bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4717: MAP kinase inhibition induces metabolic reprogramming in T-cells leading to induction of stem cell memory CD8 cells that enhance potency of adoptive cell therapy and anti-OX40 antibody
Authors: Verma Vivek , Ahmad Shamim , Zeng Peng , Mkrtichyan Mikayel , Barry Simon T. , Smith Paul D. , Rodriguez Paulo C. , Janik John E. , Gupta Seema , Khleif Samir N. 
Published: August 2018

Abstract
Adoptive T-cell therapy has demonstrated remarkable activity in refractory malignancies; however, the short survival of these cells in some patients results in treatment failure. CD8+ T-cells with self-renewable stem cell memory (TSCM) phenotype persist longer than the effector cells. Hence pharmacologic agents that maintain lymphocytes in TSCM phenotype may benefit the adoptive T cell-transfer strategies as well as combination immunotherapies. Small-molecule inhibitors of mitogen-activated protein kinase (MEKi) have been used for treatment of solid tumors. Here we report that inhibition of MEK enhances immune-driven antitumor response. We show that MEKi prevents the terminal differentiation and exhaustion of CD8+ T-cells in the tumor microenvironment. Interestingly, we further observed that MEKi leads to a significant increase in the CD62LhiCD44loSca1+ cells with low mitochondrial potential that are defined as TSCM CD8+ cells. Furthermore, ex vivo MEKi-treated CD8+ cells demonstrated a significantly higher antitumor activity in tumor-bearing mice. These MEKi treated CD8+ T-cells have higher mitochondrial respiration, which is fueled by fatty acid oxidation and exhibit significantly enhanced spare respiratory capacity (SRC). In addition, MEKi-treated cells have higher metabolic fitness, making them resistant to terminal exhaustion upon cell activation. Since OX40 co-stimulatory signals potentiate the self-renewal and homeostatic capacity of memory T-cells, we treated the tumor-bearing mice with MEKi in combination with OX40 agonistic antibody. Combining MEKi with OX40 agonist antibody significantly enhanced anti-OX40 antitumor effect. These data highlight the ability of pharmacologic MEK inhibition in inducing TSCM, which can be used ex vivo to enhance the potency of T-cell therapies and in vivo in combination immune therapy.
Citation Format: Vivek Verma, Shamim Ahmad, Peng Zeng, Mikayel Mkrtichyan, Simon T. Barry, Paul D. Smith, Paulo C. Rodriguez, John E. Janik, Seema Gupta, Samir N. Khleif. MAP kinase inhibition induces metabolic reprogramming in T-cells leading to induction of stem cell memory CD8 cells that enhance potency of adoptive cell therapy and anti-OX40 antibody [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 4717.
Abstract 4727: MicroRNA-155 as a regulator of NK cell mediated solid tumor rejection
Authors: Prasad Aman , Chan Wing Keung 
Published: August 2018

Abstract
Natural Killer (NK) cells are granular innate lymphocytes that orchestrate immune response by releasing interferon gamma (IFN-γ): a critical cytokine heavily involved in intercellular immune and inflammatory processes. Prior work from our lab has linked microRNA-155 (miR-155) to significant cell proliferation and NK cell mediated IFN-γ release. Previously, our lab has also shown that miR-155 can increase hematological malignancy rejection and NK cell cytotoxicity in T-cell lymphomas. However, it is unclear how miR-155 can affect NK cell cytotoxicity in solid tumor models. IFN-γ has been reported in the literature to directly induce apoptosis in glioblastoma solid tumors. We therefore hypothesize that miR-155 induction can increase NK cell mediated cytotoxicity and IFN-γ mediated apoptosis for solid tumor rejection. To test this, 10x106 GL261 cells were injected subcutaneously into the flanks of both wild type (WT) littermates and miR-155 transgenic (miR-155Tg) mice. CD3(-)NK1.1(+) effector splenic NK cells were isolated from WT and miR-155Tg mice for total RNA extraction and subsequent gene expression profiling on NK cell activation pathways. We found that tumor growth in WT mice was at least 2-fold greater than that of miR-155Tg mice (average 2cmx2cm vs 0.7cmx0.7cm, n=6). Tumor weights from WT and miR-155 mice were 1052 mg vs 340 mg, respectively, with an average of 2 mice per group. Furthermore, we have successfully created an IFN-γ receptor 1 (IFN-γR1) shRNA knock-down (KD) lentiviral construct in a stable glioblastoma cell line. IFN-γR1 knockdown was measured to be 90% as determined by real-time PCR analysis. Future experiments will be performed wherein IFN-γR1 KD glioblastoma cells will be injected in miR-155Tg and WT mice to evaluate tumor rejection. In summary, we demonstrate a model system to investigate the effect of miR-155 on solid tumor glioblastoma multiforme. Further characterization of gene expression profiles of purified NK cells from both WT and miR-155 mice will provide important insights on the mechanisms of NK cell medicated tumor rejection.
Citation Format: Aman Prasad, Wing Keung Chan. MicroRNA-155 as a regulator of NK cell mediated solid tumor rejection [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 4727.
Abstract 4732: Myeloid-derived suppressor cells potentiate colorectal carcinogenesis: Identification of a novel RIPK3-PGE2 circuit in tumor microenvironment
Authors: Li Yongsheng , Yan Guifang , Zhao Huakan , Zhang Qi 
Published: August 2018

Abstract
The role of receptor-interacting protein kinase 3 (RIPK3), a central factor mediating necroptosis, in tumor immunity is largely unknown. Here we show the significantly decreased RIPK3 in the tumor microenvironment of colorectal cancer (CRC) correlated with the accumulation of myeloid-derived suppressor cells (MDSCs). Deficiency of RIPK3 boosted the infiltration and immunosuppressive activity of MDSCs in vitro and in vivo. Mechanistically, the reduction of RIPK3 in MDSCs and colorectal cancer cells elicited NF-κB expression in the nuclei and the transcription of COX-2 which catalyses the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs, i.e. increased arginase 1 (Arg-1), blunted CD8+ T cell activation and accelerated tumor growth. Moreover, PGE2 inhibited RIPK3 expression while enhanced the expression of NF-κB and COX-2 in MDSCs and CRC cells. Inhibition of COX-2 or PGE2 receptors significantly reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. The patient databases also delineated the correlation of RIPK3 and COX-2 with CRC survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, and provide potential targets for the immunotherapy of CRC.
Citation Format: Yongsheng Li, Guifang Yan, Huakan Zhao, Qi Zhang. Myeloid-derived suppressor cells potentiate colorectal carcinogenesis: Identification of a novel RIPK3-PGE2 circuit in 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 4732.
Abstract 4743: Inhibition of the Hif1a-mediated checkpoint refuels NK activation in cancer
Authors: Ni Jing , Bühler Lea , Stojanovic Ana , Arnold Annette , Sexl Veronika , Cerwenka Adelheid 
Published: August 2018

Abstract
Solid tumors remain a major challenge for immunotherapy of cancer due to their immunosuppressive microenvironment. Hypoxia is a common feature of solid tumors and might affect immune cell activation within the tumor tissue. Upon hypoxia the transcription factor Hypoxia inducible factor 1a (HIF-1α) that affects many cellular processes including cell proliferation, survival and effector function becomes induced. Its impact on innate immune cells such as Natural Killer (NK) cells, however, is still incompletely understood. Natural Killer (NK) cells are considered as highly potent effector cells against tumors. Within the tumor tissue, however, NK effector function is often impaired. Our microarray analyses of tumor-infiltrated NK cells revealed upregulated levels of Hif1a. To determine the role of the HIF-1α in NK cell function, we generated the mouse strain Hif1aΔ/ΔNcr1-iCreTg in which HIF-1α is deficient in the NKp46+ lineage. Hif1a deficient NK cells showed greatly enhanced anti-tumor activity compared to wild-type NK cells, leading to a pronounced reduction of tumor growth. Tumor-infiltrated Hif1a deficient NK cells expressed lower levels of checkpoint molecules and show enhanced responses to tumor cells indicating a less exhausted phenotype. Hif1a deficient NK cells preferentially utilize oxidative phosphorylation (OXPHOS) than glycolysis to fuel their energy resulting in enhanced IFN-γ production in the hypoxic environment. In addition, using HIF-1α inhibitors we were able to greatly enhance human NK cell anti-tumor activity. Accordingly, our data reveal HIF-1α as a negative metabolic checkpoint for NK cells. Moreover, inhibition of HIF-1α holds high promise to refuel NK cell activation in cancer with a high potential for improving current strategies of NK cell-based cancer immunotherapy.
Citation Format: Jing Ni, Lea Bühler, Ana Stojanovic, Annette Arnold, Veronika Sexl, Adelheid Cerwenka. Inhibition of the Hif1a-mediated checkpoint refuels NK activation in 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 4743.
Abstract 475: Characterization of miR-21 expression in budding colon cancer cells using digital images of multiplex fluorescence stained slides obtained by confocal scanning microscopy
Authors: Nielsen Boye Schnack , Knudsen Kirsten Nguyen , Lindebjerg Jan , Kalmár Alexandra , Molnár Béla , Sorensen Flemming , Hansen Torben 
Published: August 2018

Abstract
This study was undertaken to analyze the presence and prevalence of microRNA-21 (miR-21) positive budding cancer cells in colon cancer using confocal scanning microscopy. Budding cancer cells are locally invasive cancer cells with increased metastatic properties and characteristics of epithelial to mesenchymal transition (EMT). Expression of miR-21 in stromal fibroblastic cells in colorectal cancers is well documented (1,2), whereas miR-21 expression in budding cells is poorly described. In order to characterize miR-21 positive budding cells, we first developed a multiplex fluorescence staining method by combining miR-21 in situ hybridization with immunohistochemical staining for cytokeratin and budding cell marker laminin-γ2, and stained 16 colon cancer cases (stage II, n=5, stage III, n=11). We then employed a confocal scanning microscope to obtain 15-55 GB digital images covering areas of 10-40 mm2 of the invasive front. The high resolution of the confocal digital images allowed detailed examination of the 4-fluorophore-stained slides using extended focus and z-stack images, e.g. in the discrimination of epithelial cells from adjacent stromal cells. All cytokeratin-positive budding cells were evaluated for the presence of miR-21 and laminin-γ2. Five out of the 16 cases had more than 10% miR-21 positive budding cells, a few of which were also laminin-γ2 positive. All five cases were stage III cancers. The presence of miR-21 in the budding cancer cells was not associated with the level of tumor budding. These observations suggest that the miR-21 expression in tumor budding cells increases with the progression of the cancer and is independent of laminin-γ2. References: 1. Nielsen BS et al, Clin Exp Mets 2011, 28:27-38. 2. Kjaer-Frifeldt S et al, Br J Cancer 2012, 107:1169-1174.
Citation Format: Boye Schnack Nielsen, Kirsten Nguyen Knudsen, Jan Lindebjerg, Alexandra Kalmár, Béla Molnár, Flemming Sorensen, Torben Hansen. Characterization of miR-21 expression in budding colon cancer cells using digital images of multiplex fluorescence stained slides obtained by confocal scanning microscopy [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 475.
Abstract 4776: Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer
Authors: Yoshioka Takahiro , Shien Kazuhiko , Takahashi Yuta , Kurihara Eisuke , Namba Kei , Ogoshi Yusuke , Torigoe Hidejiro , Sato Hiroki , Yamamoto Hiromasa , Soh Junichi , Fujiwara Toshiyoshi , Toyooka Shinichi 
Published: August 2018

Abstract
Purpose: Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-HER2 drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. Among HER2 targeting drug, afatinib and neratinib inhibit the activation of all HER family protein, and are called pan-HER inhibitors. In this study, we examined the effect of these pan-HER inhibitors to gastric cancer cells. Materials and Methods: We determined the molecular profiles of 12 gastric cancer cell lines. Protein level of HER2 and down-signal pathway molecules were analyzed by Western blotting, and copy number assay or gene expression assay were performed using qPCR. To detect HER2 mutation, we also performed direct-sequence of these cell lines. And next, we examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines, in vitro and in vivo. In addition, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. Results: HER2 was amplified in 5 out of 12 gastric cancer cell lines. Gene expression or protein level of HER2 were generally correlated with the copy number of HER2. HER2 mutation was found in one cell line, ECC10, at kinase domain (L755S). In the drug sensitivity analysis, both afatinib and neratinib showed an anti-tumor effect in all the HER2 amplified cell lines both in vitro and in vivo except MKN7 cell line. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene by inhibiting the activation of IGF-1R, were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, demonstrated a notable synergistic effect. Regarding HER2 alteration in 123 clinical samples, we found 19 cases of HER2 amplification and 3 cases of oncogenic mutations. Conclusion: Afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer.
Citation Format: Takahiro Yoshioka, Kazuhiko Shien, Yuta Takahashi, Eisuke Kurihara, Kei Namba, Yusuke Ogoshi, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Toshiyoshi Fujiwara, Shinichi Toyooka. Antitumor activity of pan-HER inhibitors in HER2-positive gastric 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 4776.
Abstract 4777: Antitumor effect of neratinib in lung cancers harboring HER2 oncogene alterations
Authors: Ogoshi Yusuke , Toyooka shinichi , Soh Jyunichi , Yamamoto hiromasa , Shien Kazuhiko , torigoe Hidejiro , sato Hiroki , Yoshioka Takahiro , Namba Kei , Takahashi Yuta , Kurihara Eisuke 
Published: August 2018

Abstract
Background The HER2-targeted therapy for non-small cell lung cancer (NSCLC) harboring HER2 oncogene alterations is one of promising strategy to improve the clinical outcome of treatment for NSCLC. In this study, we investigated the antitumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI) in NSCLC cells harboring HER2 alterations including mutation and amplification.
Materials and Methods We examined the sensitivity of neratinib against normal bronchial epithelial cells BEAS-2B which ectopically overexpressing wild-type or mutant HER2. Furthermore, we examined the antitumor activity of neratinib in addition to afatinib in several NSCLC cell lines harboring HER2 or EGFR alterations in in vitro and in vivo experiments, and investigated the association between their genetic alterations and sensitivity to neratinib treatment.
Results BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D, and S310F) showed constitutive autophosphorylation of HER2 and activation of downstream signaling by Western blotting. These BEAS-2B cells were sensitive to neratinib, but insensitive to erlotinib, a first generation EGFR-TKI. Neratinib also showed antiproliferative effects on both HER2-altered (H2170, Calu-3, and H1781) and EGFR-mutant (HCC827, PC9, and HCC4006) NSCLC cell lines. Neratinib administration showed strong antitumor effect on tumor growth in mouse xenograft model using HER2-altered lung cancer cell lines.
Conclusions Our study strongly suggests that neratinib is a promising therapeutic option for the treatment of HER2-altered NSCLC.
Citation Format: Yusuke Ogoshi, shinichi Toyooka, Jyunichi Soh, hiromasa Yamamoto, Kazuhiko Shien, Hidejiro torigoe, Hiroki sato, Takahiro Yoshioka, Kei Namba, Yuta Takahashi, Eisuke Kurihara. Antitumor effect of neratinib in lung cancers harboring HER2 oncogene alterations [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 4777.
Abstract 4778: Assessing efficacy of neratinib in HER2-driven lung cancer
Authors: Li Shuai , Liu Shengwu , Chen Ting , Deng Jiehui , Wu Min , Kuraguchi Mari , Tran Cam Anh , Kirschmeier Paul T. , Avogadri-Connors Francesca , Cutler Richard E. , Lalani Alshad S. , Wong Kwok-Kin 
Published: August 2018

Abstract
HER2 mutations have been classified as oncogenic drivers that are present in 2-4% of lung adenocarcinomas. However, due to limited preclinical studies and clinical trials, there is still no available standard of care for this group of lung cancer patients. To fulfill the clinical need for targeting HER2 mutations in lung cancer patients, we performed a comprehensive preclinical study to evaluate the efficacy of neratinib, an irreversible small-molecule pan-HER tyrosine kinase inhibitor that potently binds and inhibits EGFR, HER2, and HER4. We used the previously described genetically modified mouse model (GEMM) of lung adenocarcinomas driven by the major mutant form of human HER2 exon 20 insertions (A775_G776insYVMA) for testing neratinib either as a single agent or in combination with other therapies including trastuzumab in vivo. Treatment efficacy was evaluated based on both monitoring tumor volume changes and survival. Magnetic resonance imaging (MRI) was used for quantifying tumor burden. Tolerability and the overall health of animals were evaluated based on body weight change. We found that neratinib treatment alone provided a modest yet significant response in inhibiting HER2 mutant lung tumors in this model. Pharmacodynamic studies showed that neratinib effectively abolished HER2 phosphorylation and inhibited major downstream signaling targets such as pAKT and pERK. Moreover, combination therapy with neratinib and trastuzumab showed a greater treatment effect by reducing tumor burden with significantly longer progression-free survival and overall survival compared to single agents tested. In all neratinib-based regimens, body weight of treated animals remained stable. On this basis, our study provides a strong rationale to test the combination of neratinib with trastuzumab for the treatment of HER2 mutant NSCLC patients.
Citation Format: Shuai Li, Shengwu Liu, Ting Chen, Jiehui Deng, Min Wu, Mari Kuraguchi, Cam Anh Tran, Paul T. Kirschmeier, Francesca Avogadri-Connors, Richard E. Cutler, Alshad S. Lalani, Kwok-Kin Wong. Assessing efficacy of neratinib in HER2-driven lung 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 4778.
Abstract 4782: Inhibition of FGFR in breast cancer metastasis
Authors: Lin Hang , Akhand Saeed S. , Wendt Michael K. 
Published: August 2018

Abstract
Metastatic breast cancer is the most advanced stage of breast cancer. This type of cancer can spread other organs and cause 90% of cancer-related death. However, little is known about the molecular mechanisms which drive metastasis in breast cancer. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) promote tumor invasion and metastasis. Previously, it has been reported that fibroblast growth receptor 1 plays a key role during EMT: MET cycle. Therefore, optimizing FGFR inhibitors is crucial for therapeutic targeting of late-stage breast cancer. Here, we examined the efficacies of three FGFR kinase inhibitors, AZD4547, JNJ-42756493 and FIIN4, in the 4TO7 cell line both in vitro and in vivo. The 4TO7 cell line is a syngeneic model of systemic dormancy. Mammary fat pad engraftment of the 4T07 cells onto immune competent Balb/C mice results in systemic dissemination, but no macroscopic metastasis. In contrast, the 4T07 cells can escape cellular dormancy in 3D culture and form robust pulmonary tumors in mice upon tail vein inoculation. Furthermore, the 4TO7 cell line robustly responses to exogenous stimulation with FGF2. The phosphorylation of Erk1/2 downstream of FGFR was stimulated after a five-minute treatment with FGF2 and was effectively blocked with all the inhibitors tested. Furthermore, we developed a 3D culture approach that combines tumor spheroid formation in a non-adherent round bottom dish followed by placement on a bed of matrix. Our in vitro results demonstrate that both JNJ-42756493 and FIIN4 have more potent anti-proliferative activities in 3D culture and longer residence time as compared to AZD4547. In vivo, inhibition of FGFR is highly effective against 4TO7 tumors in the pulmonary microenvironment. Importantly, FIIN4 showed the least toxicity. This result suggested that covalent inhibition of FGFR is a promising cancer therapy for patients with metastatic breast cancer.
Citation Format: Hang Lin, Saeed S. Akhand, Michael K. Wendt. Inhibition of FGFR in breast cancer metastasis [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 4782.