bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 564: Targeting axonal guidance with anti-ROBO1 CAR T cells: A new therapeutic strategy for malignant brain cancer
Authors: Singh Sheila Kumari , Chokshi Chirayu R. , Brakel Benjamin , Rossotti Martin A. , Venugopal Chitra , Salim Sabra , Henry Kevin 
Published: June 2022

Abstract
No standardized treatment exists for patients with recurrent glioblastoma (GBM). Given the aggressive nature of the disease and difficulty in modeling tumor recurrence, minimal efforts have been made to design rational therapies against it. The roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment and is aberrantly upregulated in glioma where it mediates glioma cell migration. Here, we present that ROBO1 is highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs), prompting the development of an anti-ROBO1 CAR-T cell therapy. Using the binding region of a single-domain antibody targeting ROBO1, we developed second-generation anti-ROBO1 CAR-T cells specific and effective against ROBO1-expressing BTICs. Upon antigen exposure, anti-ROBO1 CAR-T cells upregulated markers of activation and degranulation. Additionally, treatment of orthotopic and patient-derived brain tumor xenograft models with anti-ROBO1 CAR-T cells resulted in reduced tumor burden and prolonged survival, demonstrating the therapy’s therapeutic potential for treating neoplastic brain malignancies.
Citation Format: Sheila Kumari Singh, Chirayu R. Chokshi, Benjamin Brakel, Martin A. Rossotti, Chitra Venugopal, Sabra Salim, Kevin Henry. Targeting axonal guidance with anti-ROBO1 CAR T cells: A new therapeutic strategy for malignant brain cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 564.
Abstract 5656: Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer
Authors: Neupane Rabin , Malla Saloni , Abou-Dahech Mariam Sami , Balaji Swapnaa , Kumari Shikha , Tang Yuan , Karthikeyan Chandrabose , Tiwari Amit K. 
Published: June 2022

Abstract
Patients with advanced or metastatic colorectal cancer (CRC) often have poor prognosis and survival. There are ongoing efforts to identify novel molecules to manage advanced and metastatic CRC. Modifications in the quinazoline ring has resulted in effective and clinically approved drugs such as gefitinib, erlotinib, vandetanib among others. We rationalized and synthesized a series of 4-anilinoquinazoline analogues, DW (1-10) and evaluated them for anticancer efficacy in human CRC cell lines (HCT116, HT29, SW620). We identified a lead molecule DW-8, with sub-micromolar potency against CRC lines with selectivity index of DW-8 being &gt;2 folds in CRC cells compared to non-cancerous line, CRL1459. Mechanistically, DW-8 produced significant morphological changes in SW620 cells. This included nuclear condensation, cell shrinkage, blebbing and apoptotic bodies formation which are the hallmarks of apoptosis. We found that the DW-8 induced apoptosis by i) producing cell cycle arrest at G2 phase; ii) activated intrinsic apoptosis as shown by cleaved caspases such as caspase-9, the executioner caspases 3 and 7; iii) produced nuclear fragmentation; and iv) increased the level of reactive oxygen species. We are now synthesizing the analogs of DW-8 and are optimizing the formulations for efficient delivery to CRC tumors in vivo. Overall, our result suggests DW-8 may represent a suitable lead for developing novel compound to treat CRC.
Citation Format: Rabin Neupane, Saloni Malla, Mariam Sami Abou-Dahech, Swapnaa Balaji, Shikha Kumari, Yuan Tang, Chandrabose Karthikeyan, Amit K. Tiwari. Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5656.
Abstract 567: CRISPR/Cas9-mediated CD39 disruption can be combined with TCR editing in T cells to improve the adoptive T cell therapy of colorectal cancer
Authors: Potenza Alessia , Balestrieri Chiara , Albarello Luca , Pedica Federica , Stasi Lorena , Manfredi Francesco , Spiga Martina , Tassi Elena , Cianciotti Beatrice Claudia , Abbati Danilo , Elmore Ugo , Biondi Andrea , Aldrighetti Luca , De Lalla Claudia , Lullo Giulia Di , Dellabona Paolo , Ruggiero Eliana , Rosati Riccardo , Bonini Chiara 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the 2nd cause of cancer-related death. Despite standard therapies, more than 50% of patients experience relapse, eventually with metastatic disease. The CRC microenvironment is densely infiltrated by T-cells, which presence correlates with improved overall survival, thus sustaining the rational for immunotherapy. Here, we paired high-dimensional flow cytometry, bulk RNA sequencing and immunohistochemistry to describe the phenotype and the exhaustion status of T-cells infiltrating primary and metastatic CRC. Analysis of the healthy, peritumoral and neoplastic tissues of treatment-naïve primary CRCs and of the peritumoral and tumoral tissues of CRC patients undergoing surgery for liver metastasis, revealed extensive transcriptional and spatial remodeling across tumors. Unsupervised analysis of flow cytometry data performed by an advanced pipeline of data handling by dimensionality reduction and clustering algorithms allowed the definition of a peculiar inhibitory receptors signature on TILs enriched both in primary CRCs and liver metastases. Of note, CD39 was upregulated in both the signatures retrieved from primary and metastatic CRC, thus suggesting its relevance as molecular target for T-cells engineering. By CRISPR/Cas9 we disrupted the CD39 gene in T cells with &gt;80% efficiency. We combined CD39 knock-out with the genetic disruption of alpha and beta chains of the endogenous TCR, observing &gt;90% efficiency for both genes, thus generating triple-knockout T-cells. By repetitively stimulating healthy donors’ peripheral blood mononuclear cells with autologous antigen-presenting cells loaded with a pool of peptides selected to be immunogenic and expressed by CRC, we obtained a library of anti-tumor TCRs to redirected the specificity of triple knock-out lymphocytes. Our preliminary experiments showed a functional advantage for TCR-redirected, CD39 disrupted T-cells in recognizing and killing CRC target cells.
Citation Format: Alessia Potenza, Chiara Balestrieri, Luca Albarello, Federica Pedica, Lorena Stasi, Francesco Manfredi, Martina Spiga, Elena Tassi, Beatrice Claudia Cianciotti, Danilo Abbati, Ugo Elmore, Andrea Biondi, Luca Aldrighetti, Claudia De Lalla, Giulia Di Lullo, Paolo Dellabona, Eliana Ruggiero, Riccardo Rosati, Chiara Bonini. CRISPR/Cas9-mediated CD39 disruption can be combined with TCR editing in T cells to improve the adoptive T cell therapy of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 567.
Abstract 571: Inclusion of a Dap10 costimulatory domain decreases cytokine release syndrome in chimeric antigen-expressing gamma delta T cells
Authors: Barber Amorette E. 
Published: June 2022

Abstract
Adoptive transfer of T cells is a promising anti-tumor therapy for many cancers. To enhance tumor recognition by T cells, chimeric antigen receptors (CAR) consisting of signaling domains fused to receptors that recognize tumor antigens can be expressed in T cells. While CAR T cells can successfully treat hematopoietic malignancies, CAR T cells have not shown success in treating solid tumors. There are many factors that may enhance CAR T cell efficacy and safety for solid tumor treatment, including addition of costimulatory domains to increase T cell functions and switching the T cell type used from alpha beta to gamma delta T cells. We developed a novel CAR (chimeric PD-1, chPD1) that targets the programmed death 1 receptor (PD-1) ligands expressed on many types of solid tumors. The aim of this study was to compare anti-tumor efficacy and safety of chPD1-expressing gamma delta and alpha beta T cells in murine breast and ovarian cancer models. Inclusion of different costimulatory domains, CD28, 4-1BB, and Dap-10, in the chPD1 receptor was also compared. There were no differences in T cell viability and proliferation when comparing costimulatory domains or T cell type. Additionally, there were no significant differences in killing of murine breast and ovarian cancer cell lines. ChPD1-CD28 T cells had increased secretion of proinflammatory and cytokine release syndrome (CRS)-inducing cytokines, including IFN-gamma, IL-2, IL-6, GM-CSF, and nitric oxide, compared to chPD1-41BB and chPD1-Dap10 receptors. Additionally, alpha beta chPD1 T cells had increased cytokine secretion of inflammatory cytokines compared to chPD1 gamma delta T cells. Furthermore, while gamma delta and alpha beta T cells expressing chPD1 receptors with a Dap10 domain had similar anti-tumor efficacy in vivo, chPD1-Dap10 gamma delta T cells had the lowest serum levels of inflammatory cytokines IFN-gamma, IL-6, and GM-CSF. Therefore, inclusion of Dap10 domains in gamma delta T cells may be a safer and more efficacious option for CAR T cell therapy of solid tumors.
Citation Format: Amorette E. Barber. Inclusion of a Dap10 costimulatory domain decreases cytokine release syndrome in chimeric antigen-expressing gamma delta T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 571.
Abstract 5722: Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration and invasion
Authors: Liu Huiyun , Heller-Trulli Daniel , Moore Claire 
Published: June 2022

Abstract
Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation, and abnormal poly(A) site choices have been associated with human diseases, including cancer. Recent work has identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, and higher level of CPSF73 correlates to poor survival in breast cancer patients. However, our understanding of the regulation of CPSF73 is still at an early stage. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D in both non-cancer cells and cancer cells leads to CPSF73 downregulation, a pre-mRNA cleavage defect and dysregulated gene expression. UBE3D dysfunction or chemical inactivation of CPFS73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down of CPSF73 inhibited stem cell renewal property. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.
This work was supported by the NSF grant NS0224 to C. Moore and the NIH grant R01 GM101010-01A1 to C. Moore.
Citation Format: Huiyun Liu, Daniel Heller-Trulli, Claire Moore. Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5722.
Abstract 5765: Genomic characterization of Chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers
Authors: Chen Xiaofeng , Pang Jiaohui , Liu Cuicui , Wang Sha , Shao Yang 
Published: June 2022

Abstract
Background: Biliary tract carcinoma (BTC) is a relatively rare cancer worldwide and accounts for 3% gastrointestinal cancers in China. BTCs are mainly classified as gallbladder cancer (GBC) and cholangiocarcinomas (CCA) with dismal prognosis. Genetic landscape of BTC can offer a comprehensive understanding of its carcinogenesis and clinical associations. The present study aims to compare the molecular features between BTC subtypes and explore clues for treatment therapies.
Methods: We analyzed 258 BTC tissue samples including 70 GBCs and 188 CCAs with targeted sequencing (NGS) using a 425 caner-relevant genes panel. We identified the somatic alterations and MSI status of all samples. TMB was counted by summing all base substitutions and indels in the coding region of targeted genes. TMB-high (TMB-H) was defined as mutation number ≥ 10mut/Mb.
Results: The most frequently mutated genes in 258 BTCs were TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%) and MCL1 (14.3%). Four gene mutations and 2 gene amplifications were significantly enriched in GBC compared to CCA (mutations P&lt;0.05, amplifications P&lt;0.01): TP53 (78.8% vs 47.9%), ARID2 (15.7% vs 3.7%), STK11 (12.9% vs 4.3%), TERT (24.3% vs 11.2%), CCNE1 and SOX2 amplifications (21.4% vs 2.7%, 4.3% vs 0%). However, ARID1A mutation (15.4% vs 5.7%), PBRM1 mutation (10.1% vs 0%), and MCL1 amplification (17.0% vs 5.7%) were more frequently existed in CAA (all P&lt;0.05). Seven actionable alterations, including IDH1/2 (5.4%), FGFR1-4 (4.7%), ERBB2 (6.2%), PIK3CA (5.4%), MET (3.5%), and BRCA1/2 (5.0%), were detected with different occurrence frequencies in two subtypes. ERBB2 was predominant in GBC (15.7% vs 7.4%, p&lt;0.001), while IDH1/2 and KRAS alteration rates were much higher in CCA (8% vs 0%, 31.4% vs 18.6%, both P&lt;0.05). FGFR3 alterations were also tended to be enriched in CCA (7.1% vs 2.7%), although no significant difference was found. In general, there were 25.7% of GBC patients harboring actionable alterations versus 29.3% of CCA patients. In addition, 40 (15.5%, 13 GBCs and 27 CCAs) and 11 (4.3%, 10 GBCs and 1 CCA) patients were TMB-H and MSI-H, respectively, suggesting the possibility of benefit from immunotherapy.
Conclusions: There were distinct molecular features in somatic variations and actionable alterations between GBSs and CCAs. In general, 44.3% of GBC and 46.3% CCA may benefit from targeted therapy and immunotherapy. This study could be helpful to establish treatment therapies for BTCs according to genetic information.
Citation Format: Xiaofeng Chen, Jiaohui Pang, Cuicui Liu, Sha Wang, Yang Shao. Genomic characterization of Chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5765.
Abstract 5777: Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients
Authors: Shen Jingnan , Li Xiaomo , Xie Xianbiao , Liu Si , Ma Tonghui 
Published: June 2022

Abstract
Background: Sarcomas represent a rare and heterogeneous group of soft tissue and bone cancers, including more than 100 histological subtypes. Although genomic profiling has identified oncogenic fusion genes as the major molecular drivers of many sarcoma subtypes, direct targeting of these fusion genes is clinically challenging and novel treatment approaches are needed.
Methods: To explore new therapeutic targets in sarcoma, we performed germline testing of 148-cancer predisposition genes (OncoPanscan࣪, Genetronhealth) on genomic DNA from a cohort of 822 unselected Chinese sarcoma patients.
Results: The median age of this cohort was 45 (1-88) years, and 84% were soft tissue sarcoma (STS), 16% were osteosarcoma. 9.3% (n =82) of patients harbored at least one predicted pathogenic germline variant in 37 cancer disposition genes including APC, BRCA1, BRCA2, CDKN2A, CHEK2, DICER1, MSH6, PMS2, SBDS, SMARCA4, and TP53. Twenty-four (2.9%) patients had a variant that mapped to a known sarcoma-associated cancer predisposition syndrome gene (CHEK2, DICER1, NF1, RECQL4, SMARCA4, TP53, WRN). The most frequently mutated genes are involved in the DNA damage repair pathway, with a prevalence of 6.3% (n =52). Twelve patients carried pathogenic mutations in TP53, which was associated with cancer-predisposing Li-Fraumeni syndrome (LFS). Interestingly, we also observed 12 patients harboring the same SBDS c.258+2T&gt;C variant. Biallelic SBDS mutations were linked to Shwachman-Diamond Syndrome (SDS) associated with leukemia predisposition. Additionally, four patients carried pathogenic mutations in SMARCA4 (n =2) and SMARCE1 (n =2), two genes encoding key components of the BAF chromatin-remodeling complex. Patients with pathogenic SMARCA4 germline variants could participate in clinical trials of EZH2 inhibitor tazemetostat. Four patients harbored pathogenic germline variants in core homologous recombination genes (BRCA1/2 and PALB2), which may be targeted with platinum-based chemotherapy or PARP inhibitor olaparib.
Conclusions: In summary, our genomic profiling approach revealed novel predisposition variants associated with sarcoma, and some of them can serve as therapeutic targets for future clinical investigation. Our work provided proof of principle that sarcoma patients may benefit from genetic counseling and participate in genomically-matched clinical trials.
Citation Format: Jingnan Shen, Xiaomo Li, Xianbiao Xie, Si Liu, Tonghui Ma. Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5777.
Abstract 5778: Early age of onset of double germline DDR-mutated gastric cancer
Authors: Qu Yurong , Shi Min , Liang Yiming , Zhu Bowen 
Published: June 2022

Abstract
Background: Gastric cancer (GC) is one of the leading causes of cancer death in China. Approximately 10% of GC cases are associated with strong familial clustering and can be attributed to genetic predisposition. However, GC is biologically and genetically highly heterogeneous, the underlying genetic cause is complicated. DNA damage repair (DDR) genes play key roles in maintaining human genomic stability. Loss of DDR function, conversely, is an important determinant of cancer risk, progression, and therapeutic response.Our aim was to analyze the germline mutational pattern of DDR-mutated Chinese GC cohort and find possible genetic factors related to the early onset of gastric cancer.
Methods: In this analysis we defined a “core DDR” gene set with 10 homologous recombination deficiency-HRD gene (BRCA1, BRCA2, ATM, PALB2, BRIP1, CDK12,CHEK1, CHEK2,FANCA and FANCL) and 4 mismatch repair-MMR gene (MLH1,MSH2,PMS2 and PMS6). The panel of 14 core DDR genes was used to analyze the germline mutation profiling of DDR-mutated GC cohort which is consisted of 144 Chinese patients with at least one germline “core DDR” gene likely pathogenic/pathogenic (LP/P) mutations. LP/P mutations were called according to the classification criteria of the American College of Medical Genetics and Genomics.
Results: The DDR-mutated GC cohort was consist with 144 patients with at least one “core DDR” gene germline mutations, and the median age of this cohort was 63 years. In this cohort, eighty-three of 144 patients carried only one HRD gene P/LP mutations (median age at onset:63), forty-two patients of 144 patients carried only one MMR gene P/LP mutation (median age at onset:65.5). Nineteen of 144 (13.2%) patients had two “core DDR” germline mutation, and the median age of these patients with double germline mutations was 49. The double DDR-mutated GC had a significantly younger median age of onset than one HRD-mutated GC (log-rank test, P =0.00746) as well as one MMR-mutated GC (log-rank test, P =0.00849). Three of the double DDR-mutated patients had family histories of gastrointestinal cancer.
Conclusion: Our data suggests that GC patients harboring any two germline mutations in the “core DDR” gene may have an earlier age of onset.
Citation Format: Yurong Qu, Min Shi, Yiming Liang, Bowen Zhu. Early age of onset of double germline DDR-mutated gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5778.
Abstract 5781: Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients
Authors: Li Li , He Kewen , Pang Jiaohui , Xu Yang , Shao Yang , Yuan Shuanghu , Yu Jinming 
Published: June 2022

Abstract
Background: The high recurrence rate of stage pIIIA-N2 NSCLC patients may reflect inadequate removal of all residual tumor cells despite conventional histologic negative surgery margin. The NGS-detected BRM status was possible to serve as a more accurate examination to identify those patients with a high-risk of postoperative recurrence.
Methods: We retrospectively studied 119 stage IIIA-N2 NSCLC patients who received curative-intent surgery plus adjuvant chemotherapy/chemoradiotherapy, and all of the patients were classified with negative resection margin by the conventional histologic method. Each patient had paired tumor and bronchial resection margin (BRM) samples, which were analyzed using next-generation sequencing (NGS) of 474 cancer-related genes, and we explored the prognostic values of various clinical and molecular features.
Results: Among the 119 stage IIIA-N2 NSCLC patients with histologic negative resection margins, the BRM samples from 56 patients (47.1%) were positive for tumor mutations, including multiple lung cancer driver mutations. The number and the variant allele frequency of genetic alterations in BRM samples were generally lower than that of the paired tumor samples. Notably, patients who were positive for NGS-detected BRM mutations had significantly shorter disease-free survival (DFS) than the negative patients (p=0.001, HR 2.18, 95%CI 1.37~3.47). Several other clinical/molecular features were also found to be significantly associated with DFS, including the metastatic lymph node ratio (MLNR), smoking history, and KRAS mutation status, and NGS-assessed BRM status remained to be statistically significant in multivariable analysis by including all of these prognostic factors (p =0.020, HR 1.82, 95%CI 1.10~3.02).
Conclusions: We demonstrated that the molecular positive margin of surgical resections was a strong and independent biomarker for disease recurrence in pIIIA-N2 NSCLC patients. Our results emphasized the clinical utility of molecular diagnostic approaches to detect minimal residual disease after surgical resection, which could potentially facilitate the stratification of high-risk patients for personalized and appropriate treatments.
Citation Format: Li Li, Kewen He, Jiaohui Pang, Yang Xu, Yang Shao, Shuanghu Yuan, Jinming Yu. Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5781.