bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 689: Anti-tumor activity of Bifidobacterium secreting dual specific T cell redirecting antibody against EGFR/HER3-expressing cancer
Authors: Kobayashi Satoshi , Shioya Koichiro , Seki Yuji , Matsumura Tomio , Kanari Yasuyoshi , Shimatani Yuko , Nakazawa Hikaru , Umetsu Mitsuo , Kataoka Shiro , Nakamura Takaaki 
Published: September 2020

Abstract
Anti-cancer therapies targeting EGFR family, including monoclonal antibodies and kinase inhibitors, are the state of art for solid tumors such as colorectal and non-small cell lung cancers. T cell redirecting bispecific antibodies are a promising approach for cancer immune therapy, whereas their application is limited to hematological malignancy due to adverse events caused by the systemic exposure to highly immunologically active molecule.
To avoid the immunological adverse events, we have created a recombinant Bifidobacterium (APS002) that specifically colonizes in solid tumor and continuously secretes T cell redirecting antibody. The antibody was designed to form a diabody based on the sequence of dual specific antibody for EGFR/HER3 and CD3.
The diabody (termed DBERB1) comprises the equal amount of two polypeptides, anti-h CD3 (VL) - anti-EGFR/hHER3 (VH) and anti-hEGFR/hHER3 (VL) - anti-hCD3 (VH), respectively. DBERB1 bound to human EGFR and HER3, and human CD3. DBERB1 demonstrated potent cytotoxic activities against EGFR- and HER3-expressing human colon cancer HCT116 cells in the presence of human peripheral blood mononuclear cells (hPBMC) with EC50 values of 3 - 9 × 10−12 M. When APS002 was i.v. dosed to HCT116 tumor-bearing SCID mice inoculated with hPBMC, APS002 colonized only in the tumor and DBERB1 was detected in the tumors but not in the plasma. The growth of HCT116 tumors was significantly suppressed by APS002 but not by Bifidobacterium transfected with control vector.
In conclusion, our study in the mouse model indicates that APS002 is a novel and an extremely potent anti-cancer agent distributed only in the tumor. We are currently preparing for pre-clinical studies for the future clinical trials.
Citation Format: Satoshi Kobayashi, Koichiro Shioya, Yuji Seki, Tomio Matsumura, Yasuyoshi Kanari, Yuko Shimatani, Hikaru Nakazawa, Mitsuo Umetsu, Shiro Kataoka, Takaaki Nakamura. Anti-tumor activity of Bifidobacterium secreting dual specific T cell redirecting antibody against EGFR/HER3-expressing 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 689.
Abstract 701: Immunogenicity risk assessment and mitigation tools
Authors: Osmani Amin , Pattijn Sofie , Schockaert Jana , Mazy Aurélie , Ackaert Chloé 
Published: September 2020

Abstract
New immuno-oncology mAbs or agents with other structures have revolutionized treatment options for several malignancies in the past few years, and more are currently being evaluated in the clinic. The development of new therapeutics comes with a series of challenges and questions, of which one is the risk for unwanted immunogenicity which can lead to decreased efficacy and safety concerns. Today, both in silico and in vitro preclinical tools are available to identify early on therapeutic candidates with a high immunogenicity risk potential. Additionally, certain tools can be used to mitigate the immunogenicity potential, and thus improve and accelerate therapeutic drug development and reduce the number of clinical failures. Often used as a first step is an in silico T cell epitope prediction algorithm such as NetMHCIIpan which can be used to assess and compare the immunogenic potential of the lead candidates and guide de-immunization strategies. Further monitoring of the immunogenic risk can be performed using different in vitro assays: a peptide screen assay, to enable the exclusion of immunogenic peptides and the inclusion of low risk sequences; a dendritic cell activation assay to assess immunogenicity signals for the whole product; the MAPPs or MHC Associated Peptide Proteomics, assay to follow uptake, processing and presenting of biotherapeutics by dendritic cells and identify specific regions of concern, and; in vitro T cell proliferation and activation assays to determine and rank the immunogenic risk of the test proteins. The compilation of the different datasets and translation of the results into a comprehensive risk management plan, allows selection of the best candidates to move forward into humans, deimmunization of test candidates and identification and discontinuation of the high-risk candidates as early as possible.
Citation Format: Amin Osmani, Sofie Pattijn, Jana Schockaert, Aurélie Mazy, Chloé Ackaert. Immunogenicity risk assessment and mitigation tools [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 701.
Abstract 710: Exosomal DNA has the potential to detect circulating tumor DNA in patients with colorectal cancer
Authors: Kuriyama Sho , Yamada Takeshi , Koizumi Michihiro , Shinji Seiichi , Matsuda Akihisa , Ohta Ryo , Takahashi Goro , Hotta Masahiro , Hara Keisuke , Takeda Kohki , Ueda Koji , Yoshida Hiroshi 
Published: September 2020

Abstract
[Introduction] Exosomes are small vesicles of endosomal origin, which are released by all cell types, and are involved in physiological and pathological processes including cancer progression and metastasis. Exosomes comprise proteins, lipids, and nucleic acids such as RNA and DNA (exoDNA). Circulating exoDNAs harboring mutations are detected in patients with pancreatic or colorectal cancer. [Objective] To evaluate the clinical utility of detecting RAS mutations in exoDNAs of patients with colorectal cancers.
[Methods] We prospectively recruited 25 patients with RAS mutations in cells of their colorectal tissues. Circulating exoDNA was extracted from exosomes in 1 ml of preoperative plasma. Circulating cell-free DNA (ccfDNA) was concurrently extracted from 1 ml of plasma. We identified RAS mutations in exoDNAs and ccfDNAs using droplet digital PCR (ddPCR, Biorad).
[Results] We analyzed the exoDNAs of patients with right-sided (n = 13) and left-sided (n = 12) colon cancers (Stage II, [n = 9]; Stage III, [n = 9], Stage IV, [n = 7]). The median concentrations of exoDNA and ccfDNA were 52.3 ng/ml (32.1-223 ng/ml) and 132 ng/ml (41.3-4333 ng/ml). RAS mutations were detected in exoDNAs of 13 patients (52.0%) and in the ccfDNAs of 5 patients (20%) (P=0.03). The sensitivities of exoDNAs and ccfDNAs were equivalent (57.1%). However, for Stages II and III, the sensitivities of exoDNAs were higher compared with those of ccfDNAs. Notably, the sensitivity of exoDNA of Stage III was 77.8%. RAS mutations were undetectable in ccfDNAs of patients without detectable mutations in exoDNAs. The median mutation allele frequencies of exoDNA and ccfDNAs were 12.1% and 18.0%, respectively.
[Conclusion] Previously reported mutation-detection rates using Stages VI and III ccfDNAs are 90% and 15%, respectively. Here, the sensitivities using ccfDNAs for Stage II or III were low as well. Conversely, the sensitivities using exoDNAs were equivalently high in Stages III and Stage IV. These findings indicate that exoDNA has superior potential for detecting circulating tumor DNA compared with that of ccfDNA
Citation Format: Sho Kuriyama, Takeshi Yamada, Michihiro Koizumi, Seiichi Shinji, Akihisa Matsuda, Ryo Ohta, Goro Takahashi, Masahiro Hotta, Keisuke Hara, Kohki Takeda, Koji Ueda, Hiroshi Yoshida. Exosomal DNA has the potential to detect circulating tumor DNA in patients with 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 710.
Abstract 72: PARK2 enhances chemosensitivity of antimicrotubule drugs in breast cancer via promoting degradation of BCL-2
Authors: Chen Hengxing , Li Yun , Li Yu , Chen Zhen , Xie Limin , Li Wenjia , Zhu Yuanxin , Lu Daning , Hong Xue , Koeffler H. Phillip , Wu Wenjing , Hu Kaishun , Yin Dong 
Published: September 2020

Abstract
Chemotherapy is applied in over 70% of breast cancer patients. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicine used for chemotherapy. However, it still lack of predictor for indicating which chemotherapy drug will benefit to patients. An urgent need is to develop biomarker used to determine which chemotherapy will work for individual patient. Antimicrotubule drugs such as docetaxel and vinorelbine are prescribed widely for breast cancer, nevertheless, about one-third of breast cancer patients suffer from the side effects of anti-microtubule drugs chemotherapy without benefit from it. Here, we report that PARK2 is a potential biomarker for chemosensitivity to antimicrotubule drugs in breast cancer. PARK2 gene encodes an E3 ubiquitin ligase. 34% of breast cancer patients exhibited PARK2 deletion. Interestingly, high PARK2 expression was positively correlated with favorable survival in breast cancer patients receiving chemotherapy, but not in those not receiving chemotherapy. Moreover, PARK2 overexpression specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 augmented resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein BCL-2. Notably, PARK2 physically interacted with BCL-2 and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo, while loss-of-function PARK2 mutants failed to enhance the sensitivity of antimicrotubule drugs. Taken together, we identified PARK2 as a novel mediator of antimicrotubule drug which provides a predictor for the chemosensitivity of antimicrotubule drugs in breast cancer.
Citation Format: Hengxing Chen, Yun Li, Yu Li, Zhen Chen, Limin Xie, Wenjia Li, Yuanxin Zhu, Daning Lu, Xue Hong, H. Phillip Koeffler, Wenjing Wu, Kaishun Hu, Dong Yin. PARK2 enhances chemosensitivity of antimicrotubule drugs in breast cancer via promoting degradation of BCL-2 [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 72.
Abstract 720: Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast cancer
Authors: Lin Po-Han , Kuo Sung-Sheng , Huang Chiun-Sheng 
Published: September 2020

Abstract
The therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer is usually assessed by the reduction of tumor size and lymph nodes. The pathologic complete response (pCR) is considered as a marker related to good prognosis. However, patients who can achieve pCR is a minor population, and pCR may be not a robust marker predicting prognosis in patients with ER-positive breast cancer. Additional markers allowing the assessment of prognosis is needed. Circulating tumor DNA (ctDNA) has been proved as a marker to detect disease progression in metastatic breast cancer and predict relapse in patients after resection of breast cancer. Therefore, we would like to assess the value of ctDNA in breast cancer patients receiving neoadjuvant therapy. The ctDNA was collected before and after completion of the neoadjuvant chemotherapy (Tend). The presence of ctDNA was detected by ultra-deep targeted next-generation sequencing. We enrolled 82 patients and 62 patients were found to have ctDNA as the biomarkers. The presence of ctDNA included nonsynonymous variants and copy number variations in TP53, PIK3CA, HER2, CDH1, PTEN, S100A, CCND1 and c-MYC. Among the 62 patients, there were 24 patients with hormone receptor (+)/Her2(-), 20 with Her2(+) and 18 with triple-negative breast cancer (TNBC). Pathologic complete response (pCR) occurred in 9 patients, partial response in 32 patients and stable/progression in 21 patients, according to the RECIST 1.1 criteria. Univariate analysis showed tumor reduction&gt;50% (p=0.032), number of metastatic lymph node (p=0.039), and status of ctDNA at Tend (p&lt;0.001) were significantly associated with disease-free survival (DFS). The 5-year DFS of patients with undetectable ctDNA at Tend (74.0%, 95% confidence interval (CI) range 98%-50%) was significantly superior to those with detected ctDNA (16.8%, 95% CI range 36.1%-0%). Multivariate analysis revealed that status of ctDNA at Tend was the only one independent factor predicting relapse (hazard ratio 7.74, 95% CI 2.81-21.35). Two patients had pCR and were found to have alterations of ctDNA at Tend; one with TNBC had distant metastases at 6 months after mastectomy and the other with Her2 (+) breast cancer had brain metastasis at the end of adjuvant trastuzumab treatment. Therefore, we concluded that the presence of ctDNA at the end of the neoadjuvant chemotherapy was a poor prognostic factor predicting relapse in patients with stage II-III breast cancer.
Citation Format: Po-Han Lin, Sung-Sheng Kuo, Chiun-Sheng Huang. Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast 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 720.
Abstract 738: Utility of Assessing HER2 RNA expression for precision medicine
Authors: Shen Yifei , Pico Christian Cruz , Mohanty Vakul , Johnson Amber , Zeng Jia , Shaw Kenna Mills , Chen Ken , Meric-Bernstam Funda 
Published: September 2020

Abstract
Genomic analysis of tumors is rapidly becoming routine clinical practice. Most of the next generation sequencing (NGS)-based oncology assay focused on DNA alteration data for single nucleotide variants (SNVs), insertions and deletions (indels) and copy number variants (CNVs) of genes which have targeted drug. Although RNA sequencing technology is increasingly being explored, its clinical utility still needs to be clarified. As there is a growing number of HER2-targeted therapies, in this study, we dissected the association between HER2 amplification, RNA overexpression, HER2 protein expression by immunohistochemistry (IHC) and reverse phase proteomic arrays (RPPA) in 618 breast tumors in the TCGA. We conducted unsupervised clustering analysis based on HER2 RNA-seq gene expression and RPPA protein data to identify HER2 overexpression samples. As expected there was a strong correlation with ERBB2 copy number with HER2 RNA expression (R2 = 0.56, P &lt;0.001), and HER2 protein expression by IHC (R2 = 0.25, P &lt; 0.001). RNA expression also correlated with HER2 IHC (R2 = 0.40, P &lt; 0.001) and HER2 protein expression by RPPA (R2 = 0.68, P &lt; 0.001). We performed unsupervised clustering analysis based on RPPA protein data and gene expression data of the HER2 gene, all the breast cancer samples were classified as two distinct clusters. Among the two subgroups, one subgroup had significantly higher expression and protein level of HER2 gene. The clustering results of most breast tumors were consistent with the IHC score and copy number data. The gene expression cutoff value to distinguish the HER2 overexpression subgroup from the other was about 204 FPKM. In addition, we identified two HER2 overexpression tumors which were classified as HER2 negative based on IHC. Studies are planned to test transcriptomic based actionability in patient derived models.
Our results suggest that RNA-seq gene expression data may identify patients with HER2 overexpression that may be classified as HER2 negative based on IHC. Further studies are needed to determine the role of HER2 RNA overexpression as a predictive marker and to determine HER2 RNA expression across tumor types.
Citation Format: Yifei Shen, Christian Cruz Pico, Vakul Mohanty, Amber Johnson, Jia Zeng, Kenna Mills Shaw, Ken Chen, Funda Meric-Bernstam. Utility of Assessing HER2 RNA expression for precision medicine [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 738.
Abstract 745: Landscape of FGFRactivating aberrations in Chinese non-small cell lung cancer
Authors: Zhou Zhen , Liu Zichuan , Ou Qiuxiang , Wu Xue , Wang Xiaonan , Shao Yang , Liu Hongyan , Yang Yu 
Published: September 2020

Abstract
Background Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in non-small cell lung cancer (NSCLC), particularly in lung squamous cell carcinoma (LUSC). We hereby assessed the frequency of FGFR aberrations in a large Chinese NSCLC population.
Methods A total of 10,966 NSCLCs whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing (NGS) of 400+ cancer-related genes were retrospectively reviewed. Patients' clinical characteristics and treatment histories were further evaluated.
Results FGFR aberrations, including mutations, fusions, and gene amplifications, were detected in approximately 1.9% (210/10,966) of the population. FGFR abnormalities were more frequently observed in LUSCs (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9596). Previously reported FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male LUSC patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus, highlighting an intriguing molecular characteristic and potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in those patients. Furthermore, FGFR fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including nine FGFR3-TACC3 cases, one FGFR2-INA fusion, one novel FGFR4-RAPGEFL1 rearrangement event, and one novel gene fusion between FGFR1 and the SLC20A2 5'-untranslated region, which may result in FGFR1 overexpression. Concomitant EGFR mutations or EGFR amplifications were observed in six patients, four of whom were previously treated with EGFR tyrosine kinase inhibitors, suggesting that FGFR fusions may act as acquired resistance to anti-EGFR therapies. In addition, FGFR amplification was detected in 24 patients, with FGFR1 amplification being the most common event. Notably, FGFR oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events.
Conclusion We herein report an incidence of FGFR anomalies in a large Chinese NSCLC population, including mutations, gene amplifications, and previously characterized and novel FGFR fusions involving TACC3, INA, RAPGEFL1, and SLC20A2.
Keywords: FGFR, activating mutation, fusion, gene amplification, NSCLC, FGFR inhibitors
Citation Format: Zhen Zhou, Zichuan Liu, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang Shao, Hongyan Liu, Yu Yang. Landscape of FGFRactivating aberrations in Chinese non-small cell 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 745.
Abstract 747: Pak1, TGFα, Ki 67 and survival in human gastric and gastroesophageal junction adenocarcinomas
Authors: Douglass Larry E. , Parritt Michael , Neltner Adam , Dooley Mariah , Robillard Michelle , Frydl Molly , Focke Leah , Damen Kyle , Deddens James A. , Carter Julia H. 
Published: September 2020

Abstract
Stomach cancer is the third most common cause of cancer mortality worldwide. Most are adenocarcinomas. Adenocarcinomas of the stomach fall into two obvious groups based on site of origin; those arising in the area of the gastroesophageal junction (GEJ) and those arising from a more distal location, which we term gastric in this study. Adenocarcinomas of the stomach fall into four obvious groups based on a combination of genomic, molecular biologic, clinical and histopathologic characteristics (Nagara A, Kikuchi O, Bass AJ, Cancer Discovery 2019; DOI: 10.1158/2159-8290.CD-19-0487). We are reporting herein a study of 99 patients with adenocarcinoma of the stomach. This study evaluates the location of the tumor, the histopathologic features of the tumor, the immunohistochemically determined nuclear and cytoplasmic expression of P21 activated kinase (Pak 1), Transforming Growth Factor α (TGFα), and Ki67, a marker of cell proliferation. This study correlates these findings with patient survival. The study reveals:
1. significantly lower survival in patients with diffuse type adenocarcinoma compared to intestinal type, in both GEJ and gastric locations.
2. both GEJ and gastric adenocarcinomas had a poor prognosis.
3. increased expression of both TGFα and Pak1 in GEJ adenocarcinomas.
4. Ki67 expression is significantly less in diffuse type than the intestinal type (p=0.01 for GEJ and 0.03 for gastric).
5. cytoplasmic Pak1 and cytoplasmic TGFα were highly positively correlated (p=0.0001).
6. Ki67 expression was significantly inversely correlated with both nuclear Pak1 (p=0.04) and nuclear TGFα (p=0.02).
7. significantly increased expression of nuclear Pak1 in gastric diffuse type compared with gastric intestinal (p=0.0002) and GEJ intestinal (p=0.0001).
These data suggest that Pak1 and TGFα might serve as diagnostic biomarkers of subtypes of adenocarcinomas of the stomach and gastroesophogeal junction.
Citation Format: Larry E. Douglass, Michael Parritt, Adam Neltner, Mariah Dooley, Michelle Robillard, Molly Frydl, Leah Focke, Kyle Damen, James A. Deddens, Julia H. Carter. Pak1, TGFα, Ki 67 and survival in human gastric and gastroesophageal junction adenocarcinomas [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 747.