. Results:: Key drivers identified included organisations making digital use of BNF/BNFc easier through measures such as electronic prescribing systems, compatible handheld devices and training/induction sessions for staff. The COVID-19 pandemic had expedited the shift to digital BNF/BNFc usage in some settings. A strong driver of digital usage was the desire by staff to use the most up-to-date information. Reduced access to print copies was a common initial driver of digital usage, whilst ease of searching and speed of access often acted to consolidate digital usage. Important resisting forces included lack of supporting organisational digital infrastructure and an onus on individuals to obtain access to digital platforms, particularly through personal smartphones. Poor prior experience of earlier digital BNF/BNFc platforms had also prevented participants from using them again. Conclusions:: More driving than resisting forces were identified and, in most settings, a transition to digital BNF/BNFc usage is underway, which has been expedited by the COVID-19 pandemic. However, this is not happening uniformly across the NHS and there continue to be strong resisting forces to digital BNF/BNFc usage, particularly at organisational level. Public interest summary:: The British National Formulary (BNF) and British National Formulary for Children (BNFc) provide information about all medicines prescribed in the UK. They are available as a book, a website and an app. As healthcare information becomes increasingly digital, it is important to understand how this is used by healthcare staff and we spoke to doctors, nurses and pharmacists about how they use the BNF/BNFc. We found that staff are increasingly using the digital BNF/BNFc and that the COVID-19 pandemic has speeded up this transition. Staff are likely to use the digital BNF/BNFc where their organisation makes it easy to do so, such as through access to IT equipment and electronic prescribing systems. However, many NHS organisations lack the facilities for widespread digital usage and staff are not routinely trained in using digital resources. Future efforts should focus on the digital technology itself, and on upskilling healthcare staff to use it.
Next-generation sequencing for guiding matched targeted therapies in people with relapsed or metastatic cancer.
BACKGROUND: Matched targeted therapies (MTT) given alone or in combination with systemic anti-cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late-stage setting. With this uncertainty, alongside the perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next-generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next-generation sequencing testing of recurrent or late-stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting. OBJECTIVES: To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO-ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti-cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next-generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow). DATA COLLECTION AND ANALYSIS: We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random-effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence. MAIN RESULTS: We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta-analysis. All included studies compared a matched targeted therapy intervention to standard-of-care treatment, non-matched targeted therapies or no treatment (best supportive care): Matched targeted therapy versus standard-of-care treatment Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate-certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low-certainty evidence) and may increase overall response rates (low-certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard-of-care treatment (low-certainty evidence). There was limited evidence of a difference in quality of life between groups (very low-certainty of evidence). Matched targeted therapy in combination with standard-of-care treatment versus standard-of-care treatment alone Matched targeted therapy in combination with standard-of-care treatment compared with standard-of-care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53-0.70, 14 studies, 2,637 participants; moderate-certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate-certainty evidence). The combination of MTT and standard-of-care treatment may also increase overall response rates (low-certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low-certainty evidence) and quality of life between the groups (very low-certainty of evidence). Matched targeted therapy versus non-matched targeted therapy Matched targeted therapy compared with non-matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate-certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low-certainty evidence). There was little to no effect on overall response rates between MTT and non-MTT. There was no clear evidence of a difference in overall response rates (low-certainty evidence) and severe adverse events between MTT and non-MTT (low-certainty evidence). None of the studies comparing MTT and non-MTT reported quality of life. Matched targeted therapy versus best supportive care Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate-certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low-certainty evidence). There was no clear evidence of a difference in overall response rates (very low-certainty of evidence) and incidence of severe adverse events (very low-certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores. Risk of bias The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk. AUTHORS' CONCLUSIONS: Matched targeted therapies guided by next-generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next-generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype-matched targeted therapies.
The Impact of Body Mass Index (BMI) on Clinical Outcomes for Patients Receiving Systemic Anti-Cancer Therapies for Advanced Clear Cell Renal Carcinoma.
IntroductionObesity is a risk factor for the development of renal cell carcinoma (RCC), however observational studies have suggested patients with RCC receiving systemic anti-cancer therapy (SACT) and BMI ≥25 kg/m2 may have a better prognosis than patients with a normal or low BMI, a phenomenon often referred to as the obesity paradox.MethodsThe impact of BMI on survival outcomes in patients with advanced clear cell RCC receiving SACT within the National Health Service (NHS) in England between 2010 and 2018 was investigated. A retrospective analysis was performed using the SACT dataset from NHS-England.ResultsA total of 1034 patients were included. The majority of patients commenced treatment with oral SACT, pazopanib (53.3%) and sunitinib (43.7%). Median overall survival for patients with BMI ≤25 kg/m2 was 12.6 months (95% CI; 10.1-14.4) and 17.9 months (15.4-20.0) for patients with BMI ≥25 kg/m2 (P < .001). The association between BMI and improved survival was greatest in the first year of commencing SACT with the adjusted mortality rate of 68.9% for patients with BMI less than 25 kg/m2 compared to 48.6% for patients with BMI greater than 25 kg/m2 (rate ratio .77, .63 to .93).ConclusionA high BMI compared to a normal or low BMI was associated with improved survival in patients with metastatic RCC who were predominantly treated with oral SACT. Improved survival in obese patients with advanced RCC may be associated with improved response to systemic targeted therapies.
Efficacy of a Novel BCL-xL Degrader, DT2216, in Preclinical Models of JAK2-mutated Post-MPN AML.
Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments don't significantly extend survival beyond 12 months. BCL-xL has been found to be overexpressed in leucocytes from MPN patients, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera (PROTAC), in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in post-MPN AML patients compared to those with de novo AML. Single-cell multi-omics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression, elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells (iPSC-HPCs), primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from post-MPN AML patients. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.
Invasive group A streptococcal infections in North West England: epidemiology, risk factors and fatal infection.
OBJECTIVES: In England, notifications of invasive group A streptococcal (iGAS) infections have increased since 2015. We describe time trends, risk factors, as well as clinical and infection characteristics amongst iGAS cases in North West England, focussing on people who inject drugs (PWIDs), prisoners and homeless populations (referred to as risk groups), and analyse factors for fatal infection. STUDY DESIGN: The study design used was a cross-sectional study. METHODS: Data for all iGAS cases notified to Public Health England North West between January 2016 and May 2019 were used. Analysis consisted of time trend analysis, descriptive statistics, hypothesis testing to investigate differences in clinical and infection characteristics between risk and non-risk groups and binary logistic regression to identify factors associated with fatal infection. RESULTS: There were 1353 cases. Two hundred and two were amongst risk groups, who were predominantly PWIDs in Greater Manchester. Soft tissue risk factors were widespread. There were differences in strain-type between risk and non-risk groups. Female gender, cancer, emm1.0 and emm5.23 were associated with increased odds of death, whilst cellulitis was associated with reduced odds. The relationship between age and death was U-shaped. CONCLUSIONS: iGAS has increased in North West England since 2016, including amongst PWIDs. This may be due to emm-type replacement, barriers to good hygiene and increasing colonisation.