bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2710: Lead based development and evaluation of selective estrogen mimics in tamoxifen resistant breast cancer
Authors: Patel Hitisha , Xiong Rui , Zhao Jiong , Molloy Mary Ellen , Tonetti Debra , Thatcher Gregory R.J 
Published: May 2015

Abstract
Tamoxifen is the standard of care for many patients with ER+ breast cancer and works by antagonizing the actions of estrogen at ER. However it poses an increased risk of endometrial cancer and thrombotic events, and most significantly, 30-50% women develop resistance to tamoxifen therapy, underlining the need for superior therapeutic options. Paradoxically, prior to tamoxifen therapy, estradiol (E2) and the ER agonist, diethylstilbestrol, had been used in breast cancer therapy, though with serious side effects. Development of Selective Estrogen Mimics (SEMs) that cause regression of tamoxifen-resistant breast cancer, but without the side effects of E2, represents a rational therapeutic strategy. Novel SEMs were developed, which in vitro in 3D cultures and in vivo caused complete regression of tamoxifen-resistant xenografts, with characteristics similar to those of E2. These SEMs did not fuel growth of estrogen-dependent T47D xenografts and did not cause uterine growth. SEM mediation of classical ER-signaling was profiled in MCF7 and MDA-MB231:β41 cells. A tamoxifen-resistant cell line, MCF-7: 5C, was used to assay induction of cell death by both E2 and the SEMs and to probe the mechanism of action. Several SEMs were observed to act as partial agonists at ERα , suggesting ideal characteristics as therapeutics. Structure-activity relationships were explored, suggesting that partial ERα agonist have the capacity to cause regression of tamoxifen-resistant tumors, without adverse effects associated with estrogenic actions in normal gynecological tissues of the breast and uterus, which might contribute to carcinogenesis. The ER-mediated agonist/antagonist activity, regression efficacy, and pharmacokinetic profiles of these SEMs were examined to obtain lead compounds that are effective with minimal estrogenic side effects. In MCF-7:5C cells, SEM-induced cell death was mediated by activation of classical nuclear ERα signaling, via induction of apoptosis. This research paves the way for use of SEMs with partial agonist activity at ER for use in tamoxifen-resistant breast cancer with enhanced safety profiles.
Citation Format: Hitisha Patel, Rui Xiong, Jiong Zhao, Mary Ellen Molloy, Debra Tonetti, Gregory R.J Thatcher. Lead based development and evaluation of selective estrogen mimics in tamoxifen resistant breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2710. doi:10.1158/1538-7445.AM2014-2710
Abstract 2728: Thermal ablative therapy with novel gold nanorods in an orthotopic model of urinary bladder cancer
Authors: Yang Xiaoping , Su Lih-Jen , Rosa Francisco G. La , Smith Elizabeth Erin , Cho Suehyun Katherine , Kavanagh Brian , Park Won , Flaig Thomas W. 
Published: May 2015

Abstract
Background
The use of nanoparticles has shown great therapeutic potential, but delivery and clearance concerns have limited their use systemically. Intravesical instillation of nanoparticles in the urinary bladder provides a unique administration route to treat superficial bladder cancer. We examined the anti-tumor effect of epidermal growth factor receptor (EGFR)-directed gold nanorods combined with photothermal treatment in a superficial bladder cancer model.
Methods
A novel orthotopic nu/nu murine xenograft model was established through intravesical instillation of T24 human bladder cancer cells labeled with Luciferase. After confirmation of positive tumor cell implantation via bioluminescence, gold nanorods linked to the anti-EGFR antibody C225 were instilled into the bladder cavity. The nanorods were specifically fashioned to respond to near infrared (NIR) light, which was externally administered via an 808 nm diode laser to the bladder. A safe and effective regimen of in vivo photothermal ablation was determined by optimizing the duration, power and distance from the tumor to the laser source. The anti-cancer effect was monitored by an in vivo imaging system in a non-invasive manner.
Results
The tumor implantation rate with the T24 human cancer cell was approximately 90%. The optimized regimen of photothermal treatment in this setting was laser power of 2.1 W/cm2 for 30 seconds at 2.5 centimeters from the skin. Using this in vivo tumor model, and near-infrared energy combined with C225-conjugated gold nanorods, we demonstrate significant therapeutic efficacy against the implanted orthotopic bladder tumor (Table) with minimal systemic toxicity using this regimen.
Conclusions
Photothermal ablation with EGFR-directed gold nanorods is effective and well tolerated in an in vivo model of urinary bladder cancer. Future clinical development would include NIR light delivery via a cystoscope in a human application
Summary of luciferase results of in vivo photothermal treatmentTotal miceLuciferase DecreaseLuciferase IncreaseLuciferase No Significant ChangeConjugated Nano Rods+Laser161303Laser Only14275
Citation Format: Xiaoping Yang, Lih-Jen Su, Francisco G. La Rosa, Elizabeth Erin Smith, Suehyun Katherine Cho, Brian Kavanagh, Won Park, Thomas W. Flaig. Thermal ablative therapy with novel gold nanorods in an orthotopic model of urinary bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2728. doi:10.1158/1538-7445.AM2014-2728
Abstract 2764: The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target
Authors: Maubant Sylvie , Maire Virginie , Tesson Bruno , Némati Fariba , Gentien David , Marty-Prouvost Bérengère , Depil Stéphane , Cruzalegui Francisco , Tucker Gordon , Roman-Roman Sergio , Dubois Thierry 
Published: May 2015

Abstract
Treatment of patients with triple-negative breast cancers (TNBCs) remains a major challenge for oncologists and alternative treatments to conventional chemotherapies are needed to improve their survival. The Wnt/beta-catenin signaling, recently reported to be activated in TNBCs, may represent an interesting pathway to target. We report that both LRP5 and LRP6 Wnt coreceptors are more strongly expressed in TNBCs than in other breast tumor subtypes. As very few studies have explored potential differences between LRP5 and LRP6, we investigated the effects of modulating specifically LRP5 or LRP6 expression on Wnt signaling, cell viability and tumorigenesis in HCC38 and MDA-MB-468 TNBC cells. We found that these two cell lines are more similar to TNBC biopsy specimens in terms of Wnt pathway gene expression profiles than any other tested cell line. Unlike LRP5, LRP6 was involved in activating the canonical Wnt pathway in response to Wnt3a. LRP5 knockdown induced caspase-dependent apoptosis, whereas LRP6 knockdown had no such effect. Importantly, LRP5-depleted cells were more sensitive to conventional chemotherapy than cells depleted of LRP6. The knockdown of LRP5 or LRP6 decreased tumorigenesis both in vitro and in vivo. Overall, these data suggest that the LRP5 and LRP6 coreceptors have different functions in TNBCs, with LRP5 playing a preponderant role in survival control. Our data suggest that both LRP5 and LRP6 are potential treatment targets in TNBCs, but that LRP5 may be the most useful target, given the impact of its depletion on cell survival as well as on the response to anti-cancer drugs.
Citation Format: Sylvie Maubant, Virginie Maire, Bruno Tesson, Fariba Némati, David Gentien, Bérengère Marty-Prouvost, Stéphane Depil, Francisco Cruzalegui, Gordon Tucker, Sergio Roman-Roman, Thierry Dubois. The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2764. doi:10.1158/1538-7445.AM2014-2764
Abstract 2776: Overexpression of HGF is an effective indicator for Met-targeting therapy in hepatocellular carcinoma
Authors: Xie Qian 
Published: May 2015

Abstract
The success of molecular targeted therapy against cancer depends on discovering the essential pathways that contribute to carcinogenesis and cancer progression and the molecular targets that control the pathway activity. By using genetically engineered mouse models, we show that overexpression of Hepatocyte growth factor (HGF) stimulated HBV surface antigen (HBsAg) production and accelerated the HCC progression. HGF transgenic mouse model produced spontaneous HCC with genomic profiles similar to that HBV-positive HCC patients with poor prognosis. Mechanistically, MET receptor expression is required for repair of virus-induced liver damage and HCC development. Importantly, HGF overexpression induces an autocrine activation which determines the sensitivity to small-molecule Met inhibitors. MET inhibitors are entering clinical trials against cancer, and our data provide a molecular basis for targeting the Met pathway in hepatitis B-induced HCC. Our results demonstrate that HGF is a driver of HBV-induced HCC progression and may serve as an effective biomarker for Met-targeted therapy, and that hgf-transgenic mouse model serves as a good tool for studying human HCC biology and preclinical evaluating therapeutics.
Citation Format: Qian Xie. Overexpression of HGF is an effective indicator for Met-targeting therapy in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2776. doi:10.1158/1538-7445.AM2014-2776
Abstract 2777: Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC
Authors: Preet Ranjan , Shanmugam Rajasubramaniam , Mohapatra Purusottam , Das Dipon , Satapathy Shakti R. , Wyatt Michael D. , Kundu Chanakya N. 
Published: May 2015

Abstract
We previously reported that quinacrine (QC) has anticancer activity against breast cancer cells. Here, we report the mechanism of action of QC and its ability to inhibit Wnt-TCF signaling in two independent breast cancer cell lines. QC altered Wnt-TCF signaling components by increasing the levels of adenomatous polyposis coli (APC), DAB2, GSK-3β and axin and decreasing the levels of β-catenin, p-GSK3β (ser 9) and CK1. QC also reduced the activity of the Wnt transcription factor TCF/LEF and its downstream targets cyclin D1 and c-MYC. Using a luciferase-based Wnt-TCF transcription factor assay, it was shown that APC levels were inversely associated with TCF/LEF activity. Induction of apoptosis and DNA damage was observed after treatment with QC, which was associated with increased expression of APC. The effects induced by QC depend on APC because the inhibition of Wnt-TCF signalling by QC is lost in APC-knockdown cells, and consequently, the extent of apoptosis and DNA damage caused by QC was reduced compared with parental cells. Further, previously we have shown that QC inhibits topoisomerase, therefore we tested the effect of another topoisomerase inhibitor, etoposide, on Wnt signaling. Interestingly, etoposide treatment also reduced TCF/LEF activity, β-catenin and cyclin D1 levels commensurate with induction of DNA damage and apoptosis. Lycopene, a plant-derived antioxidant, synergistically increased QC activity and inhibited Wnt-TCF signaling in cancer cells without affecting the MCF-10A normal breast cell line. Collectively, the data suggests that QC-mediated Wnt-TCF signal inhibition depends on APC and that the addition of lycopene synergistically increases QC anticancer activity.
Note: This abstract was not presented at the meeting.
Citation Format: Ranjan Preet, Rajasubramaniam Shanmugam, Purusottam Mohapatra, Dipon Das, Shakti R. Satapathy, Michael D. Wyatt, Chanakya N. Kundu. Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2777. doi:10.1158/1538-7445.AM2014-2777
Abstract 2786: Downregulated expression of hepatoma-derived growth factor (HDGF) reduces glioma cancer cell tumor growth and angiogenesis
Authors: Liu Li-Feng , Hsu Shu-Shong , Chen Chih-Hao 
Published: May 2015

Abstract
Hepatoma derived growth factor (HDGF) is a mitogenic growth factor in the progression of human glioma. In this paper, we study the gliomagenesis role of HDGF in syngenic glioma rat model by Lenti-virus sh-HDGF (LV-shHDGF) infection. The tumor inhibition of HDGF depletion in rat glioma C6 cells was measured by MRI scanning. We found all glioma tumors growth after implanting but only HDGF knock down tumors had a significant reduction in the tumor size at the 4th-week MRI-scanning. After tumor volume was quantified on serial brain section, we found a 10-folds of reduction in the tumor size was observed in HDGF knock down tumors than scrambles (p&lt;0.005). By survival analysis, rats with gliomas had a less median survival of 25 days and the HDGF knock down group was still alive from the time point of implanting. According to the pathological analysis, the HDGF knock down tumors presented a significant cell apoptosis and reduction in the Ki67 mitotic index, CD31 angiogenesis index, and ANG-4 that exhibited markedly reduced tumor growth and blood vessel formation than controls. In addition, Western blot analysis showed exogenous HDGF increased the expression of PI3K, phospho-Akt, phospho-FAK, phospho-MDM2, PCNA and transcription factors of Iκ-B, NF-κB, cFos, ANG-4, and HIF-α in a dose-dependent manner; however, these tumorigenesis moleculars were significantly decreased in HDGF knock down cells. We concluded that HDGF is a mitogenic growth factor in the progression of glioma and it can be a useful therapeutic target for clinical management of glioma in the future.
Note: This abstract was not presented at the meeting.
Citation Format: Li-Feng Liu, Shu-Shong Hsu, Chih-Hao Chen. Downregulated expression of hepatoma-derived growth factor (HDGF) reduces glioma cancer cell tumor growth and angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2786. doi:10.1158/1538-7445.AM2014-2786
Abstract 2800: Immunotherapy of malignant pleural mesothelioma using MET specific t – cells
Authors: Thayaparan Thivyan , Stegen Sjoukje v.d , Pereira Ana C. Parente , Petrovic Roseanna , Spicer James , Maher John 
Published: May 2015

Abstract
Background: Malignant pleural mesothelioma (MPM) is an incurable cancer predominantly induced by asbestos exposure. This aggressive tumor commonly presents at an advanced stage of disease. Although surgery, combination chemotherapy and radiotherapy may be used in disease management, median survival from diagnosis is less than 12 months. New therapeutic approaches are required to improve outcome in this disease.
Chimeric antigen receptors (CAR) are fusion molecules that couple the HLA-independent binding of a selected cell surface target antigen to the delivery of a tailored T-cell activating signal. Using CAR technology, we aim to develop a novel immunotherapy for MPM that is both safe and effective. These molecules are delivered to patient T-cells using retroviral gene transfer, thereby stably re-directing their specificity for antigen. The receptor tyrosine kinase MET is overexpressed in &gt;80% of MPM patients making it an attractive candidate for CAR directed immunotherapy.
Methods: Three MET-targeted peptide-binding motifs have been incorporated into a second generation CAR framework containing a fused CD28/CD3ζ endodomain. Functional assessment of MET-targeted CARs has been assessed by co-cultivation of genetically enhanced test and control T-cells with MPM cell lines that express MET at various levels.
Results: In preliminary studies we have shown that human T-cells engineered to express MET CARs can destroy mesothelioma tumor cell monolayers, accompanied by T-cell proliferation and cytokine production. Xenograft models are currently under development using bioluminescence to further evaluate functionality and toxicity in vivo.
Conclusions: These findings demonstrate proof of concept for the utility of CAR engineered T-cells to recognise and destroy MET-expressing MPM tumor cells. We envisage that regional i.e. intrapleural delivery of human CAR positive T-cells could be used to maximise therapeutic index of this approach.
Citation Format: Thivyan Thayaparan, Sjoukje v.d Stegen, Ana C. Parente Pereira, Roseanna Petrovic, James Spicer, John Maher. Immunotherapy of malignant pleural mesothelioma using MET specific t – cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2800. doi:10.1158/1538-7445.AM2014-2800
Abstract 2801: The use of induced pluripotent stem (iPS) cells for the safety testing of enhanced affinity TCR-transduced T cells
Authors: Adams Katherine J. , Gerry Andrew B. , Brewer Joanna E. , Pumphrey Nicholas J. , Bennett Alan D. , Jakobsen Bent K. 
Published: May 2015

Abstract
Engineering T cells with enhanced affinity T cell receptors (TCRs) is a promising therapeutic strategy for treating cancer. Engineered TCRs overcome the limitations of naturally occurring cancer-antigen specific TCRs which are typically of extremely low affinity and fail to efficiently recognize tumor cells. However, the use TCRs with enhanced affinity for adoptive therapy carries with it the risk that they might recognize normal tissue, either as on-target or off-target reactivity. Two fatalities in a clinical trial of an affinity-enhanced MAGE-A3-specific TCR have highlighted the need for more biologically relevant cellular testing systems to minimize cross-reactivity-related toxicity in future adoptive immunotherapy trials.
Cellular Dynamics International Inc. supply a range of iCell products that are highly pure induced pluripotent stem (iPS) cell-derived cells that reproduce normal human biology in an in vitro setting. The advantage of iCell cultures over standard cultures of primary cells is that they better represent human organs with respect to their antigen presentation by HLA.
In this study, a panel of iCell sub-types, representing major organs of the human body, were used to test the reactivity of T cells transduced with an enhanced affinity TCR for HLA-A2-restricted peptide antigen NY-ESO-1/LAGE-1157-165. IncuCyte FLR technology, which enables direct visualization of caspase-3/7-dependent apoptosis at 37°C in real time, was used to assess the killing of the iCells by NY-ESO TCR-transduced T cells over a 4 day time course.
While potent killing by the NY-ESO TCR-transduced T cells was observed against an HLA-A2+, NY-ESO-1+/LAGE-1+ tumor cell line, A375, no reactivity was observed against any of the tested iCells sub-types unless the iCells were pulsed with 1 µM NY-ESO peptide.
The screening of TCR-transduced T cells against biologically appropriate cell cultures, such as iCells, further advances preclinical safety testing of new TCRs for use in adoptive immunotherapy.
Citation Format: Katherine J. Adams, Andrew B. Gerry, Joanna E. Brewer, Nicholas J. Pumphrey, Alan D. Bennett, Bent K. Jakobsen. The use of induced pluripotent stem (iPS) cells for the safety testing of enhanced affinity TCR-transduced T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2801. doi:10.1158/1538-7445.AM2014-2801
Abstract 2813: Survival benefit of an add-on dendritic cell vaccine for patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter study
Authors: Kobayashi Masanori , Shigetaka Shimodaira , Nagai Kazuhiro , Ogasawara Masahiro , Takahashi Hidenori , Abe Hirofumi , Tanii Mitsugu , Okamoto Masato , Tsujitani Shun-ichi , Nagaya Masaki , Yonemitsu Yoshikazu ,   The DC vaccine study group of Japan Society of Innovative Cell Therapy (J-SICT)
Published: May 2015

Abstract
Purpose: Dendritic cell (DC)-based cancer vaccine may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it hard to detect its clinical outcome. Here we statistically identified factors determining the clinical benefit using data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimen.
Patients and Methods: Among the 354 patients who met the inclusion criteria, 255 patients who received standard chemotherapy combined with peptide-pulsed DC vaccines were analyzed.
Results: The mean survival time from diagnosis was 16.5 months (95%CI=14.4-18.5), and that from the first vaccination was 9.9 months (95%CI=8.0-12.9). Known prognostic baseline factors related to advanced pancreatic cancer, namely ECOG-PS, peritoneal metastasis, liver metastasis, and prognostic nutrition index (PNI) were also representative. Importantly, erythema reaction after vaccination was an independent and treatment-related predictive factor for better survival, and that OK432 might be a good adjuvant enhancing the antitumor immunity during DC vaccination.
Conclusion: This is the first report of a multicenter clinical study suggesting the feasibility and possible clinical benefit of an add-on DC vaccine in patients with advanced pancreatic cancer who are undergoing chemotherapy. These findings need to be addressed in well-controlled prospective randomized trials.
Citation Format: Masanori Kobayashi, Shimodaira Shigetaka, Kazuhiro Nagai, Masahiro Ogasawara, Hidenori Takahashi, Hirofumi Abe, Mitsugu Tanii, Masato Okamoto, Shun-ichi Tsujitani, Masaki Nagaya, Yoshikazu Yonemitsu, The DC vaccine study group of Japan Society of Innovative Cell Therapy (J-SICT). Survival benefit of an add-on dendritic cell vaccine for patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2813. doi:10.1158/1538-7445.AM2014-2813