bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5758: Generation and characterization of novel monoclonal antibodies against overexpressed CD109 on pancreatic cancer cells for use in diagnosis and therapy
Authors: Arias-Pinilla Gustavo A. , Dalgleish Angus , Mudan Satvinder , Bagwan Izhar , Walker Tony , Modjtahedi Helmout 
Published: August 2018

Abstract
Pancreatic cancer is one of the most aggressive and lethal types of cancer, and more effective therapeutic agents are urgently needed. Overexpressed cell surface antigens are ideal targets for therapy with monoclonal antibody (mAb)-based drugs, and several have been approved for the treatment of human cancers; however, none have approval for pancreatic cancer. Our aim was to discover novel overexpressed cell surface antigens in human pancreatic cancer cells using mAb technology. We have generated two novel mouse mAbs, KU42.33C and KU43.13A, against the human pancreatic cancer cell line BxPC-3. Using ELISA, flow cytometry, competitive assay and mass spectrometry, we discover that these two mAbs target two distinct epitopes on the external domain of CD109 that are overexpressed by varying amounts in human pancreatic cancer cell lines. Treatment with these two naked antibodies alone did not affect tumor cell growth in vitro or cell migration. Of the two mAbs, only KU42.33C was useful in determining the expression of CD109 in tumor cells by Western blot and immunohistochemistry. Immunohistochemistry of human pancreatic carcinoma arrays with mAb KU42.33C showed that 94% of the 65 human pancreatic adenocarcinoma cases were CD109 positive, with no expression in normal pancreatic tissues. Our results suggest that these two novel mAbs are excellent tools for determining the expression level of CD109 in the tumor specimens and sera of patients with a wide range of cancers, in particular pancreatic cancer, and for investigating its diagnostic, prognostic and predictive value. Further research should unravel the therapeutic potential of the humanized forms or the conjugated versions of such antibodies in patients whose tumors overexpress CD109 antigen.
Citation Format: Gustavo A. Arias-Pinilla, Angus Dalgleish, Satvinder Mudan, Izhar Bagwan, Tony Walker, Helmout Modjtahedi. Generation and characterization of novel monoclonal antibodies against overexpressed CD109 on pancreatic cancer cells for use in diagnosis and 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 5758.
Abstract 5767: Vascular endothelial growth factor receptor 2 targeted photoimmunotherapy
Authors: Mitsunaga Makoto , Nishimura Takashi , Ito Kimihiro 
Published: August 2018

Abstract
Background
Photoimmunotherapy (PIT) is a new class of molecular targeted cancer theranostics, which employs monoclonal antibody (mAb) conjugated to a photosensitizer, IR700, that is activated by focal near-infrared (NIR) light irradiation leading to necrotic cell death by cell membrane rapture where mAb-IR700 conjugates binds to target membrane proteins specifically. We have previously demonstrated HER2-targeted PIT employing trastuzumab-IR700 conjugates for HER2 expressing cancers. However, some cancer cells were survived partly because of tumor heterogeneity and inhomogeneous micro-distribution of mAb-IR700 conjugates. In this study, we developed a new type of PIT agents targeting VEGFR-2 expressed on vascular endothelium in a tumor and evaluated the feasibility by comparing conventional PIT in vitro and in vivo.
Methods
HER2-positive human gastric cancer cells, NCI-N87, were used for the experiments. HER2-targeting trastuzumab and VEGFR-2-targeting ramucirumab were conjugated to IR700. Cells were treated with mAb-IR700 conjugates followed by NIR light irradiation after washing the cells. LIVE/DEAD assay was performed to assess short-term phototoxicity and trypan blue dye exclusion assay to assess long-term phototoxicity. Next, mouse tumor xenograft models were created for in vivo PIT. Tumor-bearing mice were randomized and treated with mAb-IR700 conjugates followed by NIR light irradiation under anesthesia. Antitumor effects were monitored by measuring tumor diameters with a caliper.
Results
PIT utilizing ramucirumab-IR700 conjugates did not induce phototoxic effect in vitro because of the absence of membranous expression of VEGFR-2 in NCI-N87 cells, while PIT utilizing trastuzumab-IR700 conjugates induced rapid phototoxic effect because of the strong membranous expression of HER2 in NCI-N87 cells. By contrast, antitumor effects were observed in NCI-N87 xenograft tumors in vivo utilizing both ramucirumab- and trastuzumab-IR700 conjugates followed by NIR light irradiation. Microscopic analysis of the harvested tumors showed decreasing tumor micro-vessel densities only when tumors were treated with PIT utilizing ramucirumab-IR700 conjugates but not trastuzumab-IR700, which represents a different mechanism than that of conventional PIT targeting antigens expressed on the tumor cell membrane.
Conclusion
We demonstrated a new mechanism of PIT utilizing ramucirumab-IR700 conjugates. As VEGFR-2 is upregulated in many types of solid cancers, this method may be considered as being applicable to various types of cancers in future clinical settings.
Citation Format: Makoto Mitsunaga, Takashi Nishimura, Kimihiro Ito. Vascular endothelial growth factor receptor 2 targeted photoimmunotherapy [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 5767.
Abstract 5786: Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies
Authors: Lara Olivia D. , Rodriquez-Aguayo Cristian , Bayrakter Emine , Amero Paola , Mangala Selanere , LaFargue Chris , Tari-Ashizawa Ana , Lopez-Berestein Gabriel , Sood Anil 
Published: August 2018

Abstract
Prexigebersen (liposome-incorporated nuclease resistant antisense oligonucleotides specific for GRB2, L-GRB2) has proven highly effective in the treatment of leukemia, however its application in solid malignancies including gynecologic cancer has yet to be investigated. Given the biological significance of GRB2, we aim to assess the effect of prexigebersen in pre-clinical models. We tested the clinical significance of GRB2 using publicly available high-throughput data. We investigated the expression of GRB2 in a series of in vitro (Western Blotting) experiments in high-grade serous (HGSC) and uterine (UC) carcinoma models. We also tested in vivo (orthotopic mouse model) the biological effects of prexigebersen in HGSC models (OVCAR 5), first in a dose-defining experiment then in combination with standard dose paclitaxel. We first examined GRB2 using TCGA and GISTIC data and found alterations (amplifications, deletions and mutations) in 6% (33 of 594) of HGSC cases and 5% (25 of 547) of UC cases. Amplifications of GRB2 are associated with a decreased patient survival (p&lt;0.01) in UC, suggesting it to be an attractive therapeutic target. GRB2 was expressed in most ovarian (HEYA8, OVCAR5, SKOV3, and OVCAR3) and uterine (MFE 319, Ishikawa and Hec1a) cancer cell lines tested. We performed a dose-defining in vivo experiment on an orthotopic mouse model of ovarian cancer (OVCAR 5). We found a maximum decrease in GRB2 expression at a dose of 15 mg/kg prexigebersen and a dose dependent decrease in tumor burden (p&lt;0.05). We then performed an additional in vivo model in which prexigebersen was combined with standard dose paclitaxel. There was an eighty-six percent decrease in tumor burden (p&lt;0.05), and multinodular burden (p&lt;0.01) in the combination prexigebersen/paclitaxel group compared to control. Prexigebersen shows promising preclinical efficacy and may be a novel therapeutic strategy in gynecologic malignancies.
Citation Format: Olivia D. Lara, Cristian Rodriquez-Aguayo, Emine Bayrakter, Paola Amero, Selanere Mangala, Chris LaFargue, Ana Tari-Ashizawa, Gabriel Lopez-Berestein, Anil Sood. Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies [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 5786.
Abstract 5796: Modulation of transcription factor landscape through BET family protein inhibition is dependent on specific driver mutations in pancreatic cancer
Authors: Weldon Mikele G. , Wang Albert R. , Beyer Hope A. , Stiles Shannon G. , Iyer Gopal 
Published: August 2018

Abstract
Targeting of bromodomain and extra-terminal domain (BET) family protein activity has the potential to reduce proliferation in many cancers. However, changes in transcription factor (TF) landscape can be influenced by different mutational profiles of specific cancers. Within this mutational background, BET proteins can target these TFs and create an oncogenic phenotype. To exploit these altered TF readouts, we tested the hypothesis that inhibition of BET activity in different genetic mutations of pancreatic cancer will lead to antiproliferative effects. Towards this, we treated pancreatic cancer cell lines that had mutations in KRAS, CDKN1A, SMAD4 and TP53 with a bromodomain inhibitor. We showed that cell lines with CDKN1A deletion and wild-type SMAD4 were highly resistant to BET inhibition and had a high nanomolar IC50 concentration. Through targeted transcription factor gene expression profiling of over 400 TFs, we discovered that LMO2, GTF2B, ID1, and CREB1 were upregulated, while SALL4, TCF4, and TP63 were downregulated in these cell lines. This suggests that these TFs may be partly responsible for resistance to BET inhibition. Furthermore, we showed dramatic changes in TF landscapes in pancreatic cancer cells sensitive to BET treatment compared to the resistant cells. This indicates that for antiproliferative effects in pancreatic cancer cells, modulating BET activity may be necessary to switch on or off specific TFs. Together, these results suggest that BET inhibitors may be useful in pancreatic cancer treatment and that mutation-specific differences in TF targets of BETs may dictate the progression of pancreatic cancer.
Citation Format: Mikele G. Weldon, Albert R. Wang, Hope A. Beyer, Shannon G. Stiles, Gopal Iyer. Modulation of transcription factor landscape through BET family protein inhibition is dependent on specific driver mutations in pancreatic 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 5796.
Abstract 5797: BET inhibitor synthetic lethality in malignant peripheral nerve sheath tumors
Authors: Cooper Jonathan M. , Patel Amish J. , Chen Zhiguo , Liao Chung-Ping , Chen Kun , Wang Yong , Le Lu Q. 
Published: August 2018

Abstract
BET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in pre-clinical studies, but molecular indicators of tumor response are lacking. Through modeling tumor evolution by studying genetic lesions underlying the development of Neurofibromatosis Type 1 (NF1)-associated Malignant Peripheral Nerve Sheath Tumors (MPNST), a lethal sarcoma with no effective medical treatment, we identified a BRD4 dependency that serves as a controlled model system to delineate mechanisms of sensitivity or resistance to BET bromodomain inhibitors in this disease. In this study, we show that loss of NF1 and p53 is associated with increased BRD4 protein levels and partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 profoundly sensitizes MPNST cells to diverse BET inhibitors in culture and in vivo, while wild-type cells are spared. Collectively, genetic and pharmacological inhibition of BRD4 reveals that BET inhibitor resistance in MPNST requires wild-type BRD4 to support growth in a bromodomain-independent manner. Our findings provide a framework for understanding BET inhibitor sensitivity and resistance within distinct molecular subsets of MPNST. In addition, discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 levels nominates a BRD4-low patient subpopulation as that which might best respond to a BET inhibitor therapeutic strategy for MPNST.
Citation Format: Jonathan M. Cooper, Amish J. Patel, Zhiguo Chen, Chung-Ping Liao, Kun Chen, Yong Wang, Lu Q. Le. BET inhibitor synthetic lethality in malignant peripheral nerve sheath 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 5797.
Abstract 581: Feasibility test of KRAS mutation in urine circulating tumor DNA in metastatic pancreatic ductal adenocarcinoma
Authors: Kwon Min Jeong , Kim Min Kyeong , Woo Sang Myung , Yoon Kyong-Ah , Kim Yun Hee , Park Boram , Joo Jung Nam , Park Sang Jae , Kong Sun-Young 
Published: August 2018

Abstract
Circulating tumor DNA (ctDNA) has been known to be released from tumor cells and evaluated as potential biomarkers for therapeutic responses. In our previous study, we selected KRAS mutation and evaluated applicability as a prognostic marker through the quantitative analysis of plasma ctDNA. Then we proved that KRAS mutation of ctDNA from plasma is significant biomarker for prediction of clinical outcome in pancreatic ductal adenocarcinoma (PDA). Here we investigated whether KRAS mutation in urine ctDNA had the prognostic impact as shown of plasma ctDNA. Of the 106 patients enrolled, 67 were males and median age was 66 years. Total of 51 PDA has been enrolled in this study and the median age was 63 years old and 30 males (58.8%). Urine was separated by established centrifugation method and ctDNA were extracted using QIAamp Circulating Nucleic Acid Kit (Qiagen, Germany) from 4 mL of urine. Extracted ctDNA was quantified using the Qubit dsDNA HS Assay Kit (Thermo Fisher Scientific, USA). QX200 Droplet Digital PCR System (Biorad, USA) was applied to measure frequency of KRAS mutation by KRAS screening multiplex droplet digital PCR kit, which covers seven common mutation sites (Biorad, USA). Mutant concentration and fractional abundance were analyzed by QuantaSoft software (Biorad, USA). There was no significant difference between resectable (N=21), locally advanced (N=11) and metastatic (N=19) groups. When compared high versus low KRAS mutation concentration and KRAS fractional abundance group in each stage, high KRAS mutation groups showed short overall survival (p = 0.0321) in metastatic group. However, the correlation between plasma and urine was low (r=0.193) in metastatic group. This study represented the possibility of KRAS mutation concentration and fractional concentration of urine ctDNA as prognostic factors in metastatic PDA. Urine cfDNA role has not been well investigated in PDA. Urine is easy to obtain and is not well known for its mechanism. Therefore, we have conducted a pilot study and we will explore KRAS mutation status in urine ctDNA in further studies. (This study was supported by National Cancer Center, Korea, Grant no. 1510203.)
Citation Format: Min Jeong Kwon, Min Kyeong Kim, Sang Myung Woo, Kyong-Ah Yoon, Yun Hee Kim, Boram Park, Jung Nam Joo, Sang Jae Park, Sun-Young Kong. Feasibility test of KRAS mutation in urine circulating tumor DNA in metastatic pancreatic ductal adenocarcinoma [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 581.
Abstract 5812: Synergistic induction of urinary bladder cell death and reduction of drug resistance in vitro and effective control of xenograft tumor growth in vivo by a triple combination of gemcitabine, cisplatin, and romidepsin
Authors: Wang Hwa-Chain R. , Pattarawat Pawat 
Published: August 2018

Abstract
Human urinary bladder cancer is the fifth most commonly diagnosed cancer in the United States. Long-term survival of patients is still suboptimal with current therapeutic regimens failing to impede drug resistance and recurrence. Thus, it is urgent to develop therapeutic regimens that effectively control tumor growth, drug resistance, and recurrence to reduce the morbidity and mortality of this disease. We investigated the efficacy of combination regimens to control various human urinary bladder cancer cells in vitro and cell-derived xenografts in vivo. Our studies revealed, for the first time, a combination of gemcitabine plus cisplatin and romidepsin effective in synergistically inducing cell death and reducing drug resistance in vitro. The enhanced Ras-ERK-Nox pathway played an essential role in mediating signals to elevate reactive oxygen species, leading to enhanced caspase activation, enhanced DNA damage and oxidation, and reduced glutathione, which synergistically increased cell death and reduced drug resistance in cells treated with combined gemcitabine, cisplatin, and romidepsin. The unfolded protein response also played a role in the modulation of cyto-protection and cell death through the combined regimen. In vivo studies verified the efficacy of gemcitabine plus cisplatin and romidepsin in control of xenograft tumor growth in immune-deficient mice. Hence, our results lead us to suggest that a combination of gemcitabine, cisplatin, and romidepsin should be seriously considered as an advanced regimen over the conventional gemcitabine plus cisplatin regimen for controlling the development and recurrence of human urinary bladder cancer.
Citation Format: Hwa-Chain R. Wang, Pawat Pattarawat. Synergistic induction of urinary bladder cell death and reduction of drug resistance in vitro and effective control of xenograft tumor growth in vivo by a triple combination of gemcitabine, cisplatin, and romidepsin [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 5812.
Abstract 5815: Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages
Authors: Sonowal Himangshu , Saxena Ashish , Ramana Kota V. , Srivastava Satish K. 
Published: August 2018

Abstract
Anthracycline class of chemotherapeutic drugs such as doxorubicin and daunorubicin has been known to be effective in the therapy of various types of cancer. However, in certain cancers such as colon cancer, the use of anthracyclines is restricted due to acquired drug resistance, which requires high amounts of drugs that cause severe toxic side effects. We have recently demonstrated that aldose reductase (AR) inhibitor, fidarestat, increases the sensitivity of doxorubicin towards colon cancer cells death in vitro and in vivo and decreases cardiotoxicity. However, the mechanisms through which AR inhibitor prevents doxorubicin-induced toxicity is not understood. We have examined how AR inhibition prevents doxorubicin-induced endothelial and cardiac toxicity along with inflammatory response in in vitro and in vivo models. Our results demonstrate that fidarestat prevents doxorubicin-induced oxidative stress, endothelial cell death, and monocyte adhesion. Further, fidarestat prevents the activation of NF-κB-dependent expression of endothelial cell markers ICAM-1 and VCAM-1 and expression of various inflammatory cytokines and chemokines in human vascular endothelial cells. In addition, fidarestat prevented the doxorubicin-induced decrease in eNOS and increase in iNOS expression. Similarly, AR inhibition prevented doxorubicin-induced endothelial dysfunction, cardiac hypertrophy, and cardiomyocyte injury in mice. Fidarestat also prevented doxorubicin-induced activation of monocytes and macrophages to proinflammatory phenotype in culture as well as in mouse models. Thus, our results suggest that by preventing doxorubicin-induced inflammatory as well as oxidative stress signals, fidarestat decreases cardiotoxic effects of doxorubicin. This is a novel adjuvant therapy of cancer using aldose reductase inhibitors with anthracyclines that would increase cancer therapeutic efficacy and decrease cardiotoxic side effects.
Citation Format: Himangshu Sonowal, Ashish Saxena, Kota V. Ramana, Satish K. Srivastava. Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages [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 5815.
Abstract 5821: Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies in ovarian cancer
Authors: Kalogera Eleftheria , Roy Debarshi , Bakkum-Gamez Jamie N. , Cliby William A. , Dowdy Sean C. , Shridhar Viji 
Published: August 2018

Abstract
Objectives: To investigate the antitumor potential of the widely used anticholesterol drug Atorvastatin (ATV) alone, in combination with Carboplatin (CBPT) and with the glycolytic inhibitor PFK158 (PFKi) in ovarian cancer (OC).
Methods: MTT assay and the Chou-Talalay methodology were used to test anticancer activity in vitro; half maximal inhibitory concentration (IC50) and combination index (CI) were calculated. Cellular changes were studied with transmission electron microscopy (TEM). ATV was combined with PFKi as we previously showed that PFKi, in addition to glycolysis, inhibits lipid metabolism by targeting PLA2G3. PLA2G3 expression was studied by western blot given that downregulation in OVCAR8 using two shRNAs (sh33, sh35) induced autophagy, a prodeath condition in OC, and was associated with chemosensitization compared to nontargeted controls (NTC) (unpublished data). A random sample of 10 patient-derived OC xenografts (PDX) was studied by TEM.
Results: OVCAR8 exhibited a dose dependent proliferation inhibition when treated with ATV (IC50 8μM). PFKi and CBPT IC50 were 4μM and 78μM. PFKi treatment combined with 4μM and 8μM of ATV resulted in ATV sensitizing cells to PFKi by shifting PFKi IC50 down to 2.7μM and 0.4μM, respectively. When ATV was combined in constant ratio with CBPT, CIs were &gt;1.1 indicating antagonism. Combination of ATV 4μM with PFKi 2μM resulted in greater decrease in PLA2G3 and p62 and greater increase in cleaved PARP compared to PFKi alone suggesting higher levels of autophagy and apoptosis. ATV and combination treatment resulted in increased caveolin-1 levels, previously shown to be associated with apoptotic cell death. TEM analysis of ATV and PFKi treated cells showed greater number of lipid rich multilamellar bodies (MLB) compared to controls. PLA2G3 knockdowns exhibited higher MBL formation, lower p62, and when treated with statin and with PFKi, cleaved PARP was significantly higher compared to NTCs. TEM showed that PDXs clustered in low and high MLB groups suggesting a distinct novel phenotype.
Conclusions: ATV could enhance PFKi antitumor activity by jointly targeting PLA2G3 leading to metabolic reprogramming of OC. Importantly, ATV antagonized CBPT. Additional studies are in progress to explore the mechanistic pathway of ATV and characterize the significance of MLB in OC as a prodeath phenotype and biomarker of response.
Citation Format: Eleftheria Kalogera, Debarshi Roy, Jamie N. Bakkum-Gamez, William A. Cliby, Sean C. Dowdy, Viji Shridhar. Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies 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 5821.