bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 470: p53 isoform delta133p53 in tumor senescence
Authors: Muhlinen Natalia Von , Beck Jessica , Harris Curtis C. 
Published: August 2018

Abstract
The tumor suppressor gene TP53 expresses at least 12 isoforms due to alternative splicing, alternative initiation of translation, and alternative promoter usage. These isoforms include p53β and Δ133p53, which can modulate p53 transcriptional activity and apoptosis. The p53 isoform Δ133p53 is expressed in normal tissue, but is abnormally expressed in several cancer types. However, its role in tumor progression is still unclear. Normal somatic cells undergo a limited number of cell divisions, eventually leading to an irreversible proliferative growth arrest known as replicative senescence. Replicative senescence can act as a tumor suppressor mechanism, thus constituting a critical barrier to tumor progression in vivo. Previous studies showed that, p53β and Δ133p53 are endogenous regulators of replicative senescence in normal human fibroblasts. Interestingly, expression of Δ133p53 is upregulated in several cancer types. For instance, enhanced levels of Δ133p53 are associated with inhibition of cellular senescence in colon carcinoma as well as with progression of premalignant colon adenomas to colon carcinomas. However, little is known about the role of Δ133p53 in cancer. We are studying the roles of Δ133p53 in proliferation and senescence of cancer cell lines. We hypothesized that depletion of otherwise enhanced Δ133p53 isoform induces cellular growth arrest and increases the secretion of senescence-associated secretory phenotype (SASP) pro-inflammatory cytokines such as IL-6 and IL-8 of cancer cell lines, and thus Δ133p53 may be a therapeutic target to repress tumor cell growth.
Citation Format: Natalia Von Muhlinen, Jessica Beck, Curtis C. Harris. p53 isoform delta133p53 in tumor senescence [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 470.
Abstract 4712: AT1965, a novel B cell-activating immunotherapy, exerts potent anticancer activity
Authors: Roy Monideepa , Krishna Vineeth , Sengupta Aniruddha , Roy Sudip , Kulkarni Ashish , Sengupta Shiladitya 
Published: August 2018

Abstract
Emerging clinical evidence implicate B cells in long term survival in cancer. However, a therapeutic activation of a B cell response against cancer has not been explored. Here we describe the results with AT1965, which exerts a potent anticancer effect via the activation of B cells. AT1965 completely regressed aggressive 4T1 breast tumors established in balb/c mice. Immunophenotyping revealed that IGKC, a B cell marker, was the dominant immune biomarker that is over-expressed following AT1965 treatment. The lack of functional B cells in vivo, via the deletion of the JH gene results in the loss of heavy chain production, blocked this anti-cancer activity of AT1965. Activation of a B cell response is associated with long term memory, which should prevent relapse. To test this, tumor-bearing animals were treated with AT1965 to induce regression; Not a single animal relapsed, i.e. developed the tumor when re-challenged with the tumor thirty days after the primary tumors had regressed. T and B cells are natural partners in an immune response. We therefore tested the combination of a PD1 immune checkpoint inhibitor and AT1965 in an immunocompetent lung cancer model. Only 12.5% of the animals treated with AT1965 or the PD1-inhibitor exhibited a complete regression of lung cancer, while 37.5% exhibited delayed tumor progression. In contrast, 50% of the animals underwent complete tumor regression and 25% exhibited tumor growth inhibition when the two drugs were combined, consistent with the basic immunology premise that both B and T cells work together to mount a complete immune response. Our results indicate that B cell activation could emerge as the next paradigm in cancer immunotherapy.
Citation Format: Monideepa Roy, Vineeth Krishna, Aniruddha Sengupta, Sudip Roy, Ashish Kulkarni, Shiladitya Sengupta. AT1965, a novel B cell-activating immunotherapy, exerts potent anticancer activity [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 4712.
Abstract 4728: Iron regulation of innate immune pathogen-associated molecular pattern receptors
Authors: Stater Evan 
Published: August 2018

Abstract
Pathogen-associated molecular pattern (PAMP) receptors are key triggers of the pro-inflammatory immune effector functions of the cells of the innate immune system. Ectopic PAMP activation is a contributing factor to both cancer development and pathology, as well as host anti-tumor immune responses. Iron, an essential mineral in biological systems, has a similar dualistic role in cancer. We have shown that iron acts as a key modulator of intracellular signaling cascades downstream from PAMP activation. Cellular iron enrichment enhances the transcriptional activity of a pathogen-induced transcription factor downstream of PAMPs in an immortalized human macrophage cell line treated with a PAMP receptor-specific agonist ligand. Cell surface expression of the receptor was not affected by the iron enrichment; therefore, any modulation of receptor signaling by iron is likely downstream of the receptor. Furthermore, iron supplementation in vitro increases expression of immunity-related genes regulated by the pathogen-induced transcription factor; by contrast, treatment with iron-chelating reagents reduces expression of these genes. These results suggest that the iron content of the tumor microenvironment may have a regulatory role in pathological immunoregulation. In particular, the iron-retaining phenotype of many tumor cells may serve a novel pathological function, inhibiting PAMP-regulated anti-tumoral effector functions of tumor-infiltrating macrophages cells by iron deprivation.
Citation Format: Evan Stater. Iron regulation of innate immune pathogen-associated molecular pattern 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 4728.
Abstract 4731: Contribution of FcγRIIB to creating the suppressive tumor microenvironment
Authors: Kasahara Yuki , Shirota Hidekazu , Ishioka Chikashi 
Published: August 2018

Abstract
Various immune cells are recruited in tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities play an important role in regulating tumor growth and metastasis. However, contribution of humoral immune responses against tumor is incompletely understood. The Fc receptors constitute critical elements for activating or down-regulating immune responses through immunoglobulin immune complex. Here, we examined the potential role of inhibitory Fc receptor, Fc gamma RIIb in tumor immunity using mice model. Current findings indicate that tumor-specific antibodies are induced and control tumor immunity. Deletion of Fc gamma RIIb receptor significantly improves both cellular and humoral anti-tumor immunity, delays tumor growth. These findings indicate that spontaneous antibody against tumor create the suppressive tumor microenvironment through Fc gamma RIIb signaling, and suggests attractive therapeutic target for cancer immunotherapy.
Citation Format: Yuki Kasahara, Hidekazu Shirota, Chikashi Ishioka. Contribution of FcγRIIB to creating the suppressive tumor microenvironment [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 4731.
Abstract 4739: Elucidation of immunosuppressive microenvironment in colorectal cancer
Authors: Sasada Tetsuro , Ohtake Junya , Satoyoshi Tetsuta , Kazama Keisuke , Wada Satoshi , Yada Erika , Shiozawa Manabu 
Published: August 2018

Abstract
Colorectal cancer (CRC) is one of the most increasing cancers worldwide, and novel treatment modalities remain to be developed for advanced CRC patients. In recent years, immune checkpoint inhibitors have demonstrated impressive clinical efficacy in various types of cancers, but limited clinical responses were reported in CRC, except for MSI-high or MMR-deficient tumors. It has thus been suggested that immune suppressive mechanisms other than immune checkpoints might contribute to tumor progression in CRC. In the current study, various types of immune cells were isolated from peripheral blood or resected tumor/normal tissues and regional lymph nodes in 25 primary CRC patients, and their phenotypes and functions were comprehensively assessed. Flow cytometry analysis demonstrated a significant increase of CD4+FoxP3+ T cells, which might represent regulatory T cells, in proximal lymph nodes (N1 region), compared to distal (N2 or N3 region) or unrelated lymph nodes. In addition, the functional analysis of T cells assessed by cytokine production after non-specific stimulation (PMA and A23187) showed a significant decrease in the frequencies of IFN γ-producing CD8+ T cells in N1 region. Notably, reduction of IFN γ-producing CD8+ T cells seemed to be associated with advanced stages of disease. These results indicate that the immunosuppressive microenvironment, particularly in regional lymph nodes, may be related to tumor progression in CRC. The current study suggests that monitoring of immunosuppressive microenvironment would be useful as a predictive biomarker for cancer progression and patient prognosis in CRC. Further studies remain to be performed to more thoroughly elucidate immune suppressive mechanisms, and thereby to develop a novel immunotherapeutic strategy in CRC.
Citation Format: Tetsuro Sasada, Junya Ohtake, Tetsuta Satoyoshi, Keisuke Kazama, Satoshi Wada, Erika Yada, Manabu Shiozawa. Elucidation of immunosuppressive microenvironment in colorectal 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 4739.
Abstract 4740: CLEVER-1 as a marker to identify breast cancer patients under immunosuppression
Authors: Virtakoivu Reetta E. , Boström Pia , Aaltonen Riitta , Koskivuo Ilkka , Jalkanen Sirpa , Hollmén Maija 
Published: August 2018

Abstract
TAMs are the main innate immune cells regulating tumor growth and metastasis. In tumors, TAMs exhibit an immunosuppressive M2 phenotype attenuating anti-tumor immune responses. CLEVER-1 is a multifunctional scavenger receptor specifically expressed on a subset of M2 macrophages and human monocytes. Interestingly, a subset of CLEVER-1+ monocytes and TAMs are increased in conditions where immunosuppressive functions prevail, like pregnancy and cancer. In addition, high CLEVER-1 mRNA levels associates with poorer overall survival of breast cancer patients. Therefore, we want to investigate can CLEVER-1 be used as a surrogate marker for identifying cancer patients under immunosuppression. Since we detected CLEVER-1+ TAMs in 40% of breast cancer patients, we will characterize whether the amount of CLEVER-1+ TAMs in tumor biopsy samples correlates with the number of CLEVER-1+ monocytes in breast cancer patient blood. We will collect blood, plasma, healthy breast tissue and tumor tissue from 200 newly diagnosed treatment naive breast cancer patients. The tissue samples and the blood from each patient are characterized by flow cytometry to identify the activation status of monocyte and macrophage populations in relation to CD4/CD8, Th1, Th2, Th17 and Treg populations. By now, we have received 25 patient samples from which 12 have been initially analyzed for CLEVER-1 expression in the peripheral blood together with other immune cell populations. Our preliminary data show that CLEVER-1 expression on peripheral blood monocytes is increased in breast cancer patients who have higher levels of Tregs. Additionally, the amount of CD4+ effector T cells (Th1 and Th17) was decreased among patients, whereas the amount of Th2 CD4+ cells was increased when comparing to the blood of healthy volunteers. The abnormal Th1/Th2 ratio is linked to cancer progression. The expected outcome is that CLEVER-1 could be used as a surrogate marker to identify patients under immune suppression. These patients could benefit from anti-CLEVER-1 therapy or other clinically available immunomodulatory drugs (e.g. anti-CTLA-4; ipilimumab, anti-PD1; nivolumab).
Citation Format: Reetta E. Virtakoivu, Pia Boström, Riitta Aaltonen, Ilkka Koskivuo, Sirpa Jalkanen, Maija Hollmén. CLEVER-1 as a marker to identify breast cancer patients under immunosuppression [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 4740.
Abstract 4749: VISTA immune checkpoint deregulation in human triple-negative breast cancer
Authors: Gruber Joshua J. , Juntilla Marisa M. , Yang Soo-Ryum , Geller Benjamin , Jager Natalie , Lin Chien-Yu , Lipchik Andrew M. , Chen Justin , Ram Ashwin , Vinayak Shaveta , Telli Melinda L. , West Robert B. , Ford James M. , Snyder Michael P. 
Published: August 2018

Abstract
Immunotherapy for breast cancer has lagged behind the advances in other tumor types, suggesting the need for novel immune targets. VISTA/PD-1H is a checkpoint receptor expressed on immune cells that is an effective anti-cancer target in mouse models and now in early human clinical trials. We utilized an in vitro system to examine epigenetic changes arising early after depletion of breast cancer tumor suppressor proteins. This demonstrates that epigenetic alterations occur in normal human mammary cell lines lacking BRCA2 and result in regulation of VISTA through an NF-kB-dependent pathway. VISTA is strongly induced by growth factor limitation, an effect that is blunted by BRCA2-induced NF-kB activation and binding to a kB site in the VISTA promoter. This suggests that repression of VISTA may be an early consequence of BRCA2 depletion in pre-neoplastic tissues leading to immune infiltration. In contrast, in primary, untreated human triple-negative breast cancers, VISTA is over-expressed on tumor cells, independent of its presence on immune cells. VISTA positive TNBCs (14%) have significantly increased tumor infiltrating lymphocytes (TILs) whereas VISTA strong positive TNBCs (6%) have significantly decreased TILs and tumor PD-L1 staining, suggesting a higher level of immunosuppression. Gene expression and tumor genomics in TNBCs suggests that transcriptional networks to regulate physiologic immunoreceptor levels are corrupted during malignant transformation. In summary, this work identifies a BRCA2-loss-of-function signaling pathway that regulates an important immune checkpoint molecule via NF-kB activation in pre-neoplastic tissues and triple-negative breast cancers with important consequences for the immune microenvironment. We expect these observations to enhance immunotherapeutics for breast cancer.
Citation Format: Joshua J. Gruber, Marisa M. Juntilla, Soo-Ryum Yang, Benjamin Geller, Natalie Jager, Chien-Yu Lin, Andrew M. Lipchik, Justin Chen, Ashwin Ram, Shaveta Vinayak, Melinda L. Telli, Robert B. West, James M. Ford, Michael P. Snyder. VISTA immune checkpoint deregulation in human triple-negative breast 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 4749.
Abstract 4759: Designing clinical trials in tumor indications with a positive signal in phase 1
Authors: Chen Cong , Anderson Keaven , Mehrotra Devan V. , Rubin Eric H. , Tse Archie 
Published: August 2018

Abstract
Increasingly, the conventional proof-of-concept randomized Phase 2 study is skipped in favor of directly going to Phase 3 after an experimental oncology drug has demonstrated promising anti-tumor activity in Phase 1 with a small sample size. This shift in the balance between certainty and speed is especially evident in the immune-oncology space where the tremendous success of immune checkpoint inhibitors has brought unprecedented competition in the field. The aggressive approach can be very risky no matter how promising an experimental drug appears in Phase 1. In this presentation, we introduce a novel adaptive design that mitigates the risk of late-stage programs. The proposed approach starts with a Phase 2 trial and adds an option in the design that allows the expansion of the Phase 2 trial into Phase 3 if the interim result based on the Phase 2 endpoint is promising. If the decision is to not expand, the study is kept as a Phase 2 trial and the primary analysis is conducted at the end of Phase 2. Otherwise, the study is expanded into a Phase 3 trial and the primary analysis of the study is conducted at the end of Phase 3, utilizing data from all enrolled patients including those already used for the decision making in the ongoing trial. The proposed approach is more efficient than the conventional approach that conducts and analyzes Phase 2 and Phase 3 trials sequentially, and is less risky than the contemporary approach of skipping Phase 2. Importantly, we will show that this design controls overall Type I error regardless of the expansion criterion. As a result, the study can still be considered positive even without expansion to Phase 3.
Citation Format: Cong Chen, Keaven Anderson, Devan V. Mehrotra, Eric H. Rubin, Archie Tse. Designing clinical trials in tumor indications with a positive signal in phase 1 [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 4759.
Abstract 4779: Rogaratinib, a small molecule pan-FGFR inhibitor potently inhibits FGFR4-phosphorylation and exerts anti-tumor efficacy in vivo and in vitro
Authors: Politz Oliver , Gruenewald Sylvia , Walter Alexander , Siegel Franziska , Scholz Arne , Bender Sebastian , Kneip Christoph , Ellinghaus Peter 
Published: August 2018

Abstract
Fibroblast growth factor signaling plays an essential role in many physiological processes, including cell proliferation, survival, differentiation, migration, and apoptosis Over-activation of the pathway can lead to the development of various cancers. There are four different FGFR subtypes with over 20 ligands providing a very complex network of interactions and signaling.
FGFR4 plays an important role in normal physiology such as myogenesis muscle regeneration and bile acid synthesis Activating mutations in the kinase domain of FGFR4 have been shown to mediate cancer development, for example, breast cancer, hepatocellular carcinoma (HCC) or rhabdomyosarcoma.
Rogaratinib is a potent inhibitor of all FGFR subtypes with low nanomolar binding kinetics towards the four kinase domains. We explored the effect of rogaratinib on cell lines with high expression levels of FGFR4 mRNA, such as breast cancer cell line MDA-MB453 and rhabdomyosarcoma cell line SH30. We could show that the proliferation of these cell lines is potently inhibited by rogaratinib and accompanied with induction of apoptosis. The Mode-of-action analysis of rogaratinib activity in these cell lines showed inhibition of FGFR4-phosphorylation and downstream signaling at clinical relevant doses.
The in vitro efficacy of rogaratinib in FGFR4 dependent cell lines was further observed as in vivo efficacy in xenograft models of rhabdomyosarcoma and HCC.
Elevation of FGFR4 expression has been associated with resistance development in several cancer types such as breast cancer.
In line with the observed anti-tumor efficacy of rogartinib in vitro and in vivo in breast cancer, sarcoma and HCC models, RNA in situ hybridization by RNAscope, revealed high FGFR4 mRNA expression in TMA's from these tumor types..)
The combination of rogaratinib with standard-of-care provides further options for addressing resistance mechanisms mediated by elevated FGFR4 expression. In addition we have profiled a number of patient derived HCC xenograft models revealing the high efficacy of rogaratinib in models with elevated FGFR expression including FGFR4.
Citation Format: Oliver Politz, Sylvia Gruenewald, Alexander Walter, Franziska Siegel, Arne Scholz, Sebastian Bender, Christoph Kneip, Peter Ellinghaus. Rogaratinib, a small molecule pan-FGFR inhibitor potently inhibits FGFR4-phosphorylation and exerts anti-tumor efficacy in vivo and in vitro [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 4779.
Abstract 478: Regulation of MUC13 by microRNA in colorectal cancer
Authors: Bartu Linda , Opattova Alena , Vodicka Pavel , Vymetalkova Veronika 
Published: August 2018

Abstract
Colorectal cancer (CRC) represents a serious health problem with high incidence and mortality worldwide. The main reason of high mortality is the late diagnosis. For the Duke stage I, the average 5-years survival rate is 90%. In comparison to patients diagnosed at IV stage, the 5-years survival rate decreases to 3%. Mucinous CRC is generally defined as having greater than 50 % of the tumor area with a mucinous differentiation by histological examination. The increased incidence occurs in proximal colon and among younger patients, as compared to nonmucinous adenocarcinoma. Mucinous CRCs have been found to have a higher Duke stage at diagnosis, and, consequently a poorer prognosis. Mucines are surface or secreted glycoproteins with high molecular weight. Dysregulation of their expression may lead to malignant transformation. MUC13 overexpression influences colon cancer tumorigenesis and metastasis via multiple oncogenic proteins. Recently, we have observed that rs1532602 polymorphism in microRNA (miRNA) binding sites in MUC13 gene was associated with significantly decreased risk of CRC. The aim of the present study is to investigate regulation in vitro by miRNAs as a potential mechanism for increased MUC13 expression in CRC. Two different miRNAs were selected in this investigation. MiRNA-4647 is predicted to bind to the rs1532602 in MUC13. MiRNA-137 functions as a tumour suppressor in colon. Additionally, we investigated the impact of miRNAs mentioned above on regulation of MUC13 in a cohort of 113 patients with sporadic CRC. The present work provides important insights into role of miRNAs which bind to MUC13. Definition of functions, mechanisms of MUC13 regulation and its impact on CRC may contribute to better prediction and individual treatment of CRC. Acknowledgement: Grant Agency of the Ministry of Health of the Czech Republic (AZV MZ 15-26535A) and Grant Agency of the Czech Republic GACR 17-16857S.
Citation Format: Linda Bartu, Alena Opattova, Pavel Vodicka, Veronika Vymetalkova. Regulation of MUC13 by microRNA in colorectal 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 478.