bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer analysis to identify molecules interacting with CasL-Like 2 to promote angiogenesis via mTOR/HIF1A/VEGFA pathway in hypoxia tumor environment.
Authors: Song Yu-xin , Li Lei , Lan Jian-yun , Tang Jinhai 
Published: June 2023

e15002 Background: Cytoskeleton dynamics generate power for diverse motile and morphogenetic processes in eukaryotic cells. Aberrant actin dynamics are closely associated with pathological conditions and implicated in the occurrence of various tumors. The underlying mechanisms remain to be explored. This study aims to identify a unique redox enzyme, Molecules Interacting with CasL-Like 2 (MICALL2), as a regulator of actin filaments during tumorigenesis and to evaluate its potential value in predicting drug sensitivity to anti-angiogenesis agents. Methods: First, bioinformatic analysis was used to demonstrate MICALL2 expression level across distinct cancers and its relationship with clinical characteristics from TCGA and CPTAC databases. Functional enrichment analysis and whole-mountin situ hybridization were performed. Gene correlation analysis and IHC were used to detect the correlation between MICALL2 and HIF family. Next, chosen kidney renal clear cell carcinoma (KIRC) as a research object, the location of MICALL2 and actin was determined by immunofluorescence. IHC on MICALL2, HIF1A, VEGFA, CD31, CD34 of 44 clinical KIRC tissue samples was performed. The role of MICALL2 in proliferation, hypoxia and angiogenesis of KIRC cells was investigated using EDU staining, CCK-8 assay, ROS analysis, flow cytometry, and tubule formation assays. The effect of MICALL2 on the mTOR-related signal pathway was evaluated by western blot. Last, drug sensitivity analysis was obtained from the GDSC, CTRP, and PRISM databases to reveal the relationship between MICALL2 and anti-angiogenesis agents and cytoskeleton-regulating drugs. Results: MICALL2 expression was elevated in most cancers and correlated with poor survival outcomes. Pan-cancer analysis demonstrated that MICALL2 was co-expressed with HIF family members and strongly linked to angiogenesis pathway. Interfering the translation of MICALL2 during zebrafish embryogenesis resulted in defective caudal vein plexus morphogenesis. Additionally, KIRC patients with high MICALL2 expression displayed enhanced HIF1A expression and increased CD34-labeled neovascularization. In KIRC cells, MICALL2 was found co-located with F-actin. MICALL2 overexpressed KIRC cells exhibited more aggressive behaviors, with the tumor microenvironment remodeling to a more hypoxia condition. Up-regulation of MICALL2 promoted tumor angiogenesis via activating a novel mTOR/HIF1A/VEGFA pathway. Furthermore, tumor patients with high MICALL2 expression were more likely to be resistant to anti-angiogenesis agents and microtubule depolymerization inhibitors, but sensitive to actin polymerization inhibitors. Conclusions: Our results suggest that MICALL2 plays a crucial role in tumor angiogenesis and may be a potential predictor of anti-angiogenic agent sensitivity across multiple cancers.
Population pharmacokinetic and exposure-response safety analyses of mecbotamab vedotin (BA3011) in patients with advanced solid tumors.
Authors: Shen Guoxiang George , Briggs Emily , Crass Ryan , Karumanchi Sravan , Boyle William J. , Baker Michael G. , Martin Philippe 
Published: June 2023

e15010 Background: Mecbotamab vedotin (BA3011) is antibody-drug conjugate (ADC) consisting of a conditionally active biologic (CAB) anti-AXL humanized (IgG1) monoclonal antibody conjugated to monomethyl auristatin E (MMAE) using a cleavable linker. BA3011 is being developed for the treatment patients with advanced solid tumors including sarcoma with AXL expression. Methods: As of data cutoff date 19 April 2022, BA3011 was administered by intravenous infusion to 67 patients, with doses ranged from 0.3 to 3 mg/kg once every three weeks (Q3W), 1.2 to 1.8 mg/kg once every two weeks (Q2W) and 1.8 mg/kg twice every three weeks (2Q3W). Population pharmacokinetics (popPK) analysis was performed using sequential modeling approach, where a PK model was first developed for BA3011 ADC alone, and then an integrated model was developed for BA3011 ADC and MMAE. The popPK base model for BA3011 ADC and MMAE was used to generate empirical Bayes estimates of PK parameters for patients in Study BA3011-001 and used for the exposure-response (E-R) safety analysis. E-R time-to-event models were developed to characterize the relationship between BA3011 ADC or MMAE exposure and the time to first incidence of adverse events (AEs). Results: A popPK model with two-compartment disposition and parallel linear and nonlinear elimination of BA3011 ADC, formation of MMAE from ADC, and two-compartment disposition and linear elimination of MMAE, adequately described the PK profiles of BA3011 ADC and MMAE in patients based on model evaluation using prediction-corrected visual predictive checks. Key PK parameter estimates are summarized in the table below. In the E-R safety analysis, statistically significant correlations were demonstrated between BA3011 ADC exposure and all safety endpoints explored (TEAE Grade ≥3, neutropenia Grade ≥3, increase in AST or ALT Grade ≥1, anemia Grade ≥2, and peripheral neuropathy Grade ≥1). Correlations were statistically significant between MMAE exposure and TEAE Grade ≥3, neutropenia Grade ≥3, increase in AST or ALT Grade ≥1, but not anemia Grade ≥2 or peripheral neuropathy Grade ≥1. Time-varying Cmax was selected as the most appropriate exposure metric for each model developed, calculated over the past 24 hours, 1 week, or 3 weeks, depending on the model. Conclusions: The popPK relationship between ADC and MMAE were adequately characterized using a sequential modeling approach. BA3011 ADC exposure was correlated with all safety endpoints evaluated whereas MMAE exposure did not demonstrate correlations with anemia or peripheral neuropathy. These models are essential to generate predictions of exposure and safety for dosing regimens to be evaluated in a planned Phase 2 clinical trial. Clinical trial information: NCT03425279 . [Table: see text]
Tolerability and toxicity profiles of antibody-drug conjugates for the treatment of malignant neoplasms: A meta-analysis of randomized clinical trials.
Authors: Zhou Susu , Kuno Toshiki , Miyagi Etsuko , Wright Jason Dennis , Takagi Hisato , Suzuki Yukio 
Published: June 2023

e15011 Background: Antibody-drug conjugates (ADCs) are attractive targeted agents in anticancer treatment due to their unique mechanism of action and reduced toxicity compared to other anti-cancer drugs. Yet little is still known about the adverse events profiles associated with ADCs. Methods: A systematic review was performed including randomized controlled trials (RCTs) of anticancer treatment that evaluated the efficacy of ADCs. PubMed and EMBASE were systematically searched for studies from January 1990 to December 2022. RCTs that were registered in ClinicalTrials.gov and had final reports of comprehensive adverse events were also included. We included studies for patients with both solid and hematologic tumors. The odds ratios (ORs) of treatment-related symptoms, and hematologic, hepatic, ocular, cardiovascular, renal, and respiratory toxicities for patients treated with ADCs and those without ADCs were examined. A random effects model was developed to estimate the pooled ORs of each adverse event associated with ADC use. Subgroup analyses were also performed based on the cancer type (solid tumors versus hematologic malignancy) and ADC regimen (ADC versus ADC plus chemotherapy). Results: 20 studies involving 10,075 patients (5,745 patients with ADC and 4,330 patients without ADC) were included. Among the included trials, 14 (70.0%) were trials for solid tumors and 6 (30.0%) were trials for hematological tumors. Among the included trials, ADC monotherapy was used in 15 (75.0%) experimental arms, and combination therapy of ADC with any other chemotherapy was used in 7 (35.0%). ADCs were associated with a higher risk for all-grade fatigue (OR 1.25, 95% CI 1.08-1.45), anorexia (OR 1.36, 1.09-1.69), nausea (OR 1.46, 1.09-1.97) and sensory neuropathy (OR 2.18, 1.27-3.76). Patients treated with ADCs had a significantly lower risk of all-grade febrile neutropenia (OR 0.46, 0.22-0.96), leukopenia (OR 0.47, 0.29-0.77), and neutropenia (OR 0.56, 0.31-1.01). Whereas, they had a higher risk of all-grade increased alanine aminotransferase (OR 2.51, 1.84-3.40), increased aspartate aminotransferase (OR 2.83, 2.04-3.93), cataract (OR 4.69, 1.86-11.81), blurry vision (OR 3.12, 1.02-9.55), pericardial effusion (OR 4.27, 2.71-6.72), and epistaxis (OR 2.45, 1.50-4.01). In the subgroup analysis, a similar toxicity profile was observed when comparing the solid tumors versus hematologic malignancy groups and the ADC versus ADC plus chemotherapy groups, except for hematologic adverse events, which showed an increased risk in patients with solid tumors and those treated with both chemotherapy and ADCs. Conclusions: This comprehensive profile of adverse events associated with ADC-based treatment shows increased treatment-related symptoms, hepatic, ocular, and cardiovascular toxicities although no increase of high-grade are seen.
Preclinical antitumor activity of an anti-HER2/Trop-2 bispecific antibody-drug conjugate with a new DNA topoisomerase I inhibitor.
Authors: Zhong Helen , Xiong Yan , Huang Han , Pan Yuming , Cao Lijin , Liu Shen , Wang Na , Sun Bing , Liu Dingguo , Yuan Wei , Fang Jan , Bao Haifeng 
Published: June 2023

e15013 Background: In recent years, antibody-drug conjugates (ADCs) have made significant progress in cancer therapy and show a promising future. Among the approved ADCs, Enhertu, the HER2 directed ADC and Trodelvy, the Trop-2 directed ADC, have shown considerable clinical benefits. Bispecific antibody-drug conjugate represents a fast-growing class of next generation ADC due to its potentials in enhancing specificity, improving efficacy, and reducing toxicity. Additionally, targeting more than one molecule can be useful to avoid resistance to treatment and broaden the patient population. Methods: We generated a novel bispecific ADC (BIO-201) co-targeting HER2 and Trop-2 which are the two clinically validated tumor-associated antigens that are expressed on a wide variety of tumors. BIO-201 is consisted of a novel bispecific anti-HER2/Trop-2 antibody conjugated with a potent DNA topoisomerase I inhibitor (TOPO Ii) via a cleavable linker. TOPO Ii is a proprietary payload platform developed in house that exhibits similar characteristics including in vitro and in vivo anti-tumor activities and safety profile to DXd. The bispecific antibody was fully characterized and in vitro and in vivo anti-tumor activity of BIO-201 was assessed using preclinical models. Results: The bispecific antibody showed comparable or increased cell binding and internalization compared with the parental antibodies in various tumor cells that express different surface levels of HER2 and Trop-2. In the in vitro cytotoxicity assay, the bispecific ADC BIO-201 effectively killed cancer cells with IC50 in the sub nM range with BIO-201 being most potent against cancer cells that co-express HER2 and Trop-2. The anti-tumor activity of BIO-201 was further demonstrated in vivo in several tumor xenograft models. Treatment of BIO-201 induced significant tumor regression in HER2 or Trop-2 positive tumors, suggesting broader coverage of tumor types than conventional HER2 and Trop-2 ADCs. BIO-201 also showed similar anti-tumor activity to Herceptin-DXd. Conclusions: Taken together, these findings suggest that anti-HER2/Trop-2 bispecific ADC has potential as an effective therapy for a variety of cancers that co-express HER2/Trop-2 or express either of the targets. BIO-201 may be expected to have a similar clinical activity to Enhertu or Trodelvy but treat more patient sub-populations and indications.
A study of antibody conjugates for the treatment of inflammatory breast cancer.
Authors: Yang Teng , Guo Peng , Wei Qing 
Published: June 2023

e15016 Background: Inflammatory breast cancer (inflammatory carcinoma) is a rare metastatic malignant tumor, it accounts for about 2% of all breast cancer cases. Despite its low incidence, inflammatory breast cancer is highly invasive, its five-year survival rate is less than 41%, making its prognosis the worst of all breast cancer subtypes, and effective drugs are urgently needed in clinical practice. Therefore, our study develops novel antibody conjugate drugs that can target overexpressed-ICAM-1 in inflammatory breast cancer cells as an original molecular target precisely. Methods: In this study, flow cytometry was used to perform precise and quantitative target screening of inflammatory breast cancer cell lines (SUM-149, KPL4), the endocytosis efficiency of ADC drugs was verified by flow cytometry efficiency analysis and single-photon confocal analysis, and the cytotoxicity of different drugs and cell lines was explored by CCK8 experiment. A nude mouse model of orthotopic xenograft inflammatory breast cancer was constructed, and the in vivo therapeutic effect of inflammatory breast cancer was observed by intravenous injection of two ICAM-1 antibody conjugates (ICAM-1-MMAE and ICAM-1-DXD), also the ADC drug structure with the best therapeutic effect for inflammatory breast cancer was screened. Results: ICAM-1 molecule in a variety of inflammatory breast cancer cell lines were highly over-expressed, and the antibody internalization rate was 51% at 4h, and after the peak the endocytosis efficiency slowed down into the plateau stage; ICAM1-MMAE and ICAM1-DXD are safer than first-line chemotherapy agents for breast cancer; The tumor volume was significantly reduced after administration into the orthotopic breast cancer xenograft model, which further verified the obvious effect of ADC drugs in vivo. Conclusions: Both ICAM-1-MMAE and ICAM-1-DXD have shown significant anti-inflammatory breast cancer effects in vitro and in vivo, and this study provides potential antibody conjugate drugs for targeted therapy of inflammatory breast cancer, which is expected to help improve the poor prognosis of inflammatory breast cancer.
Relationship between EGFR inhibition in lung adenocarcinoma, cell surface expression of the placental antigen ALPP, and efficacy of ALPP-ADC therapy.
Authors: Katayama Hiroyuki , Chen Yihui , Hong Monica , Xu Hanwen , Vykouka Jody , Park Soyoung , Cai Yining , León-Letelier Ricardo A. , Irajizad Ehsan , Hsiao Fu Chung , Dennison Jennifer , Ostrin Edwin J. , Fahrmann Johannes , Hanash Samir M. 
Published: June 2023

e15018 Background: In normal tissues placental alkaline phosphatases (ALPP) and ALPPL2 are exclusively expressed in the placenta. Their discovery in the cancer surfaceome has opened the possibility of targeting ALPP/ALPPL2. However, their low expression in most cancer types limits their therapeutic potential. In this study, we report a novel mechanism of ALPP upregulation in cancer cells that renders these cells more susceptible to ALPP-targeting therapies, which we evidence in the context of lung adenocarcinoma. Methods: Surface expression of ALPP and ALPPL2 was determined following biotinylation tagging of the cancer surfaceome, isolation of biotinylated proteins using monomeric avidin and mass spectrometry of the biotinylated trypsin digested fraction. ALPP antibody was conjugated with Monomethylauristatin F (ALPP-ADC-MMAF). For orthotopic xenograft models of LUAD were injected. For gefitinib treatment, Mice xenotransplanted with H1650 were treated with gefitinib (50mg/kg) daily for 10 days starting from Day 17 post cancer cell inoculation. For the gefitinib/ALPP-ADC combinational treatment, mice received anti-ALPP-MMAF (5mg/kg) at Day 19 and Day 26. Results: We assessed ALPP and ALPPL2 surfaceome protein levels in 158 cancer cell lines and their mRNA expression levels in 10,967 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), which revealed ALPP, and to a lesser extent ALPPL2, to be variably expressed in several cancer types including lung adenocarcinoma (LUAD). We further confirmed surface expression of ALPP by tissue microarray analysis of 204 lung tumors. We report that treatment of LUAD cells with EGFR inhibitors or induction of cancer cell quiescence greatly enhanced ALPP surface expression. Mechanistically, repression of EGFR signaling resulted in activation of the transcription factor FoxO3a, which triggered expression of ALPP. Using xenograft models of LUAD, we further demonstrate that gefitinib treatment significantly upregulated surface expression of ALPP in LUAD tumors but not normal tissue. Combination therapy with gefitinib and an ALPP-ADC-MMAF resulted in superior anti-cancer efficacy compared with gefitinib or ALPP-ADC-MMAF alone. Conclusions: Our study provides mechanistic insights into ALPP upregulation in cancer cells and establishes FoxO3a as a transcriptional regulator of ALPP. Importantly, our findings have yielded a novel ‘two-hit’ combinational therapeutic strategy with enhanced ALPP targeting for greater efficacy.
Epigenetic profile of elevated cell free circulating nucleosomes in non-Hodgkin lymphoma.
Authors: Van den Ackerveken Priscilla , Lobbens Alison , Pamart Dorian , Rommelaere Guillaume , Herzog Marielle 
Published: June 2023

e15032 Background: Non-Hodgkin lymphoma (NHL) is a common type of hematological malignancy. The non-specific symptoms of lymphoma often delay diagnosis that is mainly based on a lymph node biopsy. However, due to their invasive nature, tissue biopsies have many limitations especially for monitoring therapeutic response where multiple biopsies may be required. Conversely, liquid biopsy offers a promising diagnosis and monitoring tool for cancer detection as it is noninvasive and easily repeatable over time compared to tissue biopsy. In this study, we investigated the circulating levels of intact nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) in NHL and healthy subjects. Then, as histone post-translational modifications (PTMs) of circulating nucleosomes are described as potential biomarkers of various solid cancers, we investigated the epigenetic profile of nucleosomes from NHL patients following nucleosome enrichment (Nu.Q Capture) combined with mass spectrometry (MS) compared to healthy donors. Methods: In plasma K2EDTA from 9 NHL and 5 healthy subjects, we measured levels of Nu.Q-H3.1 combined with the epigenetic profile of these circulating nucleosomes using our Nu.Q Capture- mass spectrometry protocol. Subsequently, the capability of the identified histone PTMs to differentiate between NHL and healthy plasma was tested in an independent cohort (n = 24 NHL patients and n = 35 healthy donors) and in two patients undergoing treatment course using available quantitative Nu.Q immunoassays. Results: We describe a high level of circulating H3.1-nucleosomes in human plasma NHL patients compared to healthy subjects. This level of H3.1-nucleosomes was correlated with an elevated concentration of cfDNA and is consistent with the DNA distribution size observed by the Bioanalyzer around 146 bp. In addition, the mass spectrometric analysis of the nucleosome enriched extracts allowed us to profile the epigenetic pattern of circulating nucleosomes in NHL patients. Our analysis demonstrated increased levels of H3.1 as well as the lysine acetylation and methylations of the histone H3 in plasma from NHL patients. Furthermore, the clinical validation of the histone PTMs pattern using immunoassays identified a significant increase in the levels of H3.1-nucleosomes as well as 6 histone PTMs (H3K9Me1, H3K27Me3, H3K36Me3, H3K9Ac, H3K14Ac, H3K18Ac) in NHL patients in comparison with healthy donors. Finally, the application of this histone PTMs pattern on NHL patients demonstrated the potential use of these new biomarkers present in liquid biopsy to evaluate the therapeutic response and monitoring of tumor progression. Conclusions: Our results indicate that levels of Nu.Q-H3.1 are particularly elevated in NHL patients and may be a useful diagnostic tool. Moreover, our work emphasizes the crucial roles of the epigenetic marks present on circulating nucleosomes to detect and monitor diseases such as lymphoma.
Novel blood-based assay for detection of early stage multi-cancer.
Authors: Gregg Jeffrey P. , Michor Franziska , Gilley Caitlin , Williams Miguel , Brown Esther , Gowen Kyle , KashefHaghighi Dorna , Sun James , Kia Amirali , Charlton Jocelyn 
Published: June 2023

e15035 Background: Early cancer detection has the potential to significantly improve patient outcomes and reach the Cancer Moonshot goals of reducing the death rate from cancer by at least 50 percent over the next 25 years. Harbinger Health is pioneering early cancer detection with a blood-based test that combines recent genomic and epigenomic discoveries of early cancer and biology-informed artificial intelligence. Unlike prior approaches that are purely statistical to identify informative biomarkers, Harbinger’s approach is informed by insights into specific biological events early during tumorigenesis and is therefore optimized for detecting cancer in patients with very low levels of circulating tumor DNA. Methods: Here, we present data generated using the Harbinger Health assay from 1,046 subjects, 621 with newly diagnosed, treatment-naive cancer (15 different cancer types) and 425 individuals with no history, diagnosis, or cancer symptoms. Using this sample cohort, we developed and applied a rigorous framework for training, calibration and predicting likelihood of cancer using a multi-layered logistic regression-based machine learning algorithm, generating final outputs of binary classification (cancer yes/no). Our framework involved multiple iterations of 10-fold cross-validation of the full dataset, and we report solely on samples that appear in the held-out test set in each iteration. Additionally, we developed a similar framework to predict tissue of origin (TOO) for cancer samples. Results: The overall sensitivity of cancer detection was 82% (95% confidence interval (CI): 72.7-91.0%) at 95% specificity. Notably, the sensitivity was 74% (95% CI: 54.8-92.7%) for stage 1 and 84% (95% CI: 65.3-100%) for stage 2. Furthermore, we were able to correctly predict cancer in 95% of patient samples with at least 0.037% tumor fraction. The overall sensitivity for high incident cancers were: breast (73%), prostate (82%), lung (85%), and colorectal (96%) at 95% specificity and the overall accuracy of TOO prediction was 86% when the tumor fraction was greater than 0.1% in the top 3 most prevalent cancer types (breast, colorectal and lung). Importantly, we noted that technical variability was introduced when performing assay optimization strategies, yet we observed comparable performance when assessing subsets of stably processed samples, indicating that our performance is robust. Conclusions: Overall, these results demonstrate that the Harbinger Health platform, with its biology-informed approach, has the potential for highly sensitive multi-cancer diagnostic accuracy and specifically those with early-stage cancer. The platform is now being validated in a 10,000-subject prospective clinical trial (CORE-HH/NCT05435066).