bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1752: Search for effective therapies for canine and human osteosarcoma using novel therapeutic agents
Authors: Yang Yating , Bartczak Ewa , Yuzbasiyan-Gurkan Vilma 
Published: May 2015

Abstract
Osteosarcoma (OS) is the most common primary bone tumor of both humans and dogs. Despite advances in treatment of other cancers, the survival rates for OS have stagnated for the past decades. Therefore, there is a great need to identify novel and effective treatments. Several classes of novel small molecules with anti-tumor activities have become available in the last few years. Among these are tyrosine kinase inhibitors (TKIs) which are a class of potential anti-tumor medications that are able to inhibit kinase activity of many receptor tyrosine kinases. Another class of molecules target inhibition of the proteasome which induces cell death through various mechanisms. We hypothesized that one or more of such drugs would be effective against canine and human OS cell lines. Our preliminary data identified three TKIs (sunitinib, sorafenib, gefitinib), and a proteasome inhibitor (bortezomib) as having good growth inhibition effects in low concentrations on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS) in a series of drug screening assay. We then determined the exact IC50 concentration of each drug, capable of inhibiting proliferation by 50%. The IC50 values of bortezomib range from 0.01 to 0.22 μM and the values for sorafenib were from 6 to nearly 9 μM across different cell lines tested, which were all within or close to achievable plasma concentration and tolerable levels. In addition, sunitinib, sorafenib, and bortezomib were shown to decrease cell migration ability in the wound healing assay. With the promising results from in vitro studies, these small molecule inhibitors are good candidates for further evaluation in treating human and canine OS.
Citation Format: Yating Yang, Ewa Bartczak, Vilma Yuzbasiyan-Gurkan. Search for effective therapies for canine and human osteosarcoma using novel therapeutic agents. [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 1752. doi:10.1158/1538-7445.AM2014-1752
Abstract 1756: Novel irreversible EGFR tyrosine kinase inhibitor, DBPR112, as a therapeutic candidate for lung adenocarcinoma
Authors: Shiao Hui-Yi , Hsu Tsu-An , Lin Wen-Hsing , Yang Tsong-Toh , Hsieh Hui-Fang , Chen Chiung-Tong , Yeh Teng-Kuang , Hsieh Hsing-Pang 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer death in the world and non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer deaths. In recent years, EGFR tyrosine kinase inhibitors (TKIs) have showed remarkable effects in patients with certain genetic alternations in the EGFR proteins. However, the clinical benefits of two first-generation EGFR TKIs (gefitinib and erlotinib) have been limited due to the acquired resistance from patients within 9-12 months after treatment, therefore, the discovery of next-generation EGFR-TKIs poses an utmost priority.
Our team at IBPR has identified DBPR112 as a potent EGFR-TKI, showing IC50 of 2 nM in HCC827 cells, EGFRWild-Type (IC50: 10 nM) and EGFRL858R/T790M (IC50: 70 nM), which are comparatively better than gefitinib and similar to that of BIBW2992 (afatinib, developed by Boehringer Ingelheim, and approved by FDA in 2013). DBPR112 (10, 50 and 100 mg/kg/day, 5 days/wk for 2 weeks) was orally effective against the growth of human lung HCC827 tumors subcutaneously xenografted in nude mice. A dramatic reduction in tumor size was noted with DBPR112 treatment at 50 and 100 mg/kg/day, while displaying negligible body weight loss in all dosing groups. In addition, the pharmacokinetics properties of DBPR112 are superior to those of BIBW2992; demonstrating the potential of DBPR112 as a therapeutic candidate for the treatment of lung adenocarcinoma with EGFR mutations.
This NRPB-granted 4-year top-down project was commenced in Dec. 2012 and aimed at accomplishing a comprehensive program of pre-clinical development and phase I study. To date, several pre-clinical studies and progress were steadily accomplished, including non-GMP production of 5 kg DBPR112 (tox-lot), preliminary analysis methods development, pre-formulation study, pharmacokinetics/metabolism studies and preliminary toxicology evaluation. GLP-toxicity studies, GMP-production of DBPR112 (clinical-lot) and formulation for clinical use will be scheduled in 2014 (2nd year of this top-down project), and we look forward to filing an IND application in early 2015.
Citation Format: Hui-Yi Shiao, Tsu-An Hsu, Wen-Hsing Lin, Tsong-Toh Yang, Hui-Fang Hsieh, Chiung-Tong Chen, Teng-Kuang Yeh, Hsing-Pang Hsieh. Novel irreversible EGFR tyrosine kinase inhibitor, DBPR112, as a therapeutic candidate for lung adenocarcinoma. [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 1756. doi:10.1158/1538-7445.AM2014-1756
Abstract 177: Obesity promotes growth of ovarian cancer through adipose stem cells
Authors: Zhang Yan , Solley Travis , Lu Karen , Wei Caimiao , Nowicka Alesandra , Klopp Ann 
Published: May 2015

Abstract
Introduction: Intraperitoneal spread to visceral adipose is a frequent event and a major cause of morbidity and mortality in women with ovarian cancer. Excess visceral adiposity increases the risk of ovarian cancer. We hypothesized that obesity effects may be mediated by the adipose-derived stem cell population (ASC) to enhance the initiation and progression of ovarian cancer.
Results: Intraperitoneally injected ID8 ovarian cancer cells grew significantly faster in mice with diet-induced obesity (p&lt;0.05). To determine if ASC mediated this effect, ASC were then isolated from the subcutaneous (SC-ASC) and visceral adipose (V-ASC) of mice with diet-induced obesity and lean mice. ASC from all sources expressed same mesenchymal cell surface markers and similarly increased ID8 cell proliferation and survival following paclitaxel treatment. There was no significant difference in ID8 migration in response to ASC conditioned media from lean and obese mice. ASC from obese mice exhibited impaired differentiation into adipocytes and osteocytes in-vitro as compared to ASC from lean mice. 106 renilla luciferase expressing ID8 were co-injected intra-peritoneally with equal number of different ASC isolates into C57Bl6 mice. SC-ASC from obese mice promoted growth of intraperitoneal tumor and the formation of metastasis as compared to SC-ASC from lean mice (p&lt;0.05). There was no significant difference in the effect of V-ASCs from obese and lean mice on ID8 cells. There was trend towards more rapid tumor growth in mice injected with V-ASC as compared to SC-ASC from lean mice. Ascites volume was highest in mice injected with SC-ASC derived from obese mice. SC-ASC from obese mice increased tumor vascularity while ASC from obese mice increased the formation of intra-tumoral perilipin expressing adipocytes.
Conclusions: SC-ASC from obese mice promoted tumor growth more than ASC from lean mice suggesting that obesity alters the ASC population to enhance tumor-promoting effects. Obese derived ASC exhibit impaired differentiation potential, which may be linked to tumor promoting effects. Future studies will focus on understanding the mechanisms by which obesity alters the ASC population to impact tumor progression.
Citation Format: Yan Zhang, Travis Solley, Karen Lu, Caimiao Wei, Alesandra Nowicka, Ann Klopp. Obesity promotes growth of ovarian cancer through adipose stem 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 177. doi:10.1158/1538-7445.AM2014-177
Abstract 1782: The ubiquitin protease UBP43 is a target for KRAS mutant lung cancers
Authors: Mustachio Lisa Maria , Chinyengetere Fadzai , Lu Yun , Hu Shanhu , Kawakami Masanori , Tafe Laura J. , Danilov Alexey , Sekula David J. , Ma Tian , Freemantle Sarah J. , Dmitrovsky Ethan 
Published: May 2015

Abstract
KRAS is frequently mutated in human lung cancers. Lung cancers with mutant KRAS are often resistant to current therapies. There is therefore a need to develop new ways to target these tumors with KRAS mutations. We previously found that the protein modification pathway containing the ubiquitin-like interferon-stimulated gene 15 (ISG15) destabilizes cyclin D1 and represses growth and tumorigenicity of lung cancer cells. This study substantially extends that prior work by reporting that inhibition of the ubiquitin protease UBP43, which removes ISG15 from protein substrates, also destabilizes KRAS protein levels. In a screen of murine lung cancer cells with KRAS mutations, the lines with highest KRAS protein levels had the highest levels of UBP43 protein, implying a direct link between UBP43 and KRAS. Stable overexpression of UBP43 in murine lung cancer cells increased cancer cell growth and stability of KRAS protein. In contrast, knockdown of UBP43 in murine and human lung cancer cell lines had the opposite effects on growth and KRAS protein stability. Co-immunoprecipitation experiments established an interaction between ISG15 and both wild-type KRAS and mutant KRAS. UBP43 immunohistochemical staining of human lung cancer cases showed a marked increase in UBP43 expression in KRAS mutant versus KRAS wild-type lung cancers. Preliminary findings in newly engineered mouse models revealed an increase in lung cancers in KRAS mutant/UBP43 wild-type as compared to KRAS mutant/UBP43 null mice. This finding provides a genetic basis for targeting UBP43 in lung cancers. Taken together, these studies broaden the role of UBP43 as an antineoplastic target to include an unmet medical need. This is to combat lung cancers that harbor KRAS mutations.
Citation Format: Lisa Maria Mustachio, Fadzai Chinyengetere, Yun Lu, Shanhu Hu, Masanori Kawakami, Laura J. Tafe, Alexey Danilov, David J. Sekula, Tian Ma, Sarah J. Freemantle, Ethan Dmitrovsky. The ubiquitin protease UBP43 is a target for KRAS mutant lung cancers. [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 1782. doi:10.1158/1538-7445.AM2014-1782
Abstract 1807: Pre-clinical evaluation of Mcl-1 inhibition through maritoclax in acute myeloid leukemia
Authors: Liu Qiang , Doi Kenichiro , Gowda Krishne , Barth Brian M. , Claxton David , Amin Shantu , Loughran Thomas P. , Wang Hong-Gang 
Published: May 2015

Abstract
There is an urgent and unmet medical need for development of new therapeutics for acute myeloid leukemia (AML). The anti-apoptotic Bcl-2 family protein Mcl-1 plays a critical role in AML cell survival and chemoresistance. Mcl-1 is upregulated in relapsed AML and leukemic stem cells. Inhibition of Mcl-1 expression in AML cells by kinase inhibitors or gene targeting induces apoptosis and suppresses leukemogenesis. However, the impact of targeting Mcl-1 in AML therapy with selective pharmacological inhibitors remains to be assessed. Recently, we discovered a novel Mcl-1 inhibitor, maritoclax (marinopyrrole A), which antagonizes Mcl-1 by targeting Mcl-1 for proteasomal degradation. This unique mechanism of action is in contrast to BH3 mimetics that exert their inhibitory function through disruption of the interactions between pro- and anti-apoptotic Bcl-2 family proteins. In a panel of AML cell lines, the potency of maritoclax positively correlated with Mcl-1 expression and inversely correlated with Bcl-2 and Bcl-xL expression. Maritoclax was efficacious as a single agent and markedly synergized with ABT-737 to induce apoptosis in Mcl-1 overexpressing ABT-737 and multidrug resistant AML cell lines. Moreover, maritoclax was able to overcome stroma-mediated resistance to apoptosis in AML cells. Importantly, maritoclax induced Mcl-1 degradation and apoptotic cell death selectively in clinical AML specimens with high levels of Mcl-1. To evaluate the anti-tumor activity of maritoclax in vivo, we established U937 tumor xenografts in nude mice. As a single agent, maritoclax significantly inhibited the growth of established xenografts at a dose of 20 mg/kg/d intraperitoneally. At this dosing level, no significant difference in body weight change and complete blood count was observed between maritoclax and vehicle treatment groups. Collectively, our studies demonstrated that maritoclax represents a novel class of Mcl-1 inhibitors and that the selective pharmacological inhibition of Mcl-1 may be a viable approach for the treatment of AML.
Citation Format: Qiang Liu, Kenichiro Doi, Krishne Gowda, Brian M. Barth, David Claxton, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang. Pre-clinical evaluation of Mcl-1 inhibition through maritoclax in acute myeloid leukemia. [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 1807. doi:10.1158/1538-7445.AM2014-1807
Abstract 1826: Altered expression of miRNAs in acquired trastuzumab resistance
Authors: Howe Karen , Eustace Alex J. , Gullo Giuseppe , Browne Brigid , Aherne Sinead , Crown John , O'Donovan Norma 
Published: May 2015

Abstract
HER2 positive breast cancer accounts for approximately 20-25 % of breast cancers. Trastuzumab, a humanised monoclonal antibody, is approved for the treatment of HER2 positive breast cancer. However, patients with metastatic HER2 positive breast cancer frequently develop resistance to trastuzumab. The aim of this study is to investigate microRNAs (miRNAs) in cell line models of acquired trastuzumab resistance to identifty altered miRNAs which may be biomarkers of resistance.
The trastuzumab resistant cell line, SKBR3-T was established by continuous exposure to trastuzumab (10 µg/ml) for 6 months. MiRNA extracted from SKBR3, and SKBR3-T was profiled using Taqman low density arrays (TLDA). Six differentially regulated miRNAs were identified in the SKBR3-T cells. qRT-PCR assays confirmed that four were significantly altered in the SKBR3-T compared to SKBR3 cells: miR-224 1.6 fold down-regulated (p=0.01), miR-221 5.8 fold up-regulated (p=0.04), miR-222 was 3.8 fold up-regulated (p=0.01) and miR-9 was 2.2 fold up-regulated (p=0.04). In another model of acquired trastuzumab resistance, BT474-Tr, miR-221 and -222 were also up-regulated, miR224 expression was switched off. No significant change in miR-9 was observed in BT474-Tr.
We analysed expression of the four miRNAs in a panel of HER2 positive cell lines which included 6 innate trastuzumab resistant cell lines and 3 innately sensitive cell lines. miR-224 was significantly down-regulated in the 6 resistant cell lines and miR-221 was significantly up-regulated in 3 of the 6 resistant cell lines, compared to the sensitive cell lines. miR-222 and miR-9 were not consistently altered in the resistant cell lines compared to the sensitive cell lines.
We analysed expression of these miRNAs in a small cohort of patients who showed durable complete response (pCR) (9 %) following treatment with trastuzumab and chemotherapy [1], and a control group of patients whose disease progressed following treatment. miRNA was extracted from FFPE tumor samples (n=12) and analysed by qRT-PCR. The mean levels of expression of miR-9, -221, and -222 were higher in non-responders (n=6) than responders (n=6) and the mean levels of miR-224 were lower in the non-responders compared to responders.
These results suggest that miR-9, -221, -222 and -224 may be potential biomarkers of trastuzumab resistance.
1. Gullo, G., et al., Durable complete response following chemotherapy and trastuzumab for metastatic HER2-positive breast cancer. Annals of Oncology, 2012.
Citation Format: Karen Howe, Alex J. Eustace, Giuseppe Gullo, Brigid Browne, Sinead Aherne, John Crown, Norma O'Donovan. Altered expression of miRNAs in acquired trastuzumab resistance. [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 1826. doi:10.1158/1538-7445.AM2014-1826
Abstract 1827: Inhibition of Src, HER2, and EGFR by the multi-kinase inhibitor KD019 overcomes trastuzumab resistance in breast cancer
Authors: Mo Rigen , Rao Nishta , Tonra James , Waksal Samuel , Poyurovsky Masha 
Published: May 2015

Abstract
KD019 (previously EXEL-7647) is an orally bioavailable spectrum selective small molecule kinase inhibitor of Src family nonreceptor tyrosine kinases (Src) as well as HER2, EGFR, and VEGFR2/KDR. Because of its complement of targets KD019 is able to disrupt multiple components of tumor pathology and, in earlier studies, KD019 demonstrated robust activity in multiple in vivo tumor models.
In recent years Src has emerged as a critical convergent node downstream of multiple signaling cascades initiated by transmembrane receptor tyrosine kinases (RTKs), most notably HER2, EGFR and IGF-1R. Crosstalk between Src and RTKs facilitates RTK-dependent tumor growth and, in patients with HER2-amplified (HER2+) breast cancer, where Src is upregulated, may confer resistance to anti-HER2 therapies.
Based on the target specificity of KD019, including Src, we hypothesized that KD019 may prove to be an effective treatment in overcoming trastuzumab resistance in HER2+ breast cancer. Here we present data showing that KD019 effectively inhibited growth of several trastuzumab resistant cell lines with IC50 of 0.3 uM in vitro. Not only did KD019 potently inhibit HER2 and EGFR phosphorylation in these cells, but it also efficiently inhibited the phosphorylation of c-Met through receptor hetero-oligomerization mechanism, thus downregulating another pathway by which tumors may escape HER2 targeted therapies. Further, we demonstrate that once daily dosing of KD019 strongly inhibited tumor growth in xenograft models of trastuzumab resistance and that Src activity was inhibited in KD019 treated tumors even 24 hrs after drug administration. The significance of inhibiting the specific combination of targets is underscored by the fact that KD019 was 10 fold more potent when compared to saracatinib (a selective Src inhibitor) in inhibiting growth of trastuzumab resistant cells, which are also insensitive to blockade of individual RTKs. Together, these results provide a rational for clinical investigation of KD019 in patients whose tumors are resistant to anti-HER2 therapies.
Citation Format: Rigen Mo, Nishta Rao, James Tonra, Samuel Waksal, Masha Poyurovsky. Inhibition of Src, HER2, and EGFR by the multi-kinase inhibitor KD019 overcomes trastuzumab resistance in 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 1827. doi:10.1158/1538-7445.AM2014-1827
Abstract 1833: De novo EGFR T790M mutation in lung cancer patients harboring sensitive EGFR mutations
Authors: Lee Youngjoo , Lee Geon Kook , Lee Yeon-Su , Zhang Wenji 
Published: May 2015

Abstract
Background
EGFR T790M mutation drives acquired drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in EGFR-mutant lung cancer. However, it was reported that this mutation may exist before drug exposure. This study aimed to evaluate whether the clinical outcomes are affected by the proportion of preexisting T790M mutations within a tumor.
Methods
We collected pretreatment tissues from 124 advanced non-small cell lung cancer patients with sensitizing EGFR mutations that were detected by direct sequencing. Genotyping for EGFR T790M was further performed using matrix-assisted laser desorption/ionization-time of flight/mass spectrometry. T790M-positive patients were divided to two subgroups according to T790M mutant signal frequency.
Results
The T790M mutation was found in 31 (25.0%) patients. The T790M mutation frequency at which the risk of progression to EGFR-TKI begins to increase was estimated to be 2.0%. The patients with T790M-positive tumor had shorter time to progression (TTP) after EGFR-TKI (median 6.3 months vs. 11.5 months; P &lt; 0.001) and overall survival (OS) (median 16.1 months vs. 26.5 months; P = 0.065) than those with T790M-negative tumor. Among the T790M-positive patients, the patients with high T790M frequency (n= 9) had shorter TTP (median 2.4 months vs. 6.7 months; P = 0.009) and OS (median 9.1 months vs. 18.7 months; P = 0.018) than those with low T790M frequency (n= 22).
Conclusions
Preexisting EGFR T790M mutation was noted in 25% of patients with EGFR-mutant lung cancer. Patients with high T790M mutation frequency had worse clinical outcomes to EGFR-TKI than patients with low T790M mutation frequency.
Citation Format: Youngjoo Lee, Geon Kook Lee, Yeon-Su Lee, Wenji Zhang. De novo EGFR T790M mutation in lung cancer patients harboring sensitive EGFR mutations. [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 1833. doi:10.1158/1538-7445.AM2014-1833
Abstract 1841: A miR551b/catalase/MUC1/EGFR cascade for acquired apoptosis resistance and chemoresistance in lung cancer cells
Authors: Xu Xiuling , Wells Alexandria , Padilla Mabel T. , Kim Kwang Chul , Lin Yong 
Published: May 2015

Abstract
The oncoprotein Mucin-1 (MUC1) plays multiple roles in the development of different human tumors. However, whether MUC1 is involved in acquired chemoresistance, a major challenge in cancer therapy, has not been determined. Using a lung cancer cell model with acquired apoptosis resistance (AR)-associated chemoresistance, we investigated the role and mechanism of MUC1 in acquired chemoresistance. MUC1 expression was substantially increased in cells with acquired apoptosis resistance and knockdown of MUC1 expression effectively increased sensitivity of the AR cells to apoptotic cytotoxicity induced by anticancer therapeutics, substantiating a role for MUC1 in acquired chemoresistance. Decreased hydrogen peroxide-reducing enzyme catalase and increased cellular reactive oxygen species (ROS) were found to be associated with MUC1 overexpression. Pharmacological ROS scavengers or exogenous catalase dramatically suppressed MUC1 expression, suggesting catalase suppression-mediated ROS accumulation contributes to MUC1 overexpression. Further, we found miR-551b expression was increased in the AR cells. Knockdown of miR-551b restored catalase expression, and suppressed ROS accumulation and MUC1 expression. Finally, with manipulation of MUC1 expression, we found MUC1 promotes EGFR-mediated activation of the cell survival Akt/c-FLIP/Cox2/Mcl-1 cascade and stabilization of anti-apoptosis factors c-IAP1 and c-IAP2. Thus, our results establish a role for MUC1 in acquired chemoresistance and a pathway consisting of miR-551b/catalase/ROS for MUC1overexpression, and interventions against this pathway may be exploited for overcoming acquired chemoresistance.
Citation Format: Xiuling Xu, Alexandria Wells, Mabel T. Padilla, Kwang Chul Kim, Yong Lin. A miR551b/catalase/MUC1/EGFR cascade for acquired apoptosis resistance and chemoresistance in lung cancer 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 1841. doi:10.1158/1538-7445.AM2014-1841