bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2701: Proteogenomic analysis of endoscopy biopsy identifies alterations in apoptotic pathways in trastuzumab-resistant gastric cancers
Authors: Kang Jeong Won , Choi Il Ju , Kim Hark Kyun 
Published: August 2018

Abstract
Although the combination of trastuzumab with cisplatin and fluoropyrimidine is standard therapy for metastatic HER2-positive gastric cancers, predictive biomarkers for this therapy need to be further refined. Given the multifactorial nature of clinical trastuzumab resistance, we performed nano-liquid chromatography (LC)-tandem mass spectrometry (MS/MS) proteomic analyses on 13 pairs of frozen HER2-positive tumors and adjacent normal tissue counterparts collected from patients who were treated with trastuzumab in combination with cisplatin and fluoropyrimidine (TCF). We quantified &gt;6,000 protein groups per tumor on the average, and this number was almost comparable to those obtained by NCI's Clinical Proteomic Tumor Analysis Consortium projects, which characterized resected tumors using similar nano-LC-MS/MS technologies. Nano-LC-MS/MS data for differentially expressed proteins were successfully validated by our immunostaining analyses. When we correlated proteomic data with clinical outcome, underexpression of apoptosis pathway proteins was the prominent proteomic signature in TCF-resistant tumors, as compared with TCF-sensitive tumors. Proapoptotic proteins in FAS signaling and mitochondrial apoptosis pathways were less abundant in TCF-resistant tumors than in sensitive tumors. When iTRAQ reporter ion ratios were compared between pretreatment and acquired-resistant tumors from clinical responders, apoptosis pathways were significantly enriched in proteins that were overexpressed in the acquired-resistant tumors. Assuming that the pretreatment tumors of clinical responders were mostly composed of chemosensitive clones, these antiapoptotic proteins may confer survival advantage on resistant clones, resulting in the repopulation of resistant clones overexpressing these antiapoptotic proteins. For the first time to our knowledge, therefore, our proteogenomic study of frozen endoscopic biopsy samples revealed that alterations in apoptotic pathway proteins were most significantly associated with clinical trastuzumab resistance. Our study is also the first to demonstrate that nano-LC-MS/MS technology can be applied to small biopsy tissue samples for precision medicine research.
Citation Format: Jeong Won Kang, Il Ju Choi, Hark Kyun Kim. Proteogenomic analysis of endoscopy biopsy identifies alterations in apoptotic pathways in trastuzumab-resistant gastric cancers [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 2701.
Abstract 2722: Investigation of the expression profile and functional role of PD-1, TIM-3 and LAG-3 in human tumors
Authors: Ghosh Srimoyee , Travers Jon , McEachern Kristen , Kumar Sujatha , Ramaswamy Sridhar , Jenkins David 
Published: August 2018

Abstract
While immunotherapies directed against PD-1 and PD-L1 have proven effective across multiple indications, there is still a large unmet medical need for therapies for patients who do not respond or who develop acquired resistance during the course of treatment. There are several emerging hypotheses to explain the lack of response, one of which is the upregulated expression of additional checkpoint receptors, such as TIM-3 and LAG-3, that limit the ability of PD-1 pathway blockade to re-establish effective anti-tumor immunity.
To investigate the potential role of TIM-3 and LAG-3 relative to PD-1, we set out to evaluate the expression and function of these receptors in several systems. Firstly, we used a flow cytometry approach to enumerate immune cell populations in a panel of human tumor samples, including non-small cell lung cancer (NSCLC). In these samples, PD-1, TIM-3 and LAG-3 expression was observed in both T-cell and non-T-cell populations. PD-1 was found to be co-expressed with TIM-3 and LAG-3 in CD8+ T-cells and we also found expression of TIM-3 and LAG-3 in other cell types, including regulatory T-cells and myeloid cells.
Building on the expression data, we explored the functional effects of targeting these receptors, evaluating the effect of single agent and combination effects of anti-PD-1, anti-TIM-3 and anti-LAG-3 antibodies in mouse models. In these studies, we found not only that dual-blockade of PD-1 with either anti-TIM-3 or anti-LAG-3 resulted in improvements in efficacy over monotherapy, but also that the triple combination of all 3 inhibitors was associated with further anti-tumor activity. In a humanized mouse model of NSCLC, the triple combination was associated with pharmacodynamic effects not only in T-cells, but also reductions in Tregs and macrophages.
Taken together, these studies provide further evidence to suggest that in addition to PD-1, LAG-3 and TIM-3 are important emerging immunotherapy targets and provide rationale for not only doublet but also triplet combinations as an approach to cancer therapy.
Citation Format: Srimoyee Ghosh, Jon Travers, Kristen McEachern, Sujatha Kumar, Sridhar Ramaswamy, David Jenkins. Investigation of the expression profile and functional role of PD-1, TIM-3 and LAG-3 in human tumors [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 2722.
Abstract 2729: Quantitative cell-based bioassays to advance individual or combination immune checkpoint immunotherapy
Authors: Grailer Jamison , Gilden Julia , Stecha Pete , Garvin Denise , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhi-Jie Jey 
Published: August 2018

Abstract
Immune checkpoint receptors play a critical role in maintaining immune homeostasis and are genetically and functionally associated with autoimmune disease, cancer and persistent viral infections. Blockade of immune checkpoints has emerged as a promising new approach to enhance anti-tumor immune responses. After initial successes with PD-1 and CTLA-4-targeted therapies, immunotherapy research has broadened to include additional immune checkpoint receptors targeted individually or in combination. A significant challenge in the development of biologics that target immune checkpoints is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. As an alternative to primary cell assays, we have developed a panel of cell-based reporter bioassays that can quantitatively determine the potencies of biologics targeting the immune checkpoints PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, and BTLA, or bispecific antibody or antibody cocktails targeting two immune checkpoint receptors such as PD-1+TIGIT, PD-1+LAG-3, and PD-1+CTLA-4. These assays consist of engineered T effector cells that express luciferase reporters driven by specific response elements integrating signaling from the T cell receptor and immune checkpoint target(s), and engineered artificial antigen presenting cells. These mechanism of action-based bioassays demonstrate high specificity, sensitivity and reproducibility. Therefore they can serve as valuable tools for immunotherapy drug development.
Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-Jie Jey Cheng. Quantitative cell-based bioassays to advance individual or combination immune checkpoint immunotherapy [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 2729.
Abstract 2732: Cell-based reporter bioassays to evaluate the Fc gamma receptor-dependent agonistic activities for therapeutic antibodies targeting immune costimulatory receptors
Authors: Wang Jun , Beck Michael , Grailer Jamison , Stecha Pete , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhi-Jie Jey 
Published: August 2018

Abstract
Immune costimulatory receptors synergize with TCR-CD3 signaling to promote cell cycle progression, cytokine production, T cell survival and effector functions. They belong to immunoglobulin super-family (CD28, ICOS) and tumor necrosis factor receptor (TNFR) superfamily (4-1BB, OX40, CD27, CD40, GITR, DR3, and HVEM). Preclinical and clinical evidence shows that agonist antibodies against costimulatory receptors can stimulate antitumor immunity and are emerging as a promising approach for cancer immunotherapies. Furthermore, FcγR engagement, especially FcγRIIB due to its bioavailability, has been shown to provide a crosslinking scaffold for the antibody IgG to facilitate TNFR clustering/activation and become requisites for some agonist antibody activities. Here, we report the development of a suite of cell-based reporter bioassays to quantitatively measure the potencies of therapeutic antibodies designed to target costimulatory receptors. For this, we developed engineered effector cells that express each costimulatory receptor and a luciferase reporter driven by response element that specifically responds to costimulatory receptor signaling. We also developed a FcγR-expressing cell line to evaluate the involvement of FcγR in agonist antibody-mediated costimulatory signaling. The assays are specific for each costimulatory receptor, and can be used to detect both agonistic and blocking activities for the antibodies. When co-incubated with the engineered FcγR-expressing cells, they are able to show the Fcγ receptor-dependent or independent agonist activities. In summary, these reporter bioassays can serve as powerful tools in immunotherapy drug development for antibody screening and potency determination.
Citation Format: Jun Wang, Michael Beck, Jamison Grailer, Pete Stecha, Jim Hartnett, Frank Fan, Mei Cong, Zhi-Jie Jey Cheng. Cell-based reporter bioassays to evaluate the Fc gamma receptor-dependent agonistic activities for therapeutic antibodies targeting immune costimulatory receptors [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 2732.
Abstract 2734: Novel CTLA4 antibodies demonstrate potent antitumor activity in a humanized mouse model
Authors: Xiang Jie , Guo Yanan , Shen Yuelei , Yang Benny 
Published: August 2018

Abstract
CTLA4 (cytotoxic T-lymphocyte-associated protein 4), is a member of the immunoglobulin superfamily. It is expressed in T cells upon activation and transmits an inhibitor signal to T cells. Also, it is constitutively expressed in regulatory T cells (Tregs) which is associated with their immunosuppressive phenotype. CTLA4 is homologous to the co-stimulatory protein CD28, and both receptor binds to CD80 and CD86. Cancer cells can be recognized and destructed by the host's immune system. In this setting, CTLA4 functions as a brake to dampen anti-tumor T cell responses, which promote cancer progression. Antibodies targeting CTLA4 was expected to subvert T cell inhibition. Moreover, regulatory T cells residing in the tumor microenvironment can be killed by anti-CTLA4 antibody since these cells have higher expression level of CTLA4 comparing with the activated T cells. Yervoy, an anti-CTLA4 antibody, was the first FDA-approved antibody targeting the immune checkpointfamily, and it protects a fraction of cancer patients when either used alone or in combination with other drugs. We asked whether the efficacy of anti-CTLA4 antibodies could be evaluated in humanized mouse models. And if so, whether we can use in vivo assay to guide the development of potent antibodies targeting CTLA4. Here, we describe that using the platform established at Biocytogen, we successfully discovered two antibodies whose efficacy is equivalent or exceed that of Yervoy. The clinical evaluation of these new entities are wanted.
Citation Format: Jie Xiang, Yanan Guo, Yuelei Shen, Benny Yang. Novel CTLA4 antibodies demonstrate potent antitumor activity in a humanized mouse model [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 2734.
Abstract 2759: Rational combinations for immune checkpoint blockade using β-catenin RNAi therapy
Authors: Ganesh Shanthi , Shui Serena , Craig Kevin , Wang Weimin , Brown Bob D. , Abrams Marc 
Published: August 2018

Abstract
Recent research has shown that Wnt/β-catenin signaling drives resistance to cancer immunotherapy by promoting the exclusion of T-cells from the tumor microenvironment. DCR-BCAT is an RNAi-based experimental medicine targeting β-catenin, formulated in a tumor-selective nanoparticle. We had previously reported that systemic administration of DCR-BCAT increased tumor-associated cytotoxic T-cells and dramatically improved responses to immunotherapy agents, in murine syngeneic models and GEM models. In this new work, we explore the mechanisms by which Wnt/β-catenin signaling promotes resistance to immune checkpoint blockade, and propose context-specific therapeutic combinations using RNAi therapy. We will present novel in vivo experimentation demonstrating that DCR-BCAT significantly enhances sensitivity to immunotherapy using different drug regimens in multiple tumor types.
Citation Format: Shanthi Ganesh, Serena Shui, Kevin Craig, Weimin Wang, Bob D. Brown, Marc Abrams. Rational combinations for immune checkpoint blockade using β-catenin RNAi therapy [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 2759.
Abstract 2762: Identification of novel immunotherapeutic targets in anaplastic thyroid cancer
Authors: Chakraborty Sanjukta , Maniyar Rachana R. , Tuli Neha Y. , Rahoma Ghada Ben , Singh Sarnath , Kamat Ameet , Berzofsky Craig , Budenz Cameron , Moscatello Augustine , Geliebter Jan , Tiwari Raj K. 
Published: August 2018

Abstract
Thyroid cancer is the most rapidly increasing cancer in the US with anaplastic thyroid cancer (ATC) being the rarest and most aggressive form. ATC patients display a higher mutational burden and are refractory to current mainstream treatments including second generation kinase inhibitors like vemurafenib (PLX4032). BRAFV600E is one of the most common mutations associated with this phenotype. Presence of BRAFV600E has been associated with an immunosuppressive microenvironment in thyroid cancer that presumably facilitates immune evasion. With recent advancements in immunotherapy, well defined targeted treatment plans can address the unmet medical need of ATC. In an effort to define potential immunotherapeutic targets that can be combined with small molecule inhibitors in this subtype, we evaluated the expression of immune checkpoint molecules in four thyroid cancer cell lines TPC-1 (papillary), BCPAP (BRAFV600E positive papillary), 8505C (BRAFV600E positive anaplastic) and CGTH-W-1 (follicular) by qRT PCR at the basal level and after treatment with vemurafenib and mTORC1 inhibitor rapamycin. Prominent co-stimulatory molecules like CD27, CD30, 4-1BB and DR3 were significantly downregulated at the transcript level in ATC (8505C) as compared to the other thyroid cancer subtypes. We observed a higher baseline expression of co-inhibitory molecules like full length CTLA4 (mCTLA4), soluble CTLA4 (sCTLA4), LAG3, 2B4, PD-1 and PD-L1 in ATC (8505C) compared to the other subtypes of thyroid cancer. Although vemurafenib treatment decreased the expression of PD-L1 as expected, interestingly, it enhanced the expression of co-inhibitory molecules LAIR1, 2B4, mCTLA4 and PD-1 by approximately 1.5 folds. These results suggest an inherent redundancy in inhibitory immune checkpoint molecules that presumably compensate for each other, functionally, making them novel targets in ATC. With our study we identified a distinct group of co-inhibitory molecules in ATC that can be targeted by antagonistic antibodies in a combinatorial treatment regimen with small molecule inhibitors like vemurafenib.
Citation Format: Sanjukta Chakraborty, Rachana R. Maniyar, Neha Y. Tuli, Ghada Ben Rahoma, Sarnath Singh, Ameet Kamat, Craig Berzofsky, Cameron Budenz, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Identification of novel immunotherapeutic targets in anaplastic thyroid cancer [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 2762.
Abstract 2768: Potentiating the action of antibody-dependent cell-mediated cytotoxicity with immunocytokines
Authors: Murer Patrizia , Kiefer Jonathan D. , Plüss Louis , Neri Dario 
Published: August 2018

Abstract
Intact antibodies in the IgG format typically display only moderate in vivo activity against solid tumor masses, when their mechanism of action relies on antibody-dependent cellular cytotoxicity (ADCC). The therapeutic activity is mainly limited by the lack of immune effector cells (and most notably NK cells) in the neoplastic mass.
Our group had previously reported that the therapeutic activity of Rituximab and other intact immunoglobulins could be strongly potentiated by the antibody-based targeted delivery of interleukin-2 (IL2) to the tumor environment. The combination regimen induced complete remissions of established localized lymphomas and provided long-lasting protection from disseminated lymphoma, in mouse models that featured functional NK cells.
In this study, we examined the ADCC activity of TA99, a monoclonal antibody which specifically recognizes gp75, a conserved tumor-associated antigen over-expressed in both murine and human melanoma cells. In a preventive setting TA99 in murine IgG2a format completely inhibited the formation of lung metastases in mice, which had been injected intravenously with B16F10 melanoma cells. However, when the B16F10 melanoma tumor was grown subcutaneously in immunocompetent mice, the ADCC activity was not potent enough to eradicate the pre-established tumors and only a modest tumor growth inhibition was observed. A microscopic tissue distribution analysis revealed that TA99-IgG2a had selectively accumulated in the tumor mass compared to normal organs and that NK cells within the neoplastic lesions were scarce.
In order to increase NK cell density at the tumor site and potentiate ADCC activity, we developed fusion proteins of the TA99 antibody with murine TNFα, IL2 and IL12. The antibody-cytokine fusion proteins were used alone and in combination with TA99-IgG2a. Combination treatment led to a marked increase of anti-cancer activity against established subcutaneous tumors. Our findings indicate that the targeted delivery of certain pro-inflammatory cytokines to the tumor site potentiates the anti-cancer properties of intact antibodies, enhancing their ability to induce ADCC.
Citation Format: Patrizia Murer, Jonathan D. Kiefer, Louis Plüss, Dario Neri. Potentiating the action of antibody-dependent cell-mediated cytotoxicity with immunocytokines [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 2768.
Abstract 2805: Combretastatins as highly cytotoxic natural compounds
Authors: Dzubak Petr , Rehulka Jiři , Gurska Sona , Riener Uwe , Hajduch Marian 
Published: August 2018

Abstract
Combretastatins originally isolated from the South African willow tree Combretum cafrum are highly cytotoxic natural products, but their use is limited because of the cis/trans isomerization of the cis-stilbene moiety under physiological conditions. Herein we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for cytotoxic activity in vitro against a panel of human cancer and two non-tumor fibroblast cell lines and for their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified a cyclobutenyl derivative of the natural product as a promising drug candidate with selective nanomolar cytotoxic activity towards cancer cell lines, showing high potency against multidrug-resistant cells and inhibiting tubulin polymerization. This work was supported by Ministry of Health of the Czech Republic (15-31984A), internal grant of Palacky University (IGA_LF_2017_026) and by the Czech Ministry of Education, Youth and Sports LO1304, CZ-OPENSCREEN, (LM2015063) and EATRIS (LM2015064).
Citation Format: Petr Dzubak, Jiři Rehulka, Sona Gurska, Uwe Riener, Marian Hajduch. Combretastatins as highly cytotoxic natural compounds [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 2805.
Abstract 2817: RAD6 promotes acquired chemoresistance and a poor prognostic marker in ovarian cancer
Authors: Mani Chinnadurai , Clark David , Somasagara Ranganatha , Spencer Sebastian , Tripathi Kaushlendra , Palle Komariah 
Published: August 2018

Abstract
Ovarian cancer (OC) is deadly and incurable for patients who relapse after primary cancer is treated with surgery and platinum-based chemotherapy. Unfortunately, OC has a high rate of disease recurrence (70-80%) and most recurrent tumors are chemoresistant, causing deaths of nearly 15,000 women from this disease each year in U.S.A., which highlights the need for new therapeutic strategies. Platinum drug resistance and refractory disease pose major challenges in treating this disease and are major factors contributing to the poor survival rate of OC patients. Our studies demonstrated that RAD6 (an E2 ubiquitin conjugating enzyme) signaling is stimulated upon chemotherapeutic treatment and promotes expression of DNA repair proteins including Fanconi anemia (FA) pathway. Analysis of clinical samples revealed upregulation of RAD6 in ovarian tumors compared to normal ovarian tissues and RAD6 inhibition reduces cancer cell survival. In a pilot clinical study (n=26) comparing matched OC tumors from patients before and after carboplatin chemotherapy regimen, we found that RAD6 was upregulated after treatment and correlated with both chemoresistance and poor progression-free survival. Knockdown or inhibition of catalytic activity (small-molecule inhibitor) of RAD6 attenuated carboplatin-induced monoubiquitination of target proteins such as FANCD2, PCNA and histone 2B, thereby sensitizing OC cells to carboplatin. Interestingly, inhibition of RAD6 alone in OC cells induced replication stress and reduced cell survival and proliferation by arresting cells in the G2/M phase. Moreover, RAD6 plays an important role in the activation of the trans-lesion synthesis (TLS) pathway by monoubiquitinating PCNA and in the activation of the FA DNA repair pathway. These are critical mechanisms for cells to repair DNA crosslinks induced by platinum drugs. Together with these observations, our data suggest that inhibition of RAD6 could be a viable therapeutic target for overcoming platinum resistance and disease recurrence induced by FA pathway in ovarian cancer.
Citation Format: Chinnadurai Mani, David Clark, Ranganatha Somasagara, Sebastian Spencer, Kaushlendra Tripathi, Komariah Palle. RAD6 promotes acquired chemoresistance and a poor prognostic marker in ovarian cancer [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 2817.