bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 822: Predicting response to kinase inhibitors based on tumor genomics in NF1-related MPNSTs
Authors: Grit Jamie , Pridgeon Matt , Tovar Elizabeth , Madaj Zachary , Peacock Jackie , Wulfkuhle Julia , Petricoin Emanuel , Graveel Carrie , Steensma Matt 
Published: August 2018

Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive, chemoresistant sarcomas that develop in patients with the genetic disorder Neurofibromatosis Type 1 (NF1). Loss of TRP53 and amplification of the receptor tyrosine kinase (RTK) MET is observed 25-50% of cases. To investigate the role of MET and p53 in MPNST progression, we developed three MPNST mouse models: an NF1 null and MET overexpression MPNST model (NF1-MET), an NF1 and TRP53 heterozygous knockout model (NF1-p53), and a NF1 null model (NF1). Using orthotopic tumorgrafts from these models, we tested the efficacy of MET (capmatinib) and MEK (trametinib) inhibition on MPNST growth. Trametinib moderately inhibited tumor growth in all of the models; however, combined inhibition of MEK and MET was highly effective in both the NF1-MET and NF1 models. NF1-p53 tumors were the least responsive to combined inhibition and upregulated AKT signaling in response to single agent therapy. These data suggest that alternate RTK signaling pathways downstream of MET may compensate for MEK inhibition, and that p53 loss promotes kinome reprogramming in response to targeted inhibition in MPNSTs. To determine the effects of MEK, MET, PI3K, and mTOR inhibition on kinome signaling, we generated MPNST cell lines from each of our MPNST models. Western blot analysis revealed that NF1-MET MPNST cells are highly sensitive to MET inhibition, NF1-p53 MPNST cells maintain ERK and AKT activity in the presence of MET inhibition, and NF1-p53 MPNST cells uniquely upregulate MEK signaling in response to PI3K/mTOR inhibition. These results suggest p53 plays a unique role in kinome reprograming and resistance to kinase inhibitors. Currently, we are determining the effects of combined kinase inhibition on proliferation of MPNST cells and utilizing reverse phase protein arrays to evaluate the effect of MET and MEK inhibition on the phospho-proteome in our MPNST models. By understanding these complex signaling networks we will identify combinations of targeted therapies that can be used to effectively treat MPNSTs.
Citation Format: Jamie Grit, Matt Pridgeon, Elizabeth Tovar, Zachary Madaj, Jackie Peacock, Julia Wulfkuhle, Emanuel Petricoin, Carrie Graveel, Matt Steensma. Predicting response to kinase inhibitors based on tumor genomics in NF1-related MPNSTs [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 822.
Abstract 826: Th1 cytokines and EGFR inhibition: A combinatorial therapeutic strategy in TNBC
Authors: Basu Amrita , Kodumudi Krithika , Wiener Doris , Czerniecki Brian 
Published: August 2018

Abstract
Oncodrivers are a promising target in novel breast cancer therapy development, owing to oncogene addiction of breast cancer cells to sustain their malignancy. We have previously shown progressive loss of CD4+ T-helper type 1 response to oncodrivers in triple negative breast cancer (TNBC) patients. TNBC is marked by lack of cell surface ER, PR and Her2 receptors and is the most aggressive subtype of breast cancer. Lack of therapeutic targets, resistance to existing hormone therapy, metastasis and poor survival in TNBC patients underline the need for novel TNBC therapy development. In this study, we investigated the effect of EGFR inhibitors (cetuximab, erlotinib and lapatinib) alone or combination with Th1 cytokines (IFN-γ and TNF-α) on growth and proliferation of MDA-MB-231 and MDA-MB-468 TNBC cells. We observed decrease in EGFR expression in TNBC cells when treated with IFN-γ alone and in combination with EGFR inhibitors. In addition, IFN-γ alone, in combination with TNF-α and all three EGFR inhibitors, markedly increased STAT1 phosphorylation, indicating suppression of growth and proliferation in TNBC cells. Decreased STAT3 phosphorylation by combination treatment in TNBC cells may induce apoptosis and inhibit proliferation further. Combination of cetuximab and IFN-γ increased cleaved caspase-3 expression in MDA-MB-231, but not in MDA-MB-468 TNBC cells. EGFR inhibition and Th1 cytokine treatment showed combination treatment resulted in severe cell loss and morphological alteration, while Th1 cytokines alone did not induce significant senescence in MDA-MB-231 cells in senescence associated β-galactosidase assay. We are currently investigating activation status of other signaling pathways in TNBC cells, following Th1 cytokines treatment with EGFR inhibition. Our data suggests a combinatorial treatment approach, including DC1 vaccination to elicit Th1 immune response and inhibition of EGFR oncodriver, may lead to an effective and novel therapeutic strategy for triple negative breast cancer.
Citation Format: Amrita Basu, Krithika Kodumudi, Doris Wiener, Brian Czerniecki. Th1 cytokines and EGFR inhibition: A combinatorial therapeutic strategy in TNBC [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 826.
Abstract 836: ISU104, a fully human anti-ErbB3 antibody, overcomes acquired cetuximab resistance
Authors: Kim Miyoung , Hur Youngmi , Hong Mirim , Sohn Youngsoo , Shin Kum-Joo , Kim Kyungyong , Hong Seung-Beom , Shin Kum-Joo , Bae Donggoo 
Published: August 2018

Abstract
ErbB3 is noted as one of major causes of acquired cetuximab resistance in colorectal and head and neck cancers. ErbB3 causes activation of alternative signaling pathways that bypass the original target and sustained PI3K/AKT activation, and these are associated with cetuximab resistance. We confirmed the induced ErbB3 activation by the cetuximab treatment in FaDu head and neck squamous-cell carcinoma (HNSCC) xenograft model. Immunoblot analysis was shown that twice weekly 10 mg/kg of cetuximab treatment upregulated ErbB3 expression and phosphorylation even though tumor growth was well controlled. To investigate whether ErbB3 activation by ligand, heregulin (HRG,) might induce cetuximab resistance, two cetuximab-sensitive colorectal cancer cell lines, DiFi and LIM1215, were treated 0-25 ng/mL of HRG. HRG induced dose-dependent cetuximab resistance in cell proliferation assay, and this was reversed via ISU104 treatment. To evaluate if ISU104 could overcome resistance to cetuximab in vivo, acquired cetuximab-resistant FaDu xenograft model was established. Tumors that had acquired resistance to 5 mg/kg of cetuximab treatment were significantly regressed by replaced treatment of ISU104 alone (10 mg/kg) or combination treatment of ISU104 and cetuximab, while mice continued on cetuximab only showed uncontrolled tumor growth like vehicle-treated group. Our results suggest that ISU104 effectively overcomes cetuximab resistance and may provide clinical benefit to cetuximab-resistant patients.
Citation Format: Miyoung Kim, Youngmi Hur, Mirim Hong, Youngsoo Sohn, Kum-Joo Shin, Kyungyong Kim, Seung-Beom Hong, Kum-Joo Shin, Donggoo Bae. ISU104, a fully human anti-ErbB3 antibody, overcomes acquired cetuximab resistance [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 836.
Abstract 837A: Combining CRISPR/Cas9 mutagenesis and a small-molecule inhibitor to probe the function of MELK in cancer
Authors: Giuliano Christopher J. , Lin Ann , Smith Joan C. , Palladino Ann C. , Sheltzer Jason M. 
Published: August 2018

Abstract
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. Furthermore, MELK-knockout lines remain sensitive to OTS167, suggesting that this drug blocks cell division through an off-target mechanism. By combining our MELK-knockout clones with a new highly-specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cancer patients identifies MELK expression as a correlate of mitotic activity, explaining its association with poor prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.
Citation Format: Christopher J. Giuliano, Ann Lin, Joan C. Smith, Ann C. Palladino, Jason M. Sheltzer. Combining CRISPR/Cas9 mutagenesis and a small-molecule inhibitor to probe the function of MELK 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 837A.
Abstract 841: Protection of normal tissues by DIM (3,3'-Diindolylmethane) during radiation therapy
Authors: Chen Renxiang , Li Lijun , Lin Loretta Y. , Fornace Albert J. , Li Heng-Hong 
Published: August 2018

Abstract
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Citation Format: Renxiang Chen, Lijun Li, Loretta Y. Lin, Albert J. Fornace, Heng-Hong Li. Protection of normal tissues by DIM (3,3'-Diindolylmethane) during radiation 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 841.
Abstract 857: Metal oxide nanoparticles as adjuvant for radiation therapy
Authors: Wiesmann Nadine , Kluenker Martin , Tremel Wolfgang , Brieger Juergen 
Published: August 2018

Abstract
Background: Radiation therapy comprises a fundamental component of modern tumor treatment. Unfortunately, its success is limited by the development of radiation resistances. The emerging field of nanotechnology offers great opportunities for diagnosing, imaging, as well as treating cancer. Metal oxide nanoparticles in particular zinc oxide nanoparticles (ZnO-NP) have been shown to display a selective cytotoxic effect on tumor cells via a yet unknown mechanism. Most likely the generation of reactive oxygen species (ROS), breakdown of mitochondria and DNA damage are involved. The success of radiation therapy equally relies on the generation of ROS, which develop their cytotoxic potential by damaging DNA, proteins and membranes in a fashion that exceeds the repair capacity of tumor cells. Thus, our aim was to evaluate the applicability of ZnO-NP as radiosensitizer to restore the response of tumor cells to radiation therapy.
Methods: An AlamarBlueTM assay was used to evaluate the cellular metabolic activity (CMA) of A549 adenocarcinoma cells after treatment with ZnO-NP. To assess cellular viability and cell death a flow cytometric apoptosis assay was applied and genotoxicity of ZnO-NP was analysed by γH2AX foci analysis. The performance of ZnO-NP as radiosensitizer was assessed by a colony formation assay (CFA).
Results: We were able to show that ZnO-NP-mediated cytotoxicity is conveyed by dissolved Zn2+ ions as well as by the particles themselves. Treatment with ZnO-NP resulted in double-strand breaks (DSB) of the DNA measured by γH2AX foci analysis. The apoptosis assay could show induction of apoptosis in A549 cells after treatment with 100 µg/ml ZnO-NP for four hours. The colony formation assay showed that irradiation with 2 or 4 Gray, according to dosages that are typically applied in clinical settings, in combination with ZnO-NP treatment could enhance tumor cell death and reduce clonogenic survival. This revealed that ZnO-NP could improve the success of radiation therapy.
Conclusions: Our study proves that ZnO-NP exert a cytotoxic and genotoxic effect on human tumor cells. Additionally, we could show, that ZnO-NP are able to serve as radiosensitizer. Combined treatment of human tumor cells with ZnO-NP and irradiation resulted in reduction of tumor cell survival. Since nanoparticles can in principle be targeted selectively to tumor tissue, ZnO-NP could be used to specifically sensitize tumor cells for irradiation while sparing healthy tissue. All in all, the study shows that ZnO-NPs could be a promising antitumor agent.
Citation Format: Nadine Wiesmann, Martin Kluenker, Wolfgang Tremel, Juergen Brieger. Metal oxide nanoparticles as adjuvant for radiation 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 857.
Abstract 893: Hyperthermia regulates both SLC22A16 expression and ABCG2 expression via ROS production to enhance the cytotoxicity of doxorubicin
Authors: Matsui Hirofumi 
Published: August 2018

Abstract
Introduction: Hyperthermia (HT) is a non-invasive cancer therapy. Treatment temperature between 41°C to 44°C has no cytotoxic damage in normal cells, however shows cytotoxicity in cancer cells because of the underdeveloped vascular system. HT often used with other cancer therapy such as radiation therapy and chemotherapy. However mechanism of synergistic effect using these therapies remains unclear. Compared to 37°C, 42°C is mild heat stress for cells, thus superoxide anion is released from tissue. Superoxide anion is produced by mitochondrial electron transport chain. Reactive oxygen species (ROS), produced by mild heat stress, can be released from mitochondria. We have previously reported that ATP-binding cassette sub-family G member 2 (ABCG2) expression was suppressed by increasing mitochondrial ROS, andinduction of the cancer specific porphyrin accumulation. ABCG2 is a transporter of doxorubicin (DOX), therefore we hypothesized that synergistic effect of HT and chemotherapy would be induced by down-regulation of ABCG2 expression via intracellular ROS increase. In this study, we investigated if cytotoxic effect of breast cancer cell using DOX can be enhance by HT via intracellular ROS increase. Materials and methods: The murine breast cancer cell line, 4T1E was incubated at 37°C or 42°C for 1h. Intracellular ROS generation after HT treatment was detected by electron spin resonance (ESR). Twenty four hours after HT treatment, cells were incubated in medium containing 0, 0.1 and 1 μM DOX for 24 h. Cell viability was measured using the Cell Counting Kit 8, a water-soluble tetrazolium-8 based colorimetric assay. ABCG2 expression in whole cells was analyzed by Western blotting. Results and discussion: ESR signal peak with HT treatment became high as compared to without HT treatment, indicating intracellular ROS level was increased by HT treatment. Cell viability and ABCG2 expression were decreased by DOX exposure and by HT treatment. The enhancement of HT treatment effect by DOX is considered to be result of down-regulation of ABCG2 expression by ROS. Conclusion: HT treatment involved intracellular ROS production and down-regulated the expression of ABCG2 protein. HT treatment also enhanced the cell damage by DOX.
Citation Format: Hirofumi Matsui. Hyperthermia regulates both SLC22A16 expression and ABCG2 expression via ROS production to enhance the cytotoxicity of doxorubicin [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 893.
Abstract 904: The novel C-terminal truncated 90-kDa isoform of topoisomerase IIα, TOP2α/90, is a determinant of etoposide resistance in K562 leukemia cells via heterodimerization with the TOP2α/170 isoform
Authors: Kanagasabai Ragu , Karmahapatra Soumendra , Yu Yang , Hernandez Victor A. , Kientz Corey A. , Kania Evan E. , Elton Terry S. , Yalowich Jack C. 
Published: August 2018

Abstract
DNA topoisomerase IIα (170 kDa, TOP2α/170) is essential in proliferating cells since it resolves DNA topologic entanglements during chromosome condensation, replication, and segregation. We previously characterized a C-terminally truncated TOP2α/90 isoform, detectable in human leukemia K562 cells but more abundantly expressed in a clonal subline, K/VP.5, with acquired resistance to the anticancer agent etoposide (J Pharmacol Exp Ther 2017;360:152-63). TOP2α/90 (786 amino acids) is the translation product of a TOP2α mRNA that retains a processed intron 19. TOP2α/90 lacks the active-site tyrosine-805 (Tyr805) required to generate double-strand DNA breaks as well as the nuclear localization signals present in the TOP2α/170 isoform (1531 amino acids). The function of TOP2α/90 is unknown. Here, we found that TOP2α/90, like TOP2α/170, was detectable in the nucleus and cytoplasm of K562 and K/VP.5 cells. Importantly, co-immunoprecipitation of endogenous TOP2α/90 and TOP2α/170 demonstrated heterodimerization of these isoforms. Forced expression of TOP2α/90 in K562 cells suppressed, while siRNA-mediated knockdown of TOP2α/90 in K/VP.5 cells enhanced, etoposide-mediated DNA strand breaks compared with similarly treated K562 or K/VP.5 cells transfected with empty vector or control siRNAs, respectively. In addition, forced expression of TOP2α/90 in K562 cells inhibited etoposide cytotoxicity assessed by soft agar colony formation assays. qPCR and immunoassays demonstrated expression of TOP2α/90 mRNA and protein in normal human tissues/cells and in leukemia cells from patients. Together, results strongly suggest that TOP2α/90 expression decreases drug-induced TOP2α-DNA covalent complexes and is a determinant of chemoresistance through a dominant-negative effect related to heterodimerization with TOP2α/170. Alternative processing of TOP2α pre-mRNA, and subsequent synthesis of TOP2α/90, may be an important mechanism regulating the formation and/or stability of TOP2α/170-DNA covalent complexes in response to TOP2α-targeting agents.
Citation Format: Ragu Kanagasabai, Soumendra Karmahapatra, Yang Yu, Victor A. Hernandez, Corey A. Kientz, Evan E. Kania, Terry S. Elton, Jack C. Yalowich. The novel C-terminal truncated 90-kDa isoform of topoisomerase IIα, TOP2α/90, is a determinant of etoposide resistance in K562 leukemia cells via heterodimerization with the TOP2α/170 isoform [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 904.
Abstract 905: RICTOR modulation regulates cisplatin sensitivity in lung cancer
Authors: Cheng Haiying , Fan Ni , Borczu Alain , Liu Huijie , Singh Aditi , Wang Feng , Halmos Balazs , Perez-Soler Roman 
Published: August 2018

Abstract
Background: Despite treatment advances, most lung cancer patient will still receive platinum-based chemotherapy and platinum resistance remains a serious clinical problem. RICTOR is a key component of the mTOR complex 2. Activation of RICTOR signaling has been suggested to play critical roles in regulating cancer cell migration, invasion and metastasis. A recent study indicates that RICTOR contributes to cisplatin resistance in human ovarian cancer cells. We hypothesize that activation of RICTOR signaling is associated with platinum resistance in lung cancer. Thus, we tested platinum sensitivities in lung cancer cells and xenograft mouse models with different RICTOR levels. Results: RICTOR expression was found in 79% (99/125) of primary lung tumors and 67% (24/36) lung cancer cells by immunohistochemistry. The expression of RICTOR was significantly higher in squamous cell lung cancer in comparison to lung adenocarcinoma (P&lt;0.05). Overexpression of RICTOR in the Ba/F3 cells resulted in significant cisplatin resistance, whereas down-regulation of RICTOR in H23, HCC827 and H1703 lung cancer cells led to significantly improved cisplatin sensitivity. In addition, the combination of cisplatin and RICTOR knockdown significantly promoted more apoptosis than single treatment. To test the in vivo effects of RICTOR on platinum sensitivity, we performed HCC827 xenograft mouse experiments. Cisplatin alone and RICTOR knockdown alone significantly inhibited tumor growth. Moreover, RICTOR knockdown significantly increased the sensitivities to cisplatin in the xenografts and the combination led to more pronounced tumor reduction than either alone (P&lt;0.05). Conclusion: Our study provides a novel resistance mechanism to platinum treatment in lung cancer and may serve as basis to target RICTOR to overcome platinum resistance.
Citation Format: Haiying Cheng, Ni Fan, Alain Borczu, Huijie Liu, Aditi Singh, Feng Wang, Balazs Halmos, Roman Perez-Soler. RICTOR modulation regulates cisplatin sensitivity in 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 905.