bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 559: Development of a novel approach to identify cancer drivers for hepatitis B virus-associated hepatocellular carcinoma
Authors: SHEN SHIH-CHUN , Lu Amy Jiaen , Shieh John Caleb , Su Yih-Ping , Nasir Bilal , Ling Ning , Lau Daryl T. , Steffen Jamin D. , Shieh Fwu-Shan , Song Wei , Su Ying-Hsiu 
Published: August 2018

Abstract
Infection with Hepatitis B virus (HBV) is a major etiology of hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Studies have shown that some cells infected with HBV contain integrated viral DNA, and integrated viral DNA has been observed more frequently in HCC than in non-HCC infected liver. Although integration occurs randomly throughout host chromosomes, recurrent integration sites have been reported. Interestingly, these integration sites are located in genes known to be involved in carcinogenesis. During HCC carcinogenesis, tumor cells undergo uncontrolled clonal expansion in which a particular integration junction will become dominant (or a major junction). We have adapted a method known as primer extension capture (PEC) to enrich integrated HBV DNA for next-generation sequencing (NGS) to detect these integration junctions that occur at low frequency. We next developed a novel program, “HccDriverFinder,” to identify major junctions, incorporate PubMed data mining for driver identification, detect HBV mutations (revealing a striking 98.8% HCC-linked mutations identified in cancer), and visualize integration events. By analyzing NGS data generated from 13 matched HCC and adjacent non-HCC tissue samples, we found specific integrations in known targets such as TERT and CCNE1, and uncovered new recurrent HBV integration sites in genes including CSAD and ABCC13 (both of which are reportedly linked with tumorigenesis). We have further optimized the PEC approach to enrich for the whole HBV genome and have applied it to urine DNA from 31 hepatitis, 27 cirrhosis, and 29 HCC patients for the potential of identifying HBV junctions in circulation. Our approach holds the promise of building a driver identification kit for HCC detection, drug development and precision medicine.
Citation Format: SHIH-CHUN SHEN, Amy Jiaen Lu, John Caleb Shieh, Yih-Ping Su, Bilal Nasir, Ning Ling, Daryl T. Lau, Jamin D. Steffen, Fwu-Shan Shieh, Wei Song, Ying-Hsiu Su. Development of a novel approach to identify cancer drivers for hepatitis B virus-associated hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 559.
Abstract 5591: Analytical and clinical validation of blood-based NGS panel for detection of genomic alterations in DNA repair pathways
Authors: Zhao Zhixin 
Published: August 2018

Abstract
Circulating cell-free DNA (cfDNA) and cell-free RNA (cfRNA) in cancer patients are valuable resource of biomarkers for early detection, diagnosis, treatment and monitoring of disease progression. Compared to cfDNA, cfRNA is more labile to degrade and fluctuate, and thus more challenging to be detected in blood. In the present study, we reported PrediSeq, a validated NGS-based liquid biopsy assay to detect fusions, splicing and mutation events using cfRNA. By using Predicine proprietary ultra-sensitive DeepSeaTM (Deterministic, Efficient, Precise, Sensitive Algorithm) variant detection algorithm, pre-analytical study demonstrated RNA-based detection of fusion, RNA splicing, and mutations using reference materials. In a LOD study, PrediSeq NGS assay is more sensitive than the digital PCR based assay in terms of mutation detection. In clinical validation study, tissue and plasma samples from various types of cancer patients (lung, breast, prostate etc) were used, where concordant fusion events with tissue were observed and RNA mutations confirmed variants detected at DNA level. In conclusion, a highly sensitive and accurate RNA-based liquid biopsy test has been developed to complement the use of cfDNA for detection of fusion, splicing and mutations.
Citation Format: Zhixin Zhao. Analytical and clinical validation of blood-based NGS panel for detection of genomic alterations in DNA repair pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5591.
Abstract 5607: Tissue factor is a novel oncotarget for immunotherapy of triple-negative breast cancer using a second generation ICON in orthotopic mouse models of human and murine TNBC cell line- and patient-derived xenografts
Authors: Hu Zhiwei , Shen Rulong , Campbell Amanda , McMichael Elizabeth , Yu Lianbo , Ramaswamy Bhuvaneswari , London Cheryl A. , Xu Tian , Carson William E. 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is often associated with BRCA1 and BRCA2 mutation and is a leading cause of breast cancer death. Due to the lack of validated target molecules, there is currently no approved targeted therapy for TNBC. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells and cancer stem cells in several types of solid cancers. Here we report evidence supporting the idea that TF is a novel surface target for TNBC patients and cancer lines with BRCA1 and BRCA2 mutations. We showed that TF is over-expressed on TNBC cells and tumor neovasculature in greater than 85% of TNBC patients (n=14) when using standard paraffin-embedded tumor tissues and in nearly 60% of TNBC patients (n=157) when employing tissue microarray slides, but was not detected in adjacent normal breast tissue. We also describe the development of a second-generation TF-targeting immunoconjugate with improved efficacy and higher safety threshold compared to the original immunoconjugate. We showed that L-ICON1 is effective in killing TNBC cells via antibody-dependent cell-mediated cytotoxicity in vitro and in treating human and murine TNBC cell line- and patient-derived xenografts in vivo in preclinical orthotopic mouse models. These results suggest that TF is a novel oncotarget in TNBC and targeting TF may constitute a novel targeted immunotherapy for TNBC patients. The findings in this preclinical study warrant further clinical investigation.
Citation Format: Zhiwei Hu, Rulong Shen, Amanda Campbell, Elizabeth McMichael, Lianbo Yu, Bhuvaneswari Ramaswamy, Cheryl A. London, Tian Xu, William E. Carson. Tissue factor is a novel oncotarget for immunotherapy of triple-negative breast cancer using a second generation ICON in orthotopic mouse models of human and murine TNBC cell line- and patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5607.
Abstract 5608: Evaluation of retargeted T cell cytotoxicity of a bispecific antibody targeting CDH17 and CD3 in 2D- and 3D-colon cancer models
Authors: Irigoyen Macarena , Dai Eric , Luk John , Castillo Gonzalo , Staunton Don 
Published: August 2018

Abstract
Cadherin-17 (CDH17) is an adhesion molecule that binds to self and integrin a2b1, its expression in the adult is limited to gastrointestinal tissue and is involved in cancer progression. CDH17 is expressed de novo or overexpressed in several gastro-intestinal cancers including colorectal, gastric and pancreatic, making it an ideal target for immunotherapies. A humanized bifunctional antibody was developed, ARB-201, that binds to both CDH17 and the CD3/TCR complex (CD3) with high affinity. ARB-201 induced retargeted T cell cytotoxicity was determined in a 2D and 3D model. Relative to 2D, cytotoxicity of 3D tumors may be considered more predictive of efficacy for solid tumors. DLD-1, a colorectal adenocarcinoma cell line, was targeted in the 2D and 3D T cell cytotoxicity assays. Pre-labeled DLD-1 were grown in standard 384-well microplate (2D) or Kuraray's 384-well Elplasia microplates (3D). Effector PBMCs, freshly isolated from healthy donors were added to the target DLD-1 cells containing a concentration response curve of ARB-201. Samples were evaluated for the specific cellular cytotoxicity using cell imaging. The results show at 48 hours an EC50 of 12 pM for 2D and 47 pM for the 3D model. ARB-201 induced potent T cell cytotoxicity of DLD-1. Although cytotoxicity in the 3D tumor model was relatively less, we observed an increase over time, demonstrating that ARB-201 progressively kills 3D tumor cells and possesses cytotoxic activity that may translate into clinical efficacy for solid tumors.
Citation Format: Macarena Irigoyen, Eric Dai, John Luk, Gonzalo Castillo, Don Staunton. Evaluation of retargeted T cell cytotoxicity of a bispecific antibody targeting CDH17 and CD3 in 2D- and 3D-colon cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5608.
Abstract 5615: Antibodies targeting TIP1 enhance the efficacy of radiotherapy in lung cancer and glioblastoma
Authors: Kapoor Vaishali , Singh Abhay K. , Dadey David , Hoye Kelly , Collins Andrea , Thotala Dinesh , Hallahan Dennis 
Published: August 2018

Abstract
Antigens that are over-expressed in cancer in response to radiation are being used as novel targets. We showed tax interacting protein 1 (TIP-1) to be radiation-inducible that translocated to the surface of the cancer cell following irradiation. TIP-1, which consists of a single PDZ domain plays an important role in cell signaling, cancer development, and progression. TIP-1's involvement in various survival pathways makes it an attractive target for anticancer therapeutics. We used antibodies specific to this PDZ domain to determine its role in cancer cell survival. We monitored the proliferation of lung cancer (A549 and H460) and glioblastoma (D54 and U251) cells after 24, 48, 72 and 96h treatment with the anti-PDZ antibody. We observed a time-dependent proliferation arrest with anti-PDZ antibody treatment which was associated with increased apoptosis. The anti-PDZ antibody, when combined with radiation (3Gy), led to reduced proliferation and colony formation. Anti-PDZ antibody had no effect on the proliferation of normal lung (MRC-5) and endothelial (HUVEC) cells. Cells treated with anti-PDZ antibody showed decreased levels of the phosphorylated forms of AKT, mTOR, and a downstream substrate of mTOR, 4EBP1. Anti-PDZ antibody treatment also led to an overall reduction in basal levels of AKT, mTOR, and 4EBP1. Further, we evaluated the effect of the anti-PDZ antibody on tumor growth in heterotopic mouse models of lung cancer (A549) and glioma (U251). We observed significant growth delay in mice treated with anti-PDZ antibody treatment when compared to mice treated with the isotype control. The combination of the anti-PDZ antibody with radiation showed an additive effect. Immunoblot analysis of tumor tissues also showed downregulation of phosphorylated and total levels of AKT, mTOR and 4EBP1 in the tumors treated with anti-PDZ antibody. Overall, our results suggest that TIP-1 is a promising therapeutic target for treatment of lung cancer and glioblastoma. Antibodies specific to the PDZ domain of TIP-1 enhance the efficacy of radiotherapy. The anti-PDZ antibodies need to be optimized further before translating it into the clinic.
Citation Format: Vaishali Kapoor, Abhay K. Singh, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan. Antibodies targeting TIP1 enhance the efficacy of radiotherapy in lung cancer and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5615.
Abstract 5625: Myeloid derived suppressor cells (MDSCs) express Sialyl Tn (STn) and are a therapeutic target for anti-STn antibody drug conjugates
Authors: Eavarone David A. , Rao Patricia E. , Prendergast Jillian M. , Curtis Adam D. , Zhang Rong , Shopland Lindsay S. , Stein Jenna N. , Behrens Jeff , Dransfield Daniel T. 
Published: August 2018

Abstract
Introduction: Myeloid derived suppressor cells (MDSCs) are functionally defined by their capacity to suppress T cell immunity; therefore inhibiting these cells is of great interest for immuno-oncology applications. STn, the sialylated version of the carbohydrate Tn antigen, is broadly expressed in human cancers such as breast, ovarian, bladder, cervical, colon, and lung and is rarely expressed in normal adult human tissues. The presence of STn in tumors is associated with metastatic disease, poor prognosis, and reduced overall survival. Tumor STn expression is well established and can be leveraged for targeted cancer therapy, however its expression on immuno-suppressive tumor infiltrating lymphocytes such as MDSCs has not been established. Methods: We generated humanized anti-STn mAbs having no cross-reactivity to the asialylated form of STn (Tn) or other glycan antigens. The epitope targeted by these mAbs is the STn glycan itself, not a particular glycopeptide or carrier protein, which offers the broadest potential to bind to multiple STn-glycosylated proteins on cell surfaces. We used these mAbs to quantify specifically the expression of tumor and MDSC STn expression across a set of patient tumor samples. We further treated mice with a humanized anti-STn-MMAE antibody-drug conjugate to evaluate targeted depletion of STn+ MDSCs. In order to evaluate the therapeutic potential of targeting this MDSC phenotype, we further evaluated the immunosuppressive environment of tumors containing STn+ and STn- MDSCs. Results: For the first time, we report the detection of STn on the surface of MDSCs in a growing body of patient tumor samples. Our data in patients as well as xenograft models additionally links STn expression on MDSCs to tumor cell STn expression. We have also demonstrated depletion of STn+ MDSCs after treatment with an anti-STn antibody-drug conjugate in an ovarian carcinoma xenograft model. Conclusions: Our data demonstrated that STn provides a uniquely glycan-specific and potent target for treatment of solid tumors. Anti-STn therapeutics offer the potential to go beyond tumor targeting to also directly target and deplete immune-suppressive MDSCs, thus fostering immune re-engagement and increasing the potential for better patient outcomes.
Citation Format: David A. Eavarone, Patricia E. Rao, Jillian M. Prendergast, Adam D. Curtis, Rong Zhang, Lindsay S. Shopland, Jenna N. Stein, Jeff Behrens, Daniel T. Dransfield. Myeloid derived suppressor cells (MDSCs) express Sialyl Tn (STn) and are a therapeutic target for anti-STn antibody drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5625.
Abstract 5632: Targeted immunotherapy with SV-BR-1-GM: Mechanism of action and companion diagnostic development
Authors: Lacher Markus D. , Graeve Sanne , Wiseman Charles L. , Kong Ying Y. , Kwok William W. , Williams William V. 
Published: August 2018

Abstract
SV-BR-1-GM is a GM-CSF-engineered whole-cell targeted immunotherapy derived from a breast cancer cell line (SV-BR-1). We are currently assessing SV-BR-1-GM in a phase I/IIa clinical trial in metastatic and locally recurrent breast cancer (ClinicalTrials.gov identifier NCT03066947). Subjects who fail to respond with tumor regression are offered participation in a “roll-over” study in which an immune checkpoint inhibitor (pembrolizumab or ipilimumab) is added to the SV-BR-1-GM regimen (ClinicalTrials.gov identifier NCT03328026). To identify patients likely to respond to SV-BR-1-GM we are co-developing a companion diagnostic.
In a pilot phase I study with four evaluable patients, one subject (A002), with metastatic breast cancer, experienced systemic tumor regression including in soft tissue, lung, and brain lesions. In contrast to the three nonresponders, A002 matched with SV-BR-1-GM at both a class I (HLA-A) and a class II (HLA-DRB3) HLA allele. Strikingly, SV-BR-1-GM cells also express HLA class II “accessory” factors such as HLA-DMA and -DMB, HLA-DRA, and CD74 (encoding invariant chain and CLIP), and immunostimulators such as IL6, Il18, and KITLG, and the damage-associated molecular pattern (DAMP) protein HMGB1. SV-BR-1-GM cells do not express the T cell co-stimulatory ligands CD80 or CD86. These findings are consistent with a potential to activate previously primed but not naïve CD4+ T cells. In agreement, peptide-pulsed SV-BR-1-GM cells selectively activated peptide-HLA specific, pre-primed T cells.
Given this functional data and the expression of the “immune signature”, comprised of factors including those mentioned above, we hypothesized that SV-BR-1-GM cells can act as antigen-presenting cells (APCs) and present tumor-associated antigens (TAAs) directly to HLA-matched T cells, which in turn would induce an immune response directed to the patients' tumors. To evaluate this hypothesis, we have begun developing bioassays for assessing antibody and T cell responses to SV-BR-1-GM.
Here, we present data on SV-BR-1-GM's molecular makeup and development of anti-SV-BR-1-GM humoral and cellular immune responses. Our findings support SV-BR-1-GM acting as antigen-presenting cells for HLA class I and class II restricted immune responses.
Citation Format: Markus D. Lacher, Sanne Graeve, Charles L. Wiseman, Ying Y. Kong, William W. Kwok, William V. Williams. Targeted immunotherapy with SV-BR-1-GM: Mechanism of action and companion diagnostic development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5632.
Abstract 5633: Development of glycoconjugate-based anticancer vaccines
Authors: Huang Xuefei 
Published: August 2018

Abstract
The development of an effective vaccine construct against tumor associated carbohydrate antigens (TACAs) is an attractive approach towards cancer treatment and prevention. However, a significant challenge is that TACAs are only weakly immunogenic and direct administration of TACAs cannot elicit a powerful antibody response to protect the host from cancer development. In this presentation, we will present our strategies to significantly enhance the immunogenicity of TACAs as potential anti-cancer vaccines using mucin-1 (MUC1) as a representative antigen. Mucin-1 (MUC1) is one of the top ranked tumor associated antigens. MUC1 peptides and glycopeptides have been covalently conjugated to an immunogenic carrier. Immunization of mice with these constructs led to super strong antibody responses with IgG titers over one million, which are one of the highest IgG titers reported to date. Furthermore, the constructs elicited MUC1 specific cytotoxic T cells, which can selectively kill MUC1 positive tumor cells. The abilities of MUC1 conjugates to induce both antibody and cytotoxic T cell immunity targeting tumor cells highlight the potential of these constructs as anti-tumor vaccines.
Citation Format: Xuefei Huang. Development of glycoconjugate-based anticancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5633.
Abstract 5634: Eradication of breast carcinoma with bone metastasis by autologous formalin-fixed tumor vaccine (AFTV) combined with radiation and chemotherapy
Authors: Kuranishi Fumito , Imaoka Yuki , Iwako Hiroshi , Uemae Yoji , Ishihara Takeshi , Miyazaki Tsubasa , Ohno Tadao 
Published: August 2018

Abstract
No standardized treatment has been established for skeletal metastasis of breast carcinoma which is refractory to intensive chemo-radiation therapy and therefore is assumed impossible to cure. Here we show, however, the 3rd successful case concomitantly treated with the tumor vaccine, AFTV, and chemo-radiation therapy (the 1st and 2nd cases have been presented in AACR2013 and AACR2015, respectively). A 50-year old woman presented 2.5-cm mass of tubular carcinoma in her left breast in a MRI image. The tumor accompanied with no lymph node metastasis was resected in March 2009. We found the tumor was ER(+), PgR(-), and HER2 (-). Four months after the resection, she selected one course of AFTV as the first-line therapy. Response to delayed-type hypersensitivity (DTH) test became strongly positive. We then treated her with the aromatase inhibitor, anastrozole. Six years later, in March 2015, a PET image revealed bone-metastasis to sternum which was confirmed by needle-biopsy and ABC immunostaining as class V metastatic ductal carcinoma. We treated her again with second course of AFTV and palliative radiation therapy (36Gy/12fractions/19days) together with letrozole, bisphosphonate, additional 2 shots of nivolmab (40mg/48kg body) in October and November 2015. She was diagnosed to be complete response by PET imaging in February 2016, August 2016, and August 2017. Alteration of her blood CEA level suggests that the combined treatments eradicated the metastatic breast carcinoma. In conclusion, the present case suggests that AFTV in combination with palliative X-ray irradiation and adjuvant aromatase inhibitors eradicates skeletal metastasis of breast carcinoma with enhancement of a specific anti-tumor immune reactivity.
Citation Format: Fumito Kuranishi, Yuki Imaoka, Hiroshi Iwako, Yoji Uemae, Takeshi Ishihara, Tsubasa Miyazaki, Tadao Ohno. Eradication of breast carcinoma with bone metastasis by autologous formalin-fixed tumor vaccine (AFTV) combined with radiation and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5634.