bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2640: RN927C, a potent site-specific Trop-2 antibody-drug-conjugate (ADC) for treatment of solid tumors
Authors: Liu Shu-Hui , Strop Pavel , Tran Thomas-Toan , Dorywalska Magdalena , Delaria Katherine , Ho Wei-Hsien , Dushin Russell , Pons Jaume , Rajpal Arvind , Shelton Dave 
Published: May 2015

Abstract
Human trophoblast cell surface antigen-2 (Trop-2), also known as TACSTD2, EGP-1, GA733-1 and MS1, is expressed on a variety of human carcinomas and its expression is often associated with poor prognosis of the diseases. Trop-2 is frequently detected in many tumor types at high levels, however, it is also present on the epithelium of a number of normal tissues. A comprehensively designed Trop-2-targeting ADC, balancing both efficacy and toxicity, is necessary to achieve clinical utility. We developed a site-specific cleavable Trop-2-ADC (RN927C) using a novel transglutaminase-mediated enzymatic conjugation method and a proprietary MTI (microtubule inhibitor) linker-payload. Our site-specific conjugation technology enables a precise drug-loading ratio of two and thus a better control of desired potency. Robust in vitro cytotoxicity of RN927C was observed selectively on multiple Trop-2 expressing tumor cell lines, with IC50 generally in the sub-nM range. Upon binding to surface Trop-2, RN927C internalized quickly and trafficked to the lysosomal compartment, as visualized by the co-localization of RN927C with lysosomal marker LAMP-2. As expected for a MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple tumor models including pancreatic, NSCLC, and ovarian cell line and patient-derived xenograft models. Single dose administration of RN927C at 1.5 mg/kg was generally sufficient to induce sustained regression of Trop-2 expressing tumors and showed superior efficacy over standard treatment with paclitaxol or Gemcitabine. Furthermore, addition of RN927C to Gemcitiabine greatly enhanced its in vivo efficacy. RN927C was well-tolerated in non-human primates upon repeat dosing at 6mg/kg q2w, with non-severe toxicity observed primarily in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues. Importantly, only minimal off-target hematological toxicity was observed in monkeys. Based on the combined efficacy and safety results, RN927C is expected to have a favorable therapeutic index and clinical development is currently underway.
Citation Format: Shu-Hui Liu, Pavel Strop, Thomas-Toan Tran, Magdalena Dorywalska, Katherine Delaria, Wei-Hsien Ho, Russell Dushin, Jaume Pons, Arvind Rajpal, Dave Shelton. RN927C, a potent site-specific Trop-2 antibody-drug-conjugate (ADC) for treatment of solid tumors. [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 2640. doi:10.1158/1538-7445.AM2014-2640
Abstract 269: Asymmetric laterality of breast tumors is correlated with place of birth, but not race
Authors: Sughue Trevor , Brody James P. 
Published: May 2015

Abstract
More breast cancers are diagnosed in the left breast than the right breast. The ratio of the number of tumors diagnosed in the left breast to the number diagnosed in the right in a population is called the laterality ratio. Previous studies showed that the breast cancer laterality ratio is significantly larger than 1 and significantly different in different quadrants of the breast.
We analyzed 1.2 million cases of breast cancer diagnosed in the US between 1973 and 2010 and recorded by the Surveillance, Epidemiology, and End Results (SEER) program data, November 2012 submission.
We found that the laterality ratio depends upon the country of birth, but not race of the patient. We identified five countries of birth that had p-values larger than 0.995, while we expected to see less than 1. Those born in Japan (l/r=1.14, p=0.997), the Ryuukyu Islands (l/r= 2.6, p=0.998), Laos (l/r=1.62, p=0.9999) and Algeria (l/r=2.1 p=0.9959) had significantly larger laterality ratios compared to the overall SEER population (l/r=1.04). Those born in Poland (l/r=0.92, p=0.997) had a laterality ratio significantly less than expected.
The SEER data classified patients into 30 different race categories. We expect about six of these categories to exceed the two tailed 90% confidence interval based upon chance. We found seven, three of which had p-values exceeding 0.95, but none of which exceeded 0.99. This finding suggests no correlation exists between race and laterality.
Next we sought to establish whether the difference in birthplace laterality ratios arose from (1) different distributions of the quadrant in which the tumor occurs or (2) a shift in the laterality ratio of each quadrant where the tumor occurs. First, we compared the distribution of quadrants in which a breast tumor occurs in those born in Poland with those born in Japan. We found that the relative distributions of tumor quadrants were identical. Next, we compared the laterality ratio by quadrant for the two populations. We found the only significant difference was in the laterality ratio of the upper outer quadrant. Thus, the birthplace effect appears to only occur in the upper outer quadrant of the breast.
Finally, we found a small, but statistically significant, increase in the breast cancer laterality ratio with age, and decrease with birth year and year of diagnosis.
Citation Format: Trevor Sughue, James P. Brody. Asymmetric laterality of breast tumors is correlated with place of birth, but not race. [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 269. doi:10.1158/1538-7445.AM2014-269
Abstract 2694: Novel sesquiterpene lactones derived from Vernonia cinerea inhibit STAT3 activity and suppress human glioblastoma phenotype
Authors: Miklossy Gabriella , Youn Ui Joung , Yue Peibin , Chang Leng Chee , Turkson James 
Published: May 2015

Abstract
Constitutively-active STAT3 is prevalent in glioblastoma multiforme, breast cancer and many other human tumors and is a valid target for the discovery of novel anticancer therapeutics. Screening of whole plant extracts from Vernonia cinerea identified sesquiterpene lactones of the hirsutinolide type that inhibit aberrant STAT3 activity and suppress human glioma phenotype in vitro and in vivo. Compounds 6, 10, 20 and 22 suppressed the viability of human glioma, U251MG cells that harbor aberrantly-active STAT3, with IC50 of 2.4-6 µM. Treatment of U251MG cells with any of the four natural product agents inhibited STAT3 phosphorylation in a time-dependent manner, with little or no effects on pErk1/2 and pAkt levels. By contrast, other hirsutinolides, including compounds 8, 9, 11, 18, 19 and 28 showed modest or undetectable effects on U251MG cell viability or on pSTAT3 in U251MG cells. Furthermore, treatment with compounds 6, 10 or 22 had moderate or no effects on phospho-JAK2 or phospho-Src or on the protein tyrosine phosphatase, PTP1B level, as measured by Western blot. Moreover, combined treatment with sodium orthovanadate had minimal effect on compound 6-induced decrease in pSTAT3 levels, altogether suggesting that protein tyrosine phosphatases are less likely to be the primary mechanism for down-regulation of pSTAT3 in treated U251MG cells. By contrast, co-treatment with compund 6 repressed the robust induction of pSTAT3 levels by sodium orthovanadate. Furthermore, treatment with compound 6, 10, 20 or 22 inhibited colony formation and the migration of U251MG cells in vitro, and repressed the expression of STAT3 regulated genes, including Mcl-1 in U251MG cells. In vivo anti-tumor efficacy studies of compound 6 revealed dose-dependent inhibition of the growth of human glioma tumor xenografts in mice. Our studies have identified natural product-based small molecules that potently inhibit STAT3 activity and preferentially induce antitumor cell effects in vitro and antitumor response in vivo against human glioma.
Citation Format: Gabriella Miklossy, Ui Joung Youn, Peibin Yue, Leng Chee Chang, James Turkson. Novel sesquiterpene lactones derived from Vernonia cinerea inhibit STAT3 activity and suppress human glioblastoma phenotype. [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 2694. doi:10.1158/1538-7445.AM2014-2694
Abstract 2759: Colorectal cancer cell lines with high BCL-XL and low MCL-1 expression are sensitive to a potent and selective BCL-XL inhibitor
Authors: Lam Lloyd T. , Zhang Haichao , Xue John , Hessler Paul , Tahir Stephen K. , Chen Jun , Jin Sha , Souers Andrew J. , Leverson Joel D. 
Published: May 2015

Abstract
Colorectal cancer is the second most deadly type of cancer in the United States and worldwide despite the recent approval of new therapies. The identification of novel agents that are effective against this cancer thus remains a significant goal. One hallmark of cancer is the defective regulation of programmed cell death, or apoptosis. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family members, including BCL-2, BCL-XL, and MCL-1, are known to regulate cell survival and death and have been characterized as key survival factors in multiple cancer types. As BCL-XL is overexpressed in many solid tumors, the sensitivity of a panel of 25 colorectal cancer cell lines to a potent and selective BCL-XL inhibitor was investigated. Colorectal cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity, were more sensitive to small molecule BCL-XL inhibition. In contrast, cell lines with lower expression of BCL-XL and higher expression of MCL-1 were resistant. Silencing the expression of BCL-XL via siRNA killed the cell lines that were sensitive to small molecule BCL-XL inhibition while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 restored sensitivity of resistant cells to the BCL-XL inhibitor whereas silencing of NOXA abrogated the sensitivity of cells to BCL-XL inhibitor. BCL-XL inhibition could thus be an effective treatment in a subset of colorectal cancer patients showing high BCL-XL expression.
Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for the research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: Lloyd T. Lam, Haichao Zhang, John Xue, Paul Hessler, Stephen K. Tahir, Jun Chen, Sha Jin, Andrew J. Souers, Joel D. Leverson. Colorectal cancer cell lines with high BCL-XL and low MCL-1 expression are sensitive to a potent and selective BCL-XL inhibitor. [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 2759. doi:10.1158/1538-7445.AM2014-2759
Abstract 290: Constitutional BRCA1 methylation is a major predisposition factor for high-grade serous ovarian cancer
Authors: Dobrovic Alexander , Mikeska Thomas , Alsop Kathryn , Candiloro Ida , George Joshy , Mitchell Gillian , Bowtell David 
Published: May 2015

Abstract
This study aimed to determine whether constitutional methylation of the BRCA1 promoter region was a predisposition factor for ovarian cancer. We had previously shown that in a case control study of early-onset breast cancer patients, the presence of constitutional BRCA1 methylation in the blood was associated with tumors that phenocopied pathogenic germline BRCA1 mutations, indicating that BRCA1 methylation predisposed to and drove the development of these tumors. Germline BRCA1 mutations also predispose to ovarian cancer, in particular, high-grade serous ovarian cancer. In collaboration with the Australian Ovarian Cancer Study, we determined the presence of detectable BRCA1 methylation in 154 high-grade serous cancers. Twenty patients showed detectable levels of BRCA1 methylation in DNA extracted from their peripheral blood. Remarkably, when the corresponding tumor samples were assessed for methylation, 14 of the 20 that showed any methylation corresponded to a highly methylated tumour. When tumors occurring before the age of 55 were considered, 9 of the 10 bloods with detectable mutation corresponded to a strongly methylated tumour. This study also determined the frequency of BRCA1 and BRCA2 mutations. Fifteen women had germline BRCA1 mutations and 11 had germline BRCA2 mutations. The germline BRCA1 mutation carriers were predominantly younger at diagnosis and 11 pathogenic BRCA1 mutations were seen in the under 55 group. BRCA1 methylation was mutually exclusive with BRCA1 mutation. This data strongly suggests that constitutional BRCA1 methylation can drive ovarian cancer, in particular early onset ovarian cancer, and moreover is as important a predisposition factor as BRCA1 mutation.
Citation Format: Alexander Dobrovic, Thomas Mikeska, Kathryn Alsop, Ida Candiloro, Joshy George, Gillian Mitchell, David Bowtell. Constitutional BRCA1 methylation is a major predisposition factor for high-grade serous ovarian 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 290. doi:10.1158/1538-7445.AM2014-290
Abstract 2929: The Mdm2 inhibitor NVP-CGM097 enhances the anti-tumor activity of NVP-LDK378 in ALK mutant neuroblastoma models
Authors: Wang Hui Qin , Battalagine Linda , Liang Jinsheng , Halilovic Ensar , Schlegel Robert , Huang Alan , Cao Z. Alexander , Monahan John , Li Fang 
Published: May 2015

Abstract
Neuroblastoma is the most common cancer in infancy, accounting for 15% of all childhood cancer-related death. MYCN amplification is the major genetic aberration in high-risk neuroblastoma and is associated with poor outcome. Genome-wide association studies have identified activation mutations and high-level amplification of ALK in approximately 10% of neuroblastoma patients. In addition, ALK mutations can coexist with MYCN amplification, which defines a subset of ultra-high-risk neuroblastoma patients. In contrast to the high frequency of p53 mutations observed in many human cancers of adults, mutations of p53 are less common in childhood cancers and have been reported in less than 2% of neuroblastomas. Wild-type (WT) p53 is required for the activation of p53 signaling by Mdm2 inhibitors. This suggests that neuroblastoma could be amenable to intervention with Mdm2 inhibitors. In this study, we demonstrated that the ALK inhibitor, NVP-LDK378, in combination with a novel Mdm2 inhibitor, NVP-CGM097, promoted apoptosis in ALK mutant and p53 WT neuroblastoma cell lines. NVP-LDK378 inhibited ALK phosphorylation and NVP-CGM097 caused induction of p53 and its downstream target genes in these cell lines. Meanwhile, Mdm2 inhibition in MYCN-amplified neuroblastoma cell lines significantly decreased the levels of Mycn protein. In addition, NVP-LDK378 and NVP-CGM097 combination resulted in complete tumor regression and markedly prolonged survival in neuroblastoma xenograft models. Overall, NVP-LDK378 and NVP-CGM097 combination may provide an effective treatment for ALK mutant and p53 WT neuroblastoma patients.
Citation Format: Hui Qin Wang, Linda Battalagine, Jinsheng Liang, Ensar Halilovic, Robert Schlegel, Alan Huang, Z. Alexander Cao, John Monahan, Fang Li. The Mdm2 inhibitor NVP-CGM097 enhances the anti-tumor activity of NVP-LDK378 in ALK mutant neuroblastoma models. [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 2929. doi:10.1158/1538-7445.AM2014-2929
Abstract 2973: Mouse models of lung cancer mediated by lentiviral gene delivery
Authors: Xia Yifeng , Yeddula Narayana , Ke Eugene , Leblanc Mathias , Verma Inder 
Published: May 2015

Abstract
Lung cancer, the leading cause of cancer deaths, is responsible for 1.4 million lives lost worldwide every year. Good animal models that can faithfully recapitulate the human disease are in great need for pre-clinical studies. Based on the different responses to treatment, lung cancer is divided into two major classes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Adenocarcinoma (AdC) and squamous cell lung cancer (SqCC) are two major sub-types of NSCLC. We have successfully developed a novel lentiviral gene delivery system to study the initiation and development of all these lung cancers. We used CA2Cre-shp53 lentiviral vector to initiate lung adenocarcinoma in LSL-KrasG12D mice and proved the importance of NF-κB/IKK2 pathway in tumor cell proliferation. To search for novel tumor suppressors in lung cancer, we incorporated an shRNA library targeting ∼5000 cell signal genes into our CA2Cre lentivector and did the screening in the mice. We have identified several dozens of candidates and are validating these genes back in animals. SCLC is the most malignant form of lung cancer with a five-year survival less than 6%. A mouse model with p53/Rb deletions activated by Adeno-Cre has been established in Berns lab. To improve the model and study other genes that are frequently mutated in human SCLC, we designed a single lentiviral vector to deliver oncogenes (L-myc etc.) and shRNAs against tumor suppressors (p53, Rb etc) and successfully initiated SCLC in wild-type mice. Furthermore, we included luciferase or fluorescence protein genes in the same vector to follow tumor growth and metastasis in the live animal. Using this new model, we are now studying the crosstalk of multiple mutations in the SCLC development. SqCC has not been well modeled by genetic approaches. Interestingly, when we gave KrasG12D-shp53 lentiviral vector after lung tissue damage induced by naphthalene, the mice quickly developed squamous tumors in the big bronchi other than adenocarcinomas in the peripheral lung. Kras mutations are actually not common in human SqCC patients, so we are now optimizing the model and see if more relevant genetic changes such FGFR1 amplification can also induce this type of lung cancer in mice. We hope that our unique lentiviral tool can simplify and accelerate the lung cancer study to understand the big signal pathway complex leading to tumorigenesis and metastasis in the lung and search for new therapies for this deadly human disease.
Citation Format: Yifeng Xia, Narayana Yeddula, Eugene Ke, Mathias Leblanc, Inder Verma. Mouse models of lung cancer mediated by lentiviral gene delivery. [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 2973. doi:10.1158/1538-7445.AM2014-2973
Abstract 303: Cell Slider: Using crowd sourcing for the scoring of molecular pathology
Authors: Pharoah Paul D. 
Published: May 2015

Abstract
The advent of tumour microarrays has increased the throughput of pathology sample preparation but has led to a new bottleneck at the analysis stage as many thousands of samples need to be scored by an expert pathologist. We launched Cell Slider (www.clicktocure.net), the world's first Citizen Science project in cancer research, in Autumn 2012. Cell SliderTM aims to speed up the analysis of tumour microarray images through crowd sourcing. Citizen Scientists have now generated over 1.7 million scores of tumour images from the Breast Cancer Association Consortium image database.
In order to evaluate the validity of Citizen Scientist scoring we compared the scores of Citizen Scientists with those of an experienced pathologist for 2,575 tissue cores from the SEARCH study that have been stained for expression of the estrogen receptor. Each image of a 0.6mm tissue core stained for ER was divided into 12 sub-images, each of which was scored by five citizen scientists. A weighted average of the 60 (12x5) scores was used to generate a single citizen scientist score for each tissue core.
The average number of cancer cells observed by Citizen Scientists was used to indicate whether or not the core contained cancer. The sensitivity and specificity then depends on the threshold used for positivity. Of 2,575 cores on the TMA the pathologist identified 1,792 as having cancer tissue. The kappa statistic for agreement between pathologist and Citizen Scientist was 0.72. Using a threshold to give a sensitivity of 95 per cent, the specificity was 72 per cent.
We estimated the accuracy of assignment of tumour ER status using the 1,703 cores where both pathologist and Citizen Scientists identified cancer in the TMA core. A pseudo-Allred score on a continuous scale was calculated from the individual Citizen Scientist scores for the proportion of positively stained cells and the intensity of positively stained cells. The sensitivity and specificity of ER status depends on the threshold pseudo-Allred score used to determine ER positivity. The kappa statistic for agreement between pathologist and Citizen Scientist was 0.84. Using a threshold to give a sensitivity of 95 per cent, the specificity was 90 per cent.
We have shown that crowd sourcing can be used to score breast cancer TMAs stained by immunohistochemistry with a reasonable degree of accuracy. Further analysis are underway to determine whether accuracy can be improved using difference weighting schemes and to evaluate the accuracy of scoring of typical cytoplasmic and membrane molecular markers.
Citation Format: Paul D. Pharoah. Cell Slider: Using crowd sourcing for the scoring of molecular pathology. [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 303. doi:10.1158/1538-7445.AM2014-303
Abstract 4204: Isatin analog as bruton tyrosine kinase inhibitor: A promising novel agent for multiple myeloma treatment
Authors: Gowda Krishne , Pandey Manoj K. , Sharma Arun K. , Amin Shantu 
Published: May 2015

Abstract
Multiple myeloma (MM) is a clonal malignancy of plasma cells accumulating in the bone marrow. MM cells are highly dependent on the bone marrow (BM) microenvironment for growth and survival through interactions particularly with BM stromal cells (BMSCs), which secrete important MM growth factors and cytokines. Understanding and defining these BM factors are critical to provide the rationale to functionally target these factors and/or kinases as novel biologically based therapeutics for MM. Bruton tyrosine kinase (Btk), a non-receptor tyrosine kinase resembling the Src family, plays a key role in the development and function of normal B cells through activation of the B-cell antigen receptor signaling pathway on binding to antigens. Btk further phosphorylates PLC-γ, leading to activation of MAPK, NF-κB, and AKT signaling pathways. Earlier our group synthesized a novel series of 5,7-dibromoisatin analogs. Analogs 6, 11 and 13 were potential anti-cancer agents. In the present study, through docking studies we predicted that bromo isatin analog-11 directly interacts with Btk. We found that Isatin-11 inhibits Btk activity in a dose- and time-dependent manner. Isatin-11 down-regulates the expression of Bcl-2, Bcl-xL on MM cells. Isatin-11 also activates caspase-3 and PARP-cleavage in MM cells. Taken together, these results suggest that targeting of Btk by Isatin-11 may represent a new therapeutic strategy to treat MM.
Citation Format: Krishne Gowda, Manoj K. Pandey, Arun K. Sharma, Shantu Amin. Isatin analog as bruton tyrosine kinase inhibitor: A promising novel agent for multiple myeloma treatment. [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 4204. doi:10.1158/1538-7445.AM2014-4204