bluuebunny/crossref_metadata_2025_split huggingface dataset:
BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in-human phase I study in patients with advanced solid malignancies.
Authors: Chen Hua-Jun , Wang Sheng , Su Rong , Li Xu-Feng , Tang En-Tzu , Wang Yi-Wei , Hei Yong-Jiang , Wu Yi-Long 
Published: June 2024

e15008 Background: Cadherin-3 (CDH3), a calcium-dependent cell-cell adhesion glycoprotein, is overexpressed on lung, breast, ovarian, colorectal, pancreatic, head and neck and other malignancies, but with negligible expression on nonmalignant tissues, and associated with cancer aggressiveness, invasiveness, and poor prognosis. BC3195 is known as the only antibody drug conjugate (ADC) in clinical stage, targeting CDH3 with payload of monomethyl auristatin E (MMAE). Methods: A phase I, open-label, first in human study to evaluate the safety, tolerability, PK, and preliminary antitumor activity of BC3195 is being performed in subjects with advanced solid malignancies. Disease assessments are performed every 6 weeks using RECIST v1.1. BC3195 is administered as 1 hour (h) IV infusion every 3 weeks. An evaluation of seven dose levels is planned: 0.3, 0.6, 1.2, 2.4, 3.0 and 3.6 mg/kg with a BOIN design guiding dose escalation. Results: Up to January 1st, 2024, nine patients (median age, 59; male, 56%) have been enrolled and treated with BC3195, with 3 patients each in the 0.3, 0.6 and 1.2 mg/kg dose cohorts. No DLT was observed across all the 3 dose cohorts. Treatment emergent adverse events (TEAEs) occurring in ≥3 patients included: aspartate aminotransferase increased (5/9, 55.6%), conjugated bilirubin increased (5/9, 55.6%), triglycerides increased (4/9, 44%), uric acid increased (3/9, 33.3%), heart rate increased (3/9, 33%), and hypoalbuminemia (5/9, 55.6%), cough (4/9, 44.4%), hyponatraemia (4/9, 44.4%), anemia (4/9, 44.4%), asthenia (3/9, 33.3%), rash (3/9, 33.3%), vomiting (3/9, 33.3%) and back pain (3/9, 33.3%). Two subjects experienced ≥ Grade 3 TEAEs unrelated to study drug. Six subjects were evaluable for tumor assessment, and 3 subjects (3/6, 50%) show stable disease (SD) as the best response (2 subjects with target lesion reduction). PK results demonstrated that exposure for the ADC and total antibody (TA) increased with dose, the relationship between AUC0-last and dose was greater than dose-proportional, while Cmax was linear. Free MMAE was highest at the 1.2 mg/kg dose level. Median Tmax values for ADC and TA were 1 h (end of infusion), and median Tmax for free MMAE was 25-169 h. In addition, elimination t1/2 values averaged 27-48 h, 31-68 h and 63-76 h for the ADC, TA, and MMAE, respectively. Conclusions: BC3195 exhibited favorable safety profile and PK characteristics up to 1.2mg/kg. Given BC31095’s safety and PK behavior, as well as preliminary activity at the 0.6 mg/kg dose level, patient enrollment at higher dose levels is ongoing. Clinical trial information: NCT05957471 .
Type III collagen pro-peptides (PRO-C3) as a proposed prognostic biomarker of risk of survival outcomes in clinical trials of patients with solid tumors.
Authors: Willumsen Nicholas , Nissen Neel Ingemann , Karsdal Morten Asser 
Published: June 2024

e15050 Background: Tumor fibrosis is essential for defining outcome of patients with various solid tumors. The major pathological signature of tumor fibrosis is a fibrous connective tissue formed by proliferation and activation of fibroblasts and increased synthesis and deposition of fibrillar collagens (type III collagen) leading to immune exclusion and high interstitial pressure in the tumor microenvironment. Recently, the USA FDA issued a Letter of Support to encourage the further study and use of the biomarker PRO-C3 (type III collagen pro-peptides) as a proposed prognostic biomarker of risk of survival outcomes in clinical trials of patients with solid tumors ( https://www.fda.gov/media/169332/download ). Here we summarize the published data that supports the use of PRO-C3 as a prognostic biomarker that reflects fibrotic activity in the TME. Methods: A PubMed search was used to find studies with PRO-C3, cancer and survival outcome. The hazard ratios (HR) with 95% confidence intervals (95%CI) calculated from univariate cox regression analyses for overall survival (OS) outcomes were collected for where patients were dichotomized based on their pre-treatment PRO-C3 levels and results summarized across indications including breast cancer, pancreas cancer, colorectal cancer, hepatocellular carcinoma, biliary tract cancer and malignant melanoma. Results: Nine studies were retrieved. Table 1 shows the studies with HR and 95%CI for OS after dividing patients into high and low PRO-C3. Various cutoffs were used in the different indications. In all studies, high levels of PRO-C3 were predictive of poor OS with an increased risk of dying ranging 48%-337%. Conclusions: Type III Collagen pro-peptides (PRO-C3) are prognostic for poor OS across indications. These data suggest that quantifying tumor fibrosis is important for prognostication of patients with cancer and that this can be assessed non-invasively in serum or plasma across indications. [Table: see text]
Evaluation of concordance between blood-based and matched tissue molecular testing in a regional cancer center.
Authors: Darabi Sourat , Zuazo Carlos E , Brodie Taylor , Braxton David R. , Eisenberg Burton Larry , Demeure Michael J. 
Published: June 2024

e15062 Background: Next-generation sequencing (NGS) to identify cancer-associated mutations together with an increasing array of targeted drugs with FDA approval allows for matching patients with more effective therapies. Tumor tissue molecular profiling is most often used to identify actionable biomarkers. Blood-based tests to sequence cell-free circulating tumor DNA (ctDNA) are a less invasive approach. Both methods have high specificity and sensitivity and provide insights into actionable biomarkers; however, little is known about how these NGS tests compare when used for the same patient. This study assessed the concordance of paired ctDNA and solid tumor profiling in patients treated in our regional cancer center. Methods: We retrospectively reviewed ctDNA and matching tumor sequencing data test results from CLIA/CAP laboratories between June 2018, and October 2023. The average testing turnaround time was 12.9 days for solid tumor sequencing and 7.7 days for ctDNA testing. We analyzed genomic variants, gene fusions, and microsatellite status in these patient results. The NGS tests for ctDNA included 83 relevant genes which reported single nucleotide variants, small insertions and deletions, splice variants, and limited copy number alterations and gene fusions. The NGS tests for tumor testing were performed on Formalin-Fixed Paraffin Embedded tissue samples using either a 592 relevant gene panel or whole exome sequencing, and either an RNA-based targeted capture panel of 52 genes or RNA whole transcriptome sequencing. Concordance is defined as both ctDNA and tumor testing reporting the same alterations, whereas discordant reports are defined as each reporting different alterations that didn’t overlap between ctDNA and tumor sequencing. Results: A total of 186 patients had both ctDNA and solid tumor sequencing tests done. Cancer types included pancreatic cancer (n = 42), breast cancer (n = 29), lung cancer (n = 28), colorectal cancer (n = 14), and others (n = 73). We observed concordance between tests in 76 (41%) patients in identifying the same genomic alterations. In 103 (55%) patients, we found discordant genomic findings (in the remaining 7 (4%) patients, there were no alterations detected (ND)). Among 103 patients for whom we found discordant findings between the tests, 41 (40%) showed genomic alterations only from the ctDNA test, 46 (45%) had results only from solid tumor profiling, and 16 (15%) had abnormal gene findings from both solid tumor and ctDNA testing but the results did not overlap. Conclusions: Our retrospective analysis comparing sequencing of ctDNA and tumor tissue demonstrated about 40% concordance in genomic findings. Our study indicates that these tests may be complementary. If one accepts a degree of discordance, then testing of ctDNA may be used to identify actionable genomic alterations in the setting of inaccessible or inadequate tumor samples for sequencing.
Dual targeting of αv and α5β1 integrins in triple-negative breast cancer (TNBC).
Authors: Song Fei , Do Kevin , Fein Daniel E.C. , Jahanseir Narges , Joshi Raghav , Mathew Paul 
Published: June 2024

e15073 Background: Integrin αv has been implicated in a stem-phenotype of breast cancer (1) and is cross-regulated by fibronectin-binding integrin α5β1 in tumor cells (2). We hypothesized that these integrins are expressed in TNBC cells and dual targeting of αv and α5β1 integrins by a bispecific antibody (BsAbαv/α5β1) will be superior to monospecific integrin antibodies (MsAbs) alone or in combination. Methods: A representative panel of basal-subtype TNBC lines was assembled: MDA-MB-231 (P53 mutated, KRAS mutated), MDA-MB-468 (P53 mutated, PTEN deleted, EGFR amplified) and BT-20 (P53 and PIK3CA mutated, EGFR amplified). Integrin expression was determined by flow cytometry and Western blot in cell lines and by IHC in the residual cancer burden (RCB) of TNBC specimens following neoadjuvant chemotherapy (positive: >2+ membranous, >10% cells). The impact of MsAbs targeting αv and α5β1 integrins alone or in combination versus the BsAbαv/α5β1 was assessed in adhesion, migration, and clonogenic survival. The impact of integrin blockade on nuclear localization of basal markers including FAK, YAP, EGFR and beta-catenin, was assessed. Results: Robust integrin αv expression was present in all TNBC lines with variable α5β1 expression. Marked reduction in α5 and in αv expression following BsAbαv/α5β1 was uniquely demonstrated by Western blot and/or flow cytometry compared to MsAbs, likely due to endosomal trafficking and lysosomal degradation of target integrins as reported previously (Joshi, MCR. 2020). Combined α5 and αv neutralization with MsAbs was superior to individual single agents in blocking adhesion and migration across all TNBC lines studied. However, the BsAbα5β1/αv was superior to combinatorial MsAbs in MDA-MB-468 and BT-20 lines in chemotaxis assays. A significant (>50%) reduction in clonogenic cell survival was noted with the BsAbα5β1/αv compared to MsAbs. BsAbαv/α5β1 blocked nuclear localization of FAK, EGFR, activated beta-catenin, and YAP in MDA-MB-231 uniquely compared to MsAbs alone or in combination. RCB tumor cells were strongly positive for membranous αv [7/9, (78%)]. Diffuse expression of integrin α5 (67%) in alpha smooth-muscle actin-expressing fibroblasts with dual staining for integrin αv was found. Marked CD68+ macrophage and CD3+ infiltration was seen in tumor and stroma of all RCB tumors. Conclusions: Combinatorial α5 and αv integrin targeting with BsAbα5/αvβ1 defines a novel therapeutic strategy with a distinct mechanism of action for further investigation in TNBC. Enrichment of integrins αv and α5 in the inflamed RCB of TNBC tumors and stroma respectively point to a potential role of these integrins in epithelial-stromal interactions and therapeutic resistance. 1. Desgrosellier, Dev Cell. 2014. 2. Joshi, MCR. 2020.
CancerHallmarks.com: A tool for the enrichment analysis of the cancer hallmarks.
Authors: Gyorffy Balazs , Menyhart Otilia , Kothalawala William , Santarpia Libero 
Published: June 2024

e15079 Background: The "Hallmarks of Cancer" concept is a useful framework for understanding the fundamental principles that are shared among different types of cancers. However, the lack of agreement on a specific set of genes for these hallmarks makes it difficult to compare and integrate data, leading to varying interpretations of the biological processes involved in cancer across different studies. In this study, we created a consensus set of cancer hallmark genes by combining data from multiple mapping resources and the scientific literature. Methods: We identified 6,763 candidate cancer hallmark genes associated with ten cancer hallmarks by consolidating information from seven studies. There was a considerable variation in the number of genes within the available resources, ranging between 91 and 7,779. We observed a sizable variation in the number of genes connected to each hallmark. The number of genes across cancer hallmarks ranges between 574 („enabling replicative immortality”) and 3,574 ("sustaining proliferative signaling"). The least number of genes are associated with the more recent hallmarks, published in 2011, and the hallmarks „enabling replicative immortality” and „sustaining angiogenesis”. We identified six genes linked to each of the ten cancer hallmarks: TP53, AKT1, MAP2K1, CTNNB1, HRAS, and PIK3CB. Results: As a practical utility of the hallmark concept, we analyzed the enrichment of cancer hallmarks by evaluating genes associated with overall survival. Only genes with a false discovery rate below 0.01, a hazard rate over 1, and a cutoff value over 100 were analyzed to ensure sufficient robustness of the gene sets. The hallmark "genome instability" was most prominent in liver (p=1.0E-05), lung (p=1.0E-05), and pancreatic cancers (p=0.00164). Renal cancer had higher “invasion and metastasis” (p=0.002). Both pancreatic cancer and lung adenocarcinomas were enriched for “resisting cell death” (p=0.00096 and p=0.037, respectively). Overall, while eight cancer types had no significant hallmark enrichment among druggable genes, pancreatic cancers had the most enriched hallmarks (5 out of 10), emphasizing the disease's complexity. These results highlight the usefulness of the hallmark concept as a valuable tool for organizing information, especially in establishing a direct link between genes and biological functions. Conclusions: We have created a unified list of genes linked to cancer hallmarks. We integrated the data into an easily accessible online tool (accessible at www.cancerhallmarks.com) that enables users to identify the most pertinent cancer-associated “candidate hallmark genes” in their own datasets.
A double-blind, randomized, two-arm, single-dose, parallel-group study in healthy participants to compare the pharmacokinetics, pharmacodynamics, and immunogenicity of FKS518 proposed biosimilar to denosumab with the originator (LUMIADE-1 study).
Authors: Sadek Jouliana , Dryja Anna , Szeles Peter , Buccarello Anna Lucia , Monnet Joelle 
Published: June 2024

e15097 Background: Denosumab is a RANKL inhibitor used in patients with bone metastases from solid tumors. FKS518 is a proposed biosimilar to denosumab originator product. Biosimilars offer similar efficacy, quality, safety, and favorable economic impact. Once the analytical and functional similarity of a biosimilar has been shown, a comparative human pharmacokinetics (PK) study is conducted to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference product. The present study assessed the PK equivalence of FKS518 to the originator product and provided data on the similarity of the pharmacodynamic, safety and immunogenicity profiles. Methods: A randomized, controlled, double-blind, parallel-group study in healthy volunteers was performed to compare denosumab biosimilar candidate FKS518 versus the originator product. Subjects received a single subcutaneous denosumab 60 mg injection and were followed up for 40 weeks. Primary endpoints PK parameters (Cmax, AUC0-last and AUC0-inf) were natural log transformed and analyzed using analysis of covariance methods; results were then transformed back to the original scale. Safety data were collected throughout the study and analyzed descriptively. Results: 213 male subjects 28-55 years of age, with a baseline BMI between 18.2 and 31.7 kg/m2, were randomized to the originator denosumab (n = 106) or FK518 (n = 107). Results of the primary PK analysis demonstrated bioequivalence between FKS518 and the originator denosumab product since the 90% confidence intervals (CIs) for the geometric least squares mean (LSM) ratios for the 3 primary PK parameters were completely included within the predefined 80.00% to 125.00% equivalence margin (point estimate [90%CI for the ratio]): Cmax: 104.79% [97.04%,113.15%], AUC0-last: 112.29% [104.17%,121.04%] and AUC0-inf : 112.65% [104.27%,121.70%]. Secondary PK parameters were similar as well between FKS518 and the originator: tmax (median: 217.45 hrs. vs. 216.03 hrs. respectively), t1/2 (median: 235 hrs. vs 337 hrs. respectively). The nature, frequency, severity, or resolution of adverse events were comparable across treatments. For immunogenicity, there was no difference between the 2 treatment groups in ADA and Nab incidence at each timepoint. Conclusions: PK equivalence of FKS518 and denosumab originator product was demonstrated with similar PD, safety and immunogenicity profile for the two products. This study adds to the totality of evidence supporting FKS518 as a proposed biosimilar to denosumab.
Efficacy and safety of second-line treatment with surufatinib for anlotinib-resistant radioiodine-refractory differentiated thyroid cancer: An exploratory multicenter study.
Authors: Wang Yang , Qiu Zhongling , Wang Xufu , Han Na , Li Jiao , Zhai Hongyan , Zhou Zhenhu , Gao Rui , Ji Ting , Chen Libo 
Published: June 2024

e15127 Background: Radioiodine-refractory differentiated thyroid cancer (RR-DTC) resistant to first-line targeted therapy typically exhibits rapidly progressive nature, lacking standard treatment options. This study aimed to assess the efficacy and safety of surufatinib, targeting vascular endothelial growth factor receptor 1/2/3, fibroblast growth factor receptor 1, and colony-stimulating factor-1 receptor, in RR-DTC patients who had failed anlotinib treatment. Methods: This multicenter study enrolled patients aged ≥ 18 years with at least one measurable RR-DTC lesion (RECIST 1.1), who had previously received anlotinib treatment and experienced disease progression. Primary endpoint was progression-free survival (PFS); secondary endpoints were disease control rate and safety. Results: As of December 25, 2023, 9 patients were enrolled. Median age, 56 (range, 29-69) years; Male, 88.9%; ECOG PS 0, 88.9%; papillary carcinoma/follicular carcinoma, 77.8%/22.2%. Lung (77.8%) and bone (33.3%) were the most frequently involved organs. The duration of anlotinib treatment ≤ 12 months was found in 44.4% patients. All the 9 patients underwent at least one efficacy evaluation with a median PFS of 6.3 months and disease control rate of 88.9%. Subsequent analysis revealed that median PFS extended to 9.20 months in patients younger than 56 years, compared to 5.95 months in older individuals. Patients with over 12 months of prior anlotinib treatment exhibited mPFS of 9.20 months, versus 6.25 months in those with shorter prior treatment durations. Common treatment-emergent adverse events observed were hypertension (44.4%), proteinuria (22.2%), decreased platelets (22.2%), fatigue (11.1%), and hemoptysis (11.1%). Grade 3 adverse events included proteinuria (11.1%), fatigue (11.1%), and hemoptysis (11.1%). Conclusions: In patients with anlotinib-resistant RR-DTC, second-line surufatinib treatment yielded promising efficacy and tolerable toxicity, warranting randomized controlled studies on RR-DTC refractory to first-line targeted therapy. Clinical trial information: ChiCTR2100052020 .
Single-cell and bulk sequencing analysis to evaluate the oncogenic role of PDE3A in pan-cancer and validation in breast cancer.
Authors: Pu Shengyu , Chen Bohong , Zhang Huimin , He Jianjun , Hao Na 
Published: June 2024

e15128 Background: PDE3A is involved in critical physiological processes through the hydrolysis of cycle AMP (cAMP) and GMP (cGMP). Its role in the occurrence and progression of cancer has recently attracted attention, but carcinogenic mechanism in pan-cancer has not been fully elucidated. Methods: We explored the expression, prognostic and diagnostic value, mutation, methylation, immune infiltration, and signaling pathway enrichment analysis of PDE3A in pan-cancer by combining multiple bioinformatics databases and single-cell sequencing analysis. Furthermore, we verified the protein and mRNA expression levels of PDE3A and investigated its oncogenic role in the progression of breast cancer (BRCA). Results: PDE3A was expressed at lower levels than normal tissues in most cancers and showed a wonderful prognostic value. PDE3A was strongly correlated with immune cells, especially cancer-associated fibroblast (CAF), and was involved in various vital signaling pathways. Furthermore, PDE3A could facilitate BRCA progression by promoting cells invasion and migration, and it may be associated with the efficacy of endocrine therapy in ER+ BRCA. Conclusions: We provided new insights into the carcinogenic effect of PDE3A in pan-cancer. PDE3A may be a potential biomarker for cancer diagnosis and prognosis, and it is also a promising target for cancer immunotherapy.
The Gundersen Precision Oncology Cohort: A biospecimen resource for mutation characterization and target discovery.
Authors: Kenny Paraic , Feiszt Peter 
Published: June 2024

e15184 Background: The generation and widespread sharing of large somatic mutation datasets has revolutionized our understanding of genetic mechanisms driving cancer initiation and progression. For well-understood mutations, this has created the opportunity for individualized therapeutic intervention in a wide range of malignancies. Beyond these well-characterized mutations, there exists a wide range of alterations that remain poorly understood and which require some kind of functional genomics analysis to determine whether such patients are eligible for the targeted therapy used for more typical mutations in that gene, whether these alterations are passenger mutations that don’t affect throughput on the associated signaling pathway, or reflect another more nuanced phenomenon. Whether using ectopic overexpression in cell lines or generation of genetically modified mice, addressing this problem at scale using functional genomics approaches is challenging. A key limitation is the absence of the original tissue context in which that variant co-evolved with other genetic alterations as well as data on the clinical response of the patient to successive lines of therapy. This can be addressed, in part, by the banking of tissue from patient cohorts who have had comprehensive genomic profiling as part of their routine clinical care. For this purpose, we have established the Gundersen Precision Oncology Cohort. Methods: The Gundersen Precision Oncology Cohort is a retrospective collection of tissue specimens, NGS reports and associated clinical data from deceased patients who received cancer care at the Gundersen Health System. The cohort is updated twice per year and banked tissue specimens are available for collaborative research studies. Results: At November 20, 2023 there were data from 780 patients in the cohort, with specimens tested between 2015 and 2023. 54 tumor types were represented, of which lung (n = 196), colorectal (n = 79), pancreas (n = 65), esophageal (n = 58) and breast (n = 46) were most common. The most common diagnostic companies were STRATA Oncology (n = 463) and Tempus (n = 248). Most patients had testing at a single timepoint, but longitudinal testing is available for 13 patients. We present data from some of the studied subgroups, including atypical point mutations in BRAF as well as fusions affecting BRAF and ROS1. Conclusions: This cohort, available for collaborative studies via the Gundersen Cancer Biobank, illustrates the value of banking well-annotated biospecimens to address outstanding questions in oncology.