Citations

AbstractThere is a clear and unmet need for biomarkers in hepatocellular carcinoma (HCC). Circulating cell free deoxyribonucleic acid (cfDNA) is a fragmented DNA subtype, found in the blood circulation. Circulating tumor DNA (ctDNA) is the fraction of total cfDNA, which originates from the primary tumor or metastases in patients with cancer. Earlier studies reported that quantitative measurement cfDNA has diagnostic and prognostic role for HCC. More recently, improvement in next-generation sequencing technology and better understanding of genetic or epigenetic alteration of HCC have allowed comprehensive analysis of mutational and methylation landscape of ctDNA. Hotspot mutation panels and methylation panels have both shown promising performance. None of these tests have yet been validated in longitudinal cohorts for preclinical detection of HCC. In this article, the authors discuss the currently available ctDNA detection technologies, their diagnostic and prognostic performance in HCC, and future research directions.

Abstract The presence of FMS-like receptor tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD+ leukemia cells, which are potential sources of relapse. Thus, understanding the mechanisms underlying FLT3-ITD+ AML cell persistence is essential to devise future AML therapies. Here, we show that expression of protein arginine methyltransferase 1 (PRMT1), the primary type I arginine methyltransferase, is increased significantly in AML cells relative to normal hematopoietic cells. Genome-wide analysis, coimmunoprecipitation assay, and PRMT1-knockout mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD, contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD+ AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in an FLT3 methylation–dependent manner. Moreover, the effects of FLT3-ITD methylation in AML cells were partially due to cross talk with FLT3-ITD phosphorylation at tyrosine 969. Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in patient-derived xenograft and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD+ AML cells.

Background:Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m2 (Kd70 QW) or twice‐weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW.Aims:We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials.Methods:Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW.Results:Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69).Summary/Conclusion:This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56.© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.

Background:The expression of the receptor tyrosine kinase (RTK) Axl on cancer cells has been associated with poor prognosis and implicated in disease progression. Inhibition of Axl‐RTK with TP‐0903, a high affinity Axl‐RTK inhibitor induces robust apoptosis of several tumors, including chronic lymphocytic leukemia (CLL). Axl‐RTK inhibition has also been found to induce nonspecific immunomodulatory effects in syngeneic tumor models.Aims:We aimed to investigate the impact and downstream effects of Axl‐RTK inhibition on naïve T cells and chimeric antigen receptor T cells (CART), using CD19 directed CART cells (CART19) as a model.Methods:We utilized either PMA/Ionomycin or the CD19+ mantle cell lymphoma cell line, JeKo as a stimulant for naïve T cells and CART19, respectively. Cells were analyzed for cytokine profile, T cell phenotype, and kinetics after the stimulation in the presence or the absence of the Axl‐RTK inhibitor TP‐0903. Regarding in vivo experiment, a relapse JeKo xenograft model was used. Mice were treated with vehicle alone, TP‐0903 alone, CART19 alone, or TP‐0903 + CART19. Three weeks after the treatment, mice were re‐challenged with JeKo as a CART19 relapse model.Results:Stimulation of naïve T cells in the presence of the Axl‐RTK inhibitor TP‐0903 resulted in a significant reduction of Th2 cytokines and downregulation of inhibitory receptors. The differential expansion of either effector T cells or Tregs in the presence of TP‐0903 resulted in a preferential reduction of Tregs (Fig 1A). Axl‐RTK inhibition of CART19 led to Th1 polarization upon stimulation with the JeKo, as evident by the selective reduction of Th2 cytokine. Additionally, this resulted in a reduction of myeloid attracting cytokines, such as CXCL1, IL‐8, IL‐6, and IL‐10, cytokines implicated in the development cytokine release syndrome and neurotoxicity after CART cell therapy and in adaptive resistance to immunotherapy (Fig 1B). TP‐0903 also significantly downregulated inhibitory receptors on activated CARTs (Fig 1C). In our relapsed in vivo model, mice treated with CART19 + TP‐0903 rejected the JeKo challenge while mice received CART19 alone redeveloped disease, suggesting that Axl‐RTK inhibition enhanced CART cell persistence. Peripheral blood analysis of mice after the rechallenge showed a higher number of circulating T cells and lower level of MCP‐1. Western blotting was performed to investigate the downstream effect of Axl‐RTK inhibition on CART19 and it revealed a relatively selective inhibition of LCK on stimulated CART19. Transcriptome analysis of activated CARTs treated with TP‐0903 revealed >100 genes that were differentially expressed compared to untreated cells. Among these, Th cell and Treg polarization genes were significantly altered in activated CARTs treated with TP‐0903.imageFinally, we validated our findings in phase I clinical trial of TP‐0903 (NCT02729298). T cells isolated from 3 cancer patients showed a significant reduction of Tregs and Th1 polarization. This will be further investigated in a planned phase I clinical trial of TP‐0903 in relapsed/refractory CLL (NCT03572634).Summary/Conclusion:We showed for the first time that Axl‐RTK inhibition polarizes T cells into a Th1 functional phenotype, downregulates inhibitory receptors, and reduces myeloid associated cytokine production by CART19. The combination therapy yielded synergistic cytotoxicity against JeKo in vitro and in a CART19 relapse model. These findings encourage further study of Axl‐RTK inhibition with TP‐0903 as an enhancer of T cell immunotherapies.

Background In Fontan patients with atrial arrhythmias (AA), non-vitamin K antagonist oral anticoagulants(NOACs) have a class III recommendation according to the Pediatric & Congenital Electrophysiology Society (PACES)/Heart Rhythm Society (HRS) guideline in 2014, due to lack of data on outcomes as opposed to evidence of harm. To address this gap in data, we investigated the safety and efficacy of NOACs in adults with a Fontan circulation in a worldwide study. Methods This is an international multicentre prospective cohort study, using data from the NOTE ( n on-vitamin K antagonist o ral anticoagulants for t hrombo e mbolic prevention in patients with congenital heart disease) registry. The study population comprised consecutive adults with a Fontan circulation using NOACs. Follow-up took place at 6 months and yearly thereafter. The primary endpoints were thromboembolism and major bleeding. Secondary endpoint was minor bleeding. Results From April 2014 onward, 74 patients (mean age 32±10 years (range 18–68), 54% male) with a Fontan circulation using NOACs were included. During a median follow-up of 1.2 (IQR 0.8–2.0) years, three thromboembolic events (2.9 per 100 patient-years (95% CI 0.7 to 7.6)) and three major bleedings (2.9 per 100 patient-years (95% CI 0.7 to 7.6)) occurred in five atriopulmonary Fontan and one total cavopulmonary connection Fontan patients with AA. Fifteen patients experienced minor bleeding episodes (15.8 per 100 patient-years (95% CI 9.1 to 25.2)). In patients (n=37) using vitamin K antagonists (VKAs) prior to the initiation of NOAC, annual incidence of historical thromboembolic events and major bleeding were 2.4% (95% CI 0.4% to 7.4%) (n = 2) and 1.2% (95% CI 0.7% to 5.1%) (n = 1), respectively. Conclusions In this review of the largest Fontan cohort using NOACs with prospective follow-up, NOACs appear to be well tolerated and their efficacy and safety during short-term follow-up seem comparable to VKAs. Longer term data are required to confirm these promising short-term results.

Objective Natriuretic peptides (NPs) are hormones with cardioprotective effects. NP levels vary by race; however, the pathophysiological consequences of lower NP levels are not well understood. We aimed to quantify the association between NPs and endothelial function as measured by flow-mediated dilation (FMD) and the contribution of NP levels to racial differences in endothelial function. Methods In this cross-sectional study of 2938 Multi-Ethnic Study of Atherosclerosis participants (34% Caucasian, 20% African-American, 20% Asian-American and 26% Hispanic) without cardiovascular disease at baseline, multivariable linear regression models were used to examine the association between serum N-terminal pro-B-type NP (NT-proBNP) and natural log-transformed FMD. We also tested whether NT-proBNP mediated the relationship between race and FMD using the product of coefficients method. Results Among African-American and Chinese-American individuals, lower NT-proBNP levels were associated with lower FMD, β=0.06 (95% CI: 0.03 to 0.09; p<0.001) and β=0.06 (95% CI: 0.02 to 0.09; p=0.002), respectively. Non-significant associations between NT-proBNP and FMD were found in Hispanic and Caucasian individuals. In multivariable models, endothelial function differed by race, with African-American individuals having the lowest FMD compared with Caucasians, p<0.001. Racial differences in FMD among African-Americans and Chinese-Americans were mediated in part by NT-proBNP levels (African-Americans, mediation effect: −0.03(95% CI: −0.05 to −0.01); Chinese-Americans, mediation effect: −0.03(95% CI: −0.05 to −0.01)). Conclusions Lower NP levels are associated with worse endothelial function among African-Americans and Chinese-Americans. A relative NP deficiency in some racial/ethnic groups may contribute to differences in vascular function.

Marrow adipocytes reprogrammed by myeloma cells induce bone lesions.

PURPOSEDrug development is becoming increasingly expensive and time consuming. Drug repurposing is one potential solution to accelerate drug discovery. However, limited research exists on the use of electronic health record (EHR) data for drug repurposing, and most published studies have been conducted in a hypothesis-driven manner that requires a predefined hypothesis about drugs and new indications. Whether EHRs can be used to detect drug repurposing signals is not clear. We want to demonstrate the feasibility of mining large, longitudinal EHRs for drug repurposing by detecting candidate noncancer drugs that can potentially be used for the treatment of cancer.PATIENTS AND METHODSBy linking cancer registry data to EHRs, we identified 43,310 patients with cancer treated at Vanderbilt University Medical Center (VUMC) and 98,366 treated at the Mayo Clinic. We assessed the effect of 146 noncancer drugs on cancer survival using VUMC EHR data and sought to replicate significant associations (false discovery rate < .1) using the identical approach with Mayo Clinic EHR data. To evaluate replicated signals further, we reviewed the biomedical literature and clinical trials on cancers for corroborating evidence.RESULTSWe identified 22 drugs from six drug classes (statins, proton pump inhibitors, angiotensin-converting enzyme inhibitors, β-blockers, nonsteroidal anti-inflammatory drugs, and α-1 blockers) associated with improved overall cancer survival (false discovery rate < .1) from VUMC; nine of the 22 drug associations were replicated at the Mayo Clinic. Literature and cancer clinical trial evaluations also showed very strong evidence to support the repurposing signals from EHRs.CONCLUSIONMining of EHRs for drug exposure–mediated survival signals is feasible and identifies potential candidates for antineoplastic repurposing. This study sets up a new model of mining EHRs for drug repurposing signals.