bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B21: Chemoresistant bladder cancer cells induces epithelial mesenchymal transition
Authors: Liu Jingchun , Martin Darryl T. , Wheeler Marcia A. , Weiss Robert M. 
Published: May 2015

Abstract
Although chemotherapeutic treatments are efficacious in a number of cancers, some cancer cells ultimately will become resistant to chemotherapy. It has been suggested that chronic chemotherapy-resistance is linked to the induction of epithelial mesenchymal transition (EMT). EMT is associated with increased tumor invasiveness, development of angiogenesis, and the development of drug resistance and is linked to more aggressive cancer. The objective of this study is to determine if a link exists between mitomycin C (MMC)-resistant RT-4 bladder cancer cells and the induction of EMT. EMT is a process where cells acquire molecular alterations characterized by loss of cell-cell adhesion, repression of E-cadherin expression, and increased cell mobility. Clinical studies have shown that as bladder cancer grade increases, tumors typically exhibit a decreased expression of E-cadherin, a cell-cell adhesion molecule. In addition, there is an increase in N-cadherin expression in muscle invasive bladder tumors.
We have shown that MMC-resistant human RT-4 bladder cancer cells demonstrate a decrease in cell-cell adhesion, a higher invasion potential, and a higher CD44(+)/CD24(-) ratio (96.4%) compared to parental human RT-4 bladder cancer cells. In addition, the invasion capacity of MMC-resistant RT-4 bladder cancer cells was higher than that of parental cells. The MMC-resistant RT-4 bladder cancer cells expressed higher levels of N-cadherin and numerous apoptotic related proteins including pSTAT3, RAD17, Bcl-X and catalase. Using an exon array we showed that the MMC-resistant RT-4 bladder cancer cells up-regulate several EMT markers including vimentin (77 times), transforming growth factor -beta (27 times), and Zinc finger E-box-binding homeobox 1 (33 times) and down-regulate E-cadherin (71 times).
In summary, in our MMC-resistant RT4 bladder cancer cells, EMT was activated, and there was an increase in apoptotic related proteins as well as an increase N-cadherin expression. Our data suggest a link between chemotherapy-resistant bladder cancer cells and EMT. Deactivating EMT and down-regulating apoptotic related proteins may offer a novel strategy for overcoming bladder cancer drug resistance.
Citation Format: Jingchun Liu, Darryl T. Martin, Marcia A. Wheeler, Robert M. Weiss. Chemoresistant bladder cancer cells induces epithelial mesenchymal transition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B21.
Abstract B35: The strength of drug selection determines the maximum fitness cost of resistance mutations in culture and xenografts
Authors: Albacker Lee A. , Kohler Rainer , Weissleder Ralph , Sorger Peter K. 
Published: May 2015

Abstract
This abstract is being presented as a short talk. A full abstract is printed in the Proffered Abstracts section (PR07) of the Conference Proceedings.
Citation Format: Lee A. Albacker, Rainer Kohler, Ralph Weissleder, Peter K. Sorger. The strength of drug selection determines the maximum fitness cost of resistance mutations in culture and xenografts. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B35.
Abstract B36: Modeling genetic mechanisms of resistance in melanoma primary tumor xenografts
Authors: Balbin Alejandro , Singh Angad , Korn Joshua , Gao Hui , Stuart Darrin , Green John , Crenshaw Andrew , Mahan Scott , Houde Nathan , Raza Alina , Leary Rebecca , Chiang Derek , Morrissey Michael , Winckler Wendy , William Sellers 
Published: May 2015

Abstract
Melanoma is the most lethal skin cancer and approximately 50% of the cases harbor mutations in the BRAF oncogene, with the mutation V600E representing 80-90% of all BRAF mutations in this indication. BRAF inhibitors as Vemurafenib and Dabrafenib have shown improved overall and progression free survival; however, the long term efficacy of these compounds is limited by the emergence of resistance. Several mechanisms of resistance to BRAF inhibitors have been already described, such as BRAF overexpression, increased ERBB3 signaling, expression of BRAF alternative isoforms, secondary mutations in BRAF or MEK1 and recently BRAF amplifications, among others. A fundamental aspect on devising optimal therapeutic regimes that overcome resistance is to develop preclinical models that resemble the genetic makeup of clinical patients who become resistance during the course of treatment to BRAF inhibitors. To this end, melanoma primary tumor xenografts (PTX) harboring BRAF V600E mutations were subject to treatment with BRAF inhibitors and response data was collected for a maximum of 180 days. Vehicle and treated samples were then sequenced using a targeted next generation sequencing approach in order to characterize their mutational landscape. Raw sequencing data was aligned to the human genome and potential mouse contamination was filter out before downstream analysis. Comparing SNV and copy number calls between treated and control samples revealed that focal amplifications of BRAF and de-novo mutations in the MEK1 gene were frequent genetic aberrations found in the PTX models that developed resistance. In summary, our results indicate that the genetic mechanisms of resistance observed in primary tumor xenograft models closely resemble what is observed in the clinical setting, making these models a valuable research tool for designing optimal therapeutic strategies.
Citation Format: Alejandro Balbin, Angad Singh, Joshua Korn, Hui Gao, Darrin Stuart, John Green, Andrew Crenshaw, Scott Mahan, Nathan Houde, Alina Raza, Rebecca Leary, Derek Chiang, Michael Morrissey, Wendy Winckler, Sellers William. Modeling genetic mechanisms of resistance in melanoma primary tumor xenografts. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B36.
Abstract B38: Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition
Authors: Dokmanovic Milos , Wu Yun , Shen Yi , Chen Jieqing , Hirsch Dianne S. , Wu Wen Jin 
Published: May 2015

Abstract
Trastuzumab is a humanized recombinant monoclonal antibody directed against extracellular region of ErbB2 and used for the treatment of different ErbB2-positive cancers. Based on literature reports and our clinical data from trastuzumab neoadjuvant studies, increased ErbB2-Y1248 phosphorylation is associated with a better response to trastuzumab in patient samples. Also, in trastuzumab-sensitive cell lines (SKBR3 and BT474), increased basal level and trastuzumab-mediated increase in ErbB2-Y1248 phosphorylation was readily detectable compared to trastuzumab-resistant cell line model (JIMT1). The mechanisms of trastuzumab-induced ErbB2-Y1248 phosphorylation and the role of ErbB2-Y1248 phosphorylation in trastuzumab sensitivity/resistance are still incompletely understood. We demonstrate that trastuzumab activates ErbB2 kinase activity in trastuzumab-sensitive cells, which may further contribute to trastuzumab-mediated ErbB2-Y1248 phosphorylation. However, blocking ErbB1/ErbB2 kinase activity with Lapatinib, a small molecule tyrosine kinase inhibitor only partially reduced trastuzumab-mediated ErbB2-Y1248 phosphorylation. This led to the discovery of a previously unappreciated relationship between trastuzumab and Csk-homologous kinase (CHK), a non-receptor tyrosine kinase also known as MATK. We establish that trastuzumab treatment promotes interaction between ErbB2 and CHK in trastuzumab-sensitive but not in trastuzumab-resistant cells despite similar CHK expression levels in both types of cells. Mimicking trastuzumab, CHK overexpression also induces ErbB2-Y1248 phosphorylation, Akt downregulation and cell growth inhibition and further stimulated trastuzumab-mediated reduction in total ErbB2 levels in trastuzumab sensitive cells. Also, CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition in trastuzumab-sensitive but not in trastuzumab-resistant cells. Understanding of the molecular mechanisms of trastuzumab mediated ErbB2 phosphorylation changes may suggest novel therapeutic approaches in the treatment of trastuzumab resistant cancers.
Disclaimer: The information presented in this article reflects the views of the authors and does not represent the policy of the U.S. Food and Drug Administration.
Citation Format: Milos Dokmanovic, Yun Wu, Yi Shen, Jieqing Chen, Dianne S. Hirsch, Wen Jin Wu. Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B38.
Abstract B45: A search for ideal siRNA targets involved in pathway cross-talks for combinational silencing in human cancer cells
Authors: Aliabadi Hamidreza Montazeri , Mahdipoor Parvin , Uludag Hasan 
Published: May 2015

Abstract
The heterogeneity in the pathways involved in enhanced cell proliferation and survival mechanisms, as well as the mechanisms playing a major role in development of drug resistance, is an important obstacle in cancer treatment. Signaling axes such as PI3K-AKT, Ras-Raf, MEK-ERK, and JAK-STAT pathways have not only been established as major processes involved in enhanced proliferation and activation of the transcription of multiple anti-apoptosis proteins, but are also shown to be interconnected in forming a vast intracellular signaling network. RNA interference, and more specifically, small interfering RNA (siRNA), is a post-transcriptional down-regulation of the expression of a specific protein, and has been studied extensively in the last decade as not only an investigational tool, but also as a therapeutic approach especially in cancer treatment. In the present study, we undertook a systematic approach to simultaneous silencing of two proteins involved in intracellular signaling network in order to inhibit more than one pathway involved in proliferation and survival of cancer cells. After carefully selecting the proteins with pivotal roles in cell survival through diverse pathways, we studied silencing each protein individually and in all possible dual combinations, and evaluated the cell response as the mRNA level of the selected proteins as well as the viable cell number. Our studies reveled that silencing JAK2, STAT3, and JUN have a significant effect on the expression level of anti-apoptotic proteins, e.g., Mcl-1 and survivin, and could negatively impact the survival of MDA435 cells. These results indicate a promising potential for combinational siRNA silencing as an effective anticancer strategy.
Citation Format: Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Hasan Uludag. A search for ideal siRNA targets involved in pathway cross-talks for combinational silencing in human cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B45.
Abstract B47: The role of ZNF217 in the development of breast cancer chemoresistance
Authors: Suarez Christopher , Badve Sunil S. , Littlepage Laurie E. 
Published: May 2015

Abstract
Breast cancer is the second leading cause of cancer related deaths with an estimated 232,340 new cases and 39,620 deaths in 2013. Despite 93% of patients being diagnosed with local or regional stage disease, most patient deaths result from metastasis as a result of recurrent disease after the development of therapeutic resistance. Developing a better understanding of the molecular mechanisms of therapeutic resistance is critical to help identify novel therapeutics that overcome metastasis, resistance, and death.
We previously identified the transcription factor ZNF217 as a prognostic indicator for breast cancer patients. ZNF217 is overexpressed in breast cancer and numerous other cancers, and this overexpression promotes reduced survival, increased metastasis, and reduced response to therapy. We found that Znf217 overexpression promotes an increase in cancer phenotypes, including self-renewal capacity, invasion, and metastasis. We next determined if Znf217 overexpression in vivo contributed to chemotherapy resistance. We treated mice overexpressing Znf217 or vector with a combination therapy of microtubule inhibitor epothilone B, adriamycin, and cyclophosphamide (EAC). The mice that overexpressed Znf217 had increased tumor volume and decreased survival compared to control mice. Mice overexpressing Znf217, that were treated with EAC, developed a significant increase in tumor volume over control mice within 21 days of EAC treatment. This confirmed that mice overexpressing Znf217 developed resistance to the EAC chemotherapy.
To overcome breast cancer chemoresistance caused by ZNF217 overexpression, we identified triciribine as a drug that kills cells that overexpress ZNF217. We found that triciribine treatment inhibited tumor burden in vivo in tumors that overexpressed Znf217 and also had synergy with doxorubicin in human xenografts. We now are confirming these results using patient-derived tumor xenografts to compare therapeutic response of human tumors with high versus low levels of ZNF217 expression. Utilizing animal models that overexpress ZNF217 will allow us to identify combination therapies that are able to overcome resistance. In addition, these studies will provide an ideal model system to search for mechanistic insight into the process of developing therapeutic resistance.
Citation Format: Christopher Suarez, Sunil S. Badve, Laurie E. Littlepage. The role of ZNF217 in the development of breast cancer chemoresistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B47.
Abstract B57: miR-34 mimics synergize with small molecule inhibitors targeting the EGFR and Raf kinase pathways
Authors: Zhao Jane , Kelnar Kevin , Daige Chris , Wiggins Jason , Priddy Leslie , Muenzer Terri , Tran Julie , Brown David , Bader Andreas G. 
Published: May 2015

Abstract
Sorafenib (Nexavar®) and erlotinib (Tarceva®) are FDA-approved therapies for patients with hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC), respectively. Sorafenib is a multi-kinase inhibitor targeting the Raf/Mek/Erk pathway, and erlotinib is a tyrosine kinase inhibitor antagonizing epidermal growth factor receptor (EGFR). Due to their selective inhibitory action and observed toxicities, current treatment options for liver and lung cancer are limited and many cancers develop resistance. Naturally occurring tumor suppressor microRNAs inhibit tumor growth by regulating multiple oncogenes at once and, therefore, microRNA mimics, which are copies of the naturally occurring microRNAs, may be used in combination with the respective standard of care drugs to bring this tumor suppressor activity back into tumor cells and thereby augment drug sensitivity. Here, we investigated the relationship of a mimic of the tumor suppressor microRNA miR-34 in combination with erlotinib or sorafenib and determined the therapeutic activity of the combination in lung and liver cancer cells. Data derived from isobolograms, combination index plots and curve shift analyses indicate synergy in all cancer cell lines tested. Synergy was observed at multiple microRNA and drug ratios and at drug concentrations that induce 50% or greater cancer cell inhibition. Data from cell and animal studies will be presented.
Citation Format: Jane Zhao, Kevin Kelnar, Chris Daige, Jason Wiggins, Leslie Priddy, Terri Muenzer, Julie Tran, David Brown, Andreas G. Bader. miR-34 mimics synergize with small molecule inhibitors targeting the EGFR and Raf kinase pathways. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B57.
Abstract IA01: Immunologic heterogeneity of cancer: Determinants of response and resistance to immunotherapy
Authors: Topalian Suzanne L. 
Published: May 2015

Abstract
Complex interactions between the immune system and cancer influencing tumor invasion, metastasis, and treatment outcomes are poorly understood. Similar to the influence of intra- and inter-tumoral genetic heterogeneity on response and resistance to molecularly targeted therapies, immunologic heterogeneity may explain the outgrowth of resistant tumor clones under the selection pressure of immunotherapy. Evidence for this phenomenon emerged from the results of high-dose IL-2 therapy, with responding metastases showing brisk CD8+ T cell infiltration, while non-responding lesions in the same patients were lymphocyte-poor. It has also been shown in patients receiving adoptive cell transfer therapies (TILs, CARs), with initial tumor regression followed by the outgrowth of tumors that have down-regulated target antigens. More recently, clinical experience with drugs blocking immune checkpoint molecules such as CTLA-4, PD-1 and PD-L1 has revealed unconventional response patterns in 5-10% of patients, including mixed tumor regressions (simultaneous progression/regression at different metastatic sites in an individual patient). Our investigations of the immunosuppressive ligand PD-L1, expressed by many human tumors, as a potential biomarker of response to anti-PD-1 therapy have revealed intra-tumoral as well as inter-tumoral heterogeneity of expression. Within individual tumor lesions, PD-L1 protein expression (IHC) can be patchy or focal, co-localizing with lymphoid infiltrates. Further study on a molecular level revealed expression of IFN-g in the same microenvironment as PD-L1, along with PD-1 and other immunosuppressive molecules, generating the adaptive immune resistance hypothesis. Examination of PD-L1 protein expression in multiple tumor lesions from individual patients showed variability over time and at distinct anatomic sites, consistent with the dynamic and context-dependent nature of immune responses, suggesting that inter-lesional variability could influence susceptibility to anti-PD-1 or PD-L1 therapy. Innovative approaches such as neoadjuvant immunotherapy trials or rapid autopsy analysis are needed to gain a deeper knowledge of tumor immunologic heterogeneity and potential intersections with genetic heterogeneity. This will be critical to understanding the evolution of anti-tumor immunity and developing more effective immune-based and combinatorial therapies.
This work was supported by grants from Bristol-Myers Squibb, the National Cancer Institute (R01 CA142779), the Melanoma Research Alliance, the Barney Family Foundation, the Dermatology Foundation, and Stand Up To Cancer.
Citation Format: Suzanne L. Topalian. Immunologic heterogeneity of cancer: Determinants of response and resistance to immunotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA01.
Abstract IA03: Mutations, drugs, and breast cancer: How are we going to figure it out?
Authors: Ellis Matthew J. 
Published: May 2015

Abstract
Massively parallel DNA and RNA sequencing approaches have generated high dimensional data on thousands of breast cancer genomes. Broad-based conclusions include challenges to the multistep model of breast carcinogenesis and the monoclonality of cancer, a link between leukemogenesis and luminal breast cancer and the discovery of new mutagenesis mechanisms. Unfortunately novel and immediately applicable therapeutic insights have been somewhat sparse. Many of the processes that are disrupted by newly discovered somatic mutations include genes with roles in splicing, histone methylation and long non-coding RNA function. Drugs targeting these processes are in the earliest stages of development, emphasizing a pressing unmet need to move drug discovery efforts beyond our current intense focus on kinase inhibitors. Despite the evident complexity, promising examples are emerging including new efforts to target mutations in two well-established drivers in breast cancer: HER2 in HER2 mutant breast cancer and mutant ESR1 in ESR1 endocrine refractory luminal-type breast cancer. A case for the importance of genome-annotated patient-derived breast cancer xenografts (PDX) will also be made. PDX models are potentially more reliable preclinical setting than cell lines and are a setting in which the biological rules for genome driven therapeutic planning could be developed. A call is also made for a new generation of prospective clinical trials that are fully focused on exploring interactions between cancer genomics and drug outcomes as a primary objective. Finally the integration of DNA and RNA based sequencing studies with mass-spectrometry-based peptide sequencing promises a more complete view of the biochemistry of breast cancer cells and represents a new discovery horizon in efforts to drug the pathophysiology of complex epithelial malignancies.
Citation Format: Matthew J. Ellis. Mutations, drugs, and breast cancer: How are we going to figure it out? [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA03.