bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5327: KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo
Authors: Ge Chuansheng , Zhang Lei , Liao Baisong 
Published: September 2020

Abstract
Prostate cancer is the common cancer in men and the second leading cause of cancer-related deaths in men. This disease depends on dihydrotestosterone (DHT) which activates the androgen receptor (AR) signal. Endocrine therapy (including castration surgery, anti-androgen deprivation therapy or combined androgen blockade therapy) is a preferred treatment for prostate cancer. The treatment is very effective for the majority of patients at the initial stage, but after a median period of treatment for 14 to 30 months, most patients will gradually develop metastatic castration resistant prostate cancer (mCRPC) with a median survival of less than 20 months, and urgently need a further treatment. Androgen receptor antagonists in combination with anti-androgen drugs are currently the most effective drug treatment to manage mCRPC where castration has failed. Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide belong to this class of androgen receptor or androgen synthesis inhibitors. Here we show that KPG-121, a small molecule immunomodulator, significantly enhances the therapeutic effects of Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide in pre-clinical mCRPC tumor models. The phase 1 trials were initiated to evaluate the safety, PK profile and preliminary efficacy of the combinatorial therapy in the patients with metastatic castration resistant prostate cancer in the US (IND 134979). KPG-121 is a novel generation of Lenalidomide analogue. KPG-121 is structurally similar to lenalidomide but with stronger binding with CRBN target, enhanced immunomodulatory activity, better anti-proliferative and anti-angiogenic properties compared to lenalidomide. Results from in vivo metastatic castration resistant prostate cancer xenograft models demonstrated that KPG-121 at tested daily dose levels ranging from 1.0 mg/kg to 10 mg/kg in combination with Enzalutamide, Abiraterone Acetate, Apalutamide or Darolutamide significantly improved anti-tumor efficacy compared to the AR signaling inhibitors alone. In addition, KPG-121 showed favorable DMPK profiles and potentially manageable toxicity in pre-clinical IND enabling study.
Citation Format: Chuansheng Ge, Lei Zhang, Baisong Liao. KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5327.
Abstract 5345: Heterogeneous tumor PSMA expression represents a resistance mechanism to PSMA-targeted radioligand therapy
Authors: Lueckerath Katharina , Current Kyle , Meyer Catherine , Magyar Clara , Mona Christine E. , Almajano Joel , Slavik Roger , Stuparu Andreea D. , Cheng Chloe , Dawson David , Radu Caius , Czernin Johannes 
Published: September 2020

Abstract
Radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-targeting ligands is effective in ~50% of patients with advanced prostate cancer (PC). Causes for RLT failure are not well understood. The prevalent PSMA heterogeneity in PC might contribute to RLT failure. Here we investigate the relationship between RLT efficacy and PSMA levels per cell, and PSMA heterogeneity. PC cells expressing different levels of PSMA (RM1-PSMA low, medium, high, or RM1-YFP that do not express PSMA), or a mix of PSMA− and PSMA+ cells (RM1-YFP/ RM1-PSMA-high; PC3/ PC3-PIP) at various ratios were subcutaneously injected into NSG mice. Mice were treated with 177Lu- or 225Ac-PSMA617 (RLT) and tumor growth was monitored. In a subset of mice, radioligand uptake (γ-counting), DNA damage and PSMA expression (anti-53BP1 and -PSMA immunohistochemistry, respectively) were quantified in tumors resected 2 days after RLT. Increasing PSMA levels and fractions of PSMA+ cells improved RLT efficacy in both, the RM1 and PC3 model. PSMA expression correlated with radioligand uptake into the tumor and the degree of DNA damage and. Treatment with 225Ac-PSMA617 (vs. 177Lu-PSMA617) improved RLT outcomes and tended to enhance the differences in therapeutic efficacy between experimental groups. Taken together, we demonstrate in mouse models of PC that optimal anti-tumor efficacy of RLT hinges on homogenously high target expression. Although PSMA-RLT is effective even in tumors with low PSMA levels or with a small number of PSMA+ cells, low or heterogeneous PSMA expression might result in undertreatment and selection of treatment resistant clones. Systematic assessment of intra- and inter-lesion PSMA heterogeneity is currently not feasible clinically; however, this issue might be addressed by individual patient dosimetry to optimize safely delivered maximal tumor doses. Clinical studies designed to determine intra- and inter-lesion PSMA heterogeneity and to optimize PSMA-RLT for each patient are highly warranted.
Citation Format: Katharina Lueckerath, Kyle Current, Catherine Meyer, Clara Magyar, Christine E. Mona, Joel Almajano, Roger Slavik, Andreea D. Stuparu, Chloe Cheng, David Dawson, Caius Radu, Johannes Czernin. Heterogeneous tumor PSMA expression represents a resistance mechanism to PSMA-targeted radioligand therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5345.
Abstract 5367: Identification and clinical value of the circulating tumor cells (CTCs) in the colorectal cancer
Authors: Hamid Faysal-Bin , Islam Farhad , Lu Cu-Tai , Matos Marco , Cheng Tracie , Gopalan Vinod , Lam Alfred King-yin 
Published: September 2020

Abstract
The number of circulating tumor cells (CTCs) hase been found as a promising predictive and diagnostic biomarker of colorectal cancer (CRC). The purpose of the study was to enumerate and characterize CTCs from the CRC patients and evaluate the correlation with the clinical stages.Peripheral blood from 57 CRC patients and 6 healthy donors were subjected to isolate CTC by a negative selection (EasySepTM) method. The CTCs were detected by the immunofluorescence staining with the tumor cell markers such as epithelial cell adhesion molecule (EPCAM) and cytokeratin (CK) antibodies and counted them. The extent of positive expressions of EPCAM and cytokeratin (CK) proteins were used to characterize the CTCs and the subpopulations were correlated with the tumor stages of the CRC patients. P&lt;0.05 was considered as statistically significant.CTCs were detected in 72% (41/57) of the CRC patients. Comparing to the healthy donors (HD), the CTC count was higher (p=0.0062) in the CRC patients. In addition, CTC clusters were found in 32% (18/57) of patients with CRC while total CTCs were significantly higher than the cluster count (p=0.001). Among the CRC patients, CTCs were more abundant in the advanced stages compared to the early stages (p=0.0019). Moreover, we found the length of the individual CTCs were significantly larger than the CTCs in the cluster (p&lt;0.0001) and significantly correlated (p=0.036) with the tumor stages. However, we identified the EPCAMPosCkPos subclones in 38 (93%) out of 41 CTC positive cases and a median of 8.0 (range: 0-60) CTCs were counted. In contrast, EPCAMPosCkNeg subpopulations were detected in 27 (66%) patients and the median CTC count was 2.0 (range: 0-18). Interestingly, EPCAMPosCkPos CTC subclones were significantly higher (p=0.011) than EPCAMPosCkNeg subclones, and the number of EPCAMPosCkPos CTCs was merely associated (p=0.0068) with the tumor stages. We conclude that the morphological and phenotypic features of the CTCs are closely relevant to the clinical stages, which could provide vital information to improve the patient stratification and treatment selection.
Citation Format: Faysal-Bin Hamid, Farhad Islam, Cu-Tai Lu, Marco Matos, Tracie Cheng, Vinod Gopalan, Alfred King-yin Lam. Identification and clinical value of the circulating tumor cells (CTCs) in the colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5367.
Abstract 5403: Targeting death-receptors in therapy resistant progressive neuroblastoma: A preliminary insight
Authors: Somasundaram Dinesh Babu , Maher Andrew , Aravindan Sheeja , Herman Terence S. , Aravindan Natarajan 
Published: September 2020

Abstract
Neuroblastoma is the most common cancer in infants and accounts for 9.1% of childhood cancer-related deaths. Despite the current standard of care (SOC), drug-resistant neuroblastoma significantly compromises patient survival. Hence it is critical to identify new and less toxic therapeutic approaches for better patient outcomes. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which mediates its effect through the activation of the death receptor (DR) 4 and 5 are found on many cell types and are the main pathway for apoptosis. These can death receptors can kill most tumor cell types expressing TRAIL-receptor 1. Mining RNA-Seq data across multiple cohorts of neuroblastoma patients indicated that high levels of DR4 and DR5 significantly associated with poor clinical outcomes (OS, EFS, RFS). Further, examining the surface expression of DR4 and DR5 by immunohistochemistry using anti-human rabbit monoclonal antibodies on custom-archived TMAs for 100 NB patients revealed profound correlation with poor OS and RFS. Immunoblot analysis for DR4 and DR5 level in a panel of stage 4 patient-derived cell-lines during diagnosis and from progressive disease after therapy displayed high-levels of death receptor expression in progressive disease. Preliminary co-culture investigations with genetically engineered mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) mimicking targeted delivery showed heightened differentiation and death (limited dilution tumorosphere assay) of therapy resistant cells. Further these studies exhibited inhibition of tumor cell migration and invasion. The results demonstrate the benefit of targeted TRAIL delivery in in the treatment of therapy resistant neuroblastoma and further imply that the genetically engineered MSCs could serve as a clinically valuable tool for improved therapeutic strategy in this setting.
Citation Format: Dinesh Babu Somasundaram, Andrew Maher, Sheeja Aravindan, Terence S. Herman, Natarajan Aravindan. Targeting death-receptors in therapy resistant progressive neuroblastoma: A preliminary insight [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5403.
Abstract 5408: Chloroquine inhibits PARP expression in hepatoblastoma
Authors: Pihlajoki Marjut , Eloranta Katja , Kyrönlahti Antti , Heikinheimo Markku 
Published: September 2020

Abstract
Hepatoblastoma is the most common pediatric liver malignancy accounting 1 % of all pediatric malignancies. Despite advances in medical treatment and surgical techniques, the prognosis for advanced metastatic hepatoblastoma remains poor, underscoring the need for new therapeutic modalities. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types. In this study we examined the antineoplastic activity of CQ on HB cells. Established human HB cell line (HUH6) cells were cultured in presence of clinically acceptable concentrations of CQ. Morphology, viability, and apoptosis were assessed after 48 h and 96 h of CQ treatment showing decreased cell survival and increased caspase 3/7 activity representing induction of apoptosis. Metabolomic profiling of CQ treated HUH6 cells demonstrated significant decrease in NAD+ and aspartate concentration. Furthermore, RT-qPCR based Death Pathway Finder array was conducted to elucidate the molecular mechanisms underlying the CQ effect showing downregulated expression of PARP1 and PARP2. Quantitative western blotting was performed to validate differentially expressed genes at the protein level. Taken together, CQ treatment inhibits cell survival in HB cells in vitro, presumably by disturbing NAD+/NADH balance, impairing aspartate biosynthesis, and reducing PARP expression. CQ thus holds potential as a new treatment modality in HB management.
Citation Format: Marjut Pihlajoki, Katja Eloranta, Antti Kyrönlahti, Markku Heikinheimo. Chloroquine inhibits PARP expression in hepatoblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5408.
Abstract 5469: iCVA- A knowledge-based cancer variation annotation application
Authors: Kumar Gaurav , Kelly Melanie , Fortina Paolo , Ertel Adam 
Published: September 2020

Abstract
A typical genomic sequencing experiment results in a long list of statistically significant variant candidates among protein-coding genes without any unifying biological theme. This leads to a daunting task of identifying the causal variants and genes to accurately diagnose the disease for clinical or research utility. While a number of downstream tools exist to aid in cancer genome annotation and interpretation, including Clinical Interpretations of Variants in Cancer (CIViC), ClinGen, Database of Curated Mutations (DoCM), Oncotator, and Variant Interpretation for Cancer (VIC), these only provide selective information (somatic/germline/gene-variant specific) or are time/resource consuming. To address this challenge, we developed a software called iCVA using the following methodology: 1) we obtained a priori defined gene sets for different cancer-inducing mechanisms such as pro-oncogenesis, tumor-suppression, DNA repair, angiogenesis, inflammation, metabolism, hypoxia, cell cycle and immune system. 2) genomic variation data were integrated from 1000 Genome, Exome Sequencing Project, Exome Aggregation Consortium (ExAC), ClinVar, dbSNP, GNOMAD, The Cancer Genome Atlas (TCGA), the Catalogue of Somatic Mutations in Cancer (COSMIC) and the International Cancer Gene Census (ICGC), and re-classified into a consensus classification according to ACMG guidelines. 3) Finally, we devised a reporting system to process mutation data from a sequencing experiment to utilize the harmonized pathway and mutational information integrated in a local database to identify and classify cancer-specific gene mutations. The iCVA reporting system classifies mutations as germline or somatic and then sub-classifies these into different cancer-specific mechanisms, including those known to be targetable through existing therapies. To our knowledge, iCVA is the first tool to provide a comprehensive report on cancer variants in a simplified and faster manner, to accelerate the genomic characterization of cancer samples analyzed by high-throughput DNA sequencing.
Citation Format: Gaurav Kumar, Melanie Kelly, Paolo Fortina, Adam Ertel. iCVA- A knowledge-based cancer variation annotation application [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5469.
Abstract 5518: Tumor infiltrating B cells and tertiary lymphoid structures are associated with tumor response to PD-L1 blockade in NSCLC
Authors: Patil Namrata S. 
Published: September 2020

Abstract
Inhibitors of the programmed cell death-1/programmed cell death ligand1 (PD-1/PD-L1) signaling axis have demonstrated sustained efficacy in NSCLC, however there are gaps in our understanding of the mechanisms of how PD-1/ PD-L1 blockade improve patient outcomes, especially as they relate to long term survival. Differential gene expression analysis in tumors from NSCLC patients who derived &gt;12 months OS benefit on atezolizumab monotherapy showed high expression of B cell transcripts in the randomized phase II POPLAR and phase III OAK studies (&gt; median, HR: 0.61, 95% CI 0.47-0.78, and HR=0.54, CI 0.42-0.7, p&lt;0.001 respectively). Immunofluorescence imaging confirmed the presence of CD79+ B cells in these tumors. High expression of CD79A was associated with the presence of tertiary lymphoid structures (TLS) that in turn were associated with atezolizumab survival benefit. B cell receptor sequencing of patient biopsies pre and post atezolizumab treatment suggest clonal expansion of tumor infiltrating plasma cells in patients responsive to atezolizumab. Collectively, these results suggest that NSCLC tumor patients enriched for CD79A+ B cells and IgG+ plasma cells derive greater overall survival benefit from atezolizumab and emphasize the potential of these genes as actionable biomarkers in NSCLC.
Citation Format: Namrata S. Patil. Tumor infiltrating B cells and tertiary lymphoid structures are associated with tumor response to PD-L1 blockade in NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5518.
Abstract 5594: Inmune gene expression by nCounter in mucinous adenocarcinoma lung cancer
Authors: Lladó Ruth Román , Esteban Cristina Aguado , Giménez-Capitán Ana , Daisuke Ueda , Ito Masaoki , Tsutani Yasuhiro , Miyata Yoshihiro , Teixidó Cristina , Reguart Noemí , Okada Morihito , Rodríguez Sonia , Balada Ariadna , Aldeguer Erika , Ramirez Santiago Viteri , Cao Maria Gonzalez , Aguilar Andrés , Rosell Rafael , Vila Miguel Angel Molina 
Published: September 2020

Abstract
Introduction: Although immune checkpoint inhibitors have become a standard of care for multiple cancer types; currently used biomarkers, such as PD-L1 expression, MSI or TMB, fail to identify all responders. In addition, little is known about markers of response to immunotherapy in some infrequent histological subtypes, such as mucinous adenocarcinoma of the lung. Gene expression signatures incorporating not only PD-L1 but also other immune modulators can have a better predictive power, particularly in these histological subtypes.
Methods: A cohort of 165 baseline samples from with stage I-IV non-small cell lung cancer (NSCLC) patients was retrospectively analyzed, 55 stage I-IIIA mucinous adenocarcinomas (MA), 31 stage I-IIIA nonmucinous adenocarcinomas (NMA) and 79 stage IIIB-IV NMAs. RNA was extracted from FFPE tumor samples and the expression levels of a 7-gene immune signature (CD4, CD8A, FOXP3, GZMM, INFG, CD274 and PDCD1) were determined using a nCounter panel. Krustal-Wallis test was used for statistical comparisons.
Results: No significant differences were observed in the expression levels of FOXP3 and PDCD1 (codifying forkhead box P3 and PD-1) between the three groups analyzed. In contrast, GZMM, IFNG and CD4 expression (codifying granzyme M, interferon gamma and CD4) was significantly higher in early stage MA compared to stage I-IIIA or stage IIIB-IV NMA. CD8A expression was significantly higher in early stage tumors, independently of the presence of mucinous component. In addition, the levels of CD274 mRNA (codifying PD-L1) were significantly higher in early stage MA compared to advanced stage NMA. Finally, among the stage I-IIIA MA, 27/55 (49%) were KRAS-mutant, but they did not show significant differences with KRAS-wt MAs in the expression of any of the genes tested.
Conclusions: Mucinous adenocarcinoma of the lung shows a different pattern of expression of immune-related genes, which may influence response to immunotherapy.
Citation Format: Ruth Román Lladó, Cristina Aguado Esteban, Ana Giménez-Capitán, Ueda Daisuke, Masaoki Ito, Yasuhiro Tsutani, Yoshihiro Miyata, Cristina Teixidó, Noemí Reguart, Morihito Okada, Sonia Rodríguez, Ariadna Balada, Erika Aldeguer, Santiago Viteri Ramirez, Maria Gonzalez Cao, Andrés Aguilar, Rafael Rosell, Miguel Angel Molina Vila. Inmune gene expression by nCounter in mucinous adenocarcinoma lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5594.
Abstract 564: Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various FGFR-deregulated cancer cell lines and xenograft models
Authors: Sootome Hiroshi , Miura Akihiro , Komori Toshiharu , Hirai Hiroshi 
Published: September 2020

Abstract
Introduction: Futibatinib, a selective, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, has antitumor activity in FGFR-deregulated cancer models. The potential synergistic antitumor effects of targeted therapy plus chemotherapy (chemo) was evaluated by combining futibatinib with cytotoxic agents in in vitro and in vivo models.
Methods: Gastric, breast, lung, endometrial, and bladder cancer cell lines with various FGFR aberrations were treated with futibatinib and cytotoxic agents (5-FU, paclitaxel, cisplatin, or gemcitabine) individually or in combination. In vitro cytotoxicity of futibatinib was assessed by PARP cleavage activity. Any combination effect on cell growth was determined by the Bliss independence method, combination index (CI; CalcuSyn software), or isobologram analysis. The antitumor effects of futibatinib plus S-1 or paclitaxel and futibatinib plus gemcitabine or cisplatin were evaluated in gastric FGFR2-amplified SNU-16 and endometrial FGFR2-N549K-mutated AN3CA mouse xenograft models, respectively, by measuring relative tumor volume (RTV).
Results: A synergistic effect on cell growth inhibition was observed with futibatinib plus chemo in SNU-16 cells (CIs at ED90 were 0.50 [5-FU], 0.71 [paclitaxel], 0.76 [cisplatin], and 0.29 [gemcitabine]). Increased PARP cleavage and decreased cell growth were observed in SNU-16 cells treated with futibatinib plus 5-FU vs monotherapy. Synergized cell growth inhibition occurred in various FGFR-deregulated cancer cell lines. In xenograft models, vs monotherapy, a significant reduction (P&lt;0.01) in RTV occurred with futibatinib plus S-1, paclitaxel (Table), or cisplatin and a numerically greater reduction with futibatinib plus gemcitabine.
Table.Relative tumor volume in SNU-16 mouse xenografts treated with futibatinib or paclitaxel or combination therapyTreatment (mg/kg/d)Relative tumor volumeDay 0Day 4Day 8Day 11Day 15Control11.562.373.344.58Futibatinib (5)a11.321.952.773.83Futibatinib (15)a11.211.822.453.16Paclitaxel (60)b10.480.410.410.59Futibatinib + paclitaxel (5 + 60)c10.470.270.170.14Futibatinib + paclitaxel (15 + 60)c10.440.220.120.07aDays 1-14 (oral).bDay 1 (intravenous).cDays 1-14 + Day 1.
Conclusions: Futibatinib showed a synergistic antitumor effect in vitro and in vivo when combined with various cytotoxic agents. These data are promising and warrant further investigation.
Citation Format: Hiroshi Sootome, Akihiro Miura, Toshiharu Komori, Hiroshi Hirai. Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various FGFR-deregulated cancer cell lines and xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 564.