bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 881: Leveraging the molecular heterogeneity of patient-derived tumor samples to simulate clinical trial settings and model combination treatments
Authors: Streiner Nicole , Praveen Kesavan Nair , Ruiz-Larroya Tatiana , Vo Martin , Murali Bhavya , Hoffmaster Steve , Broudy Thomas , Mirsaidi Cyrus , Anderes Kenna 
Published: August 2012

Abstract
Combination therapy, with rare exception, is a requirement for successfully treating cancer patients. Advances in genetic characterization coupled with a growing understanding of tumor heterogeneity are poised to revolutionize future strategies for combination treatments. Historically, working out the best combinations has been challenging and largely through iterative cycles of clinical trial and error due to gross limitations of preclinical models to accurately predict activity. Current strategies for developing new anticancer drugs rely heavily on preclinical testing in cancer cell lines and their derived in vivo xenograft models. These models are fraught with significant limitations including highly passaged cancer cell lines grown on plastic that ignores the microenvironment and tempered representation of the complex heterogeneity of cancer. Tumor cell microenvironment has significant impact on growth kinetics, cell signaling and response to drug treatments. 3D models attempt to recapitulate elements of the microenvironment, are more biologically relevant models compared to 2D models and have gained preference among cancer researchers and drug developers. The purpose of this study is to investigate the utility of molecularly characterized patient derived lung tumor cells (PTCs) for steering decisions for effective combination treatments in the clinical setting. We have established preclinical lung cancer models using PTCs grown in a 3D culture system. Here we present a retrospective study in lung PTCs evaluating single agents and combinations of molecularly targeted as well as cytotoxic agents including erlotinib, crizotinib, etoposide, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan and irinotecan. We utilized a range of methods (PCR, FISH, IF, WB) to determine the genetic and molecular features of the PTCs prior to performing drug treatments. We used high content imaging to evaluate subpopulations within PTCs, colony morphology and proliferative endpoints. Our results identified responder and non-responder populations and emphasize the need to base combination treatment strategies on subpopulation analysis of the tumor. Patient-derived tumor cell models grown in 3D culture conditions coupled with molecular characterization are essential for conducting hypothesis driven studies. This approach offers an informed starting point for subsequent in vivo studies from which data can guide personalized medicine decisions toward true translation in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 881. doi:1538-7445.AM2012-881
Abstract 886: Developing a new concept for specific targeting of cancer cells
Authors: Kosak Ken M. 
Published: August 2012

Abstract
The purpose of this work is to demonstrate the feasibility for 100% specific killing of cancer cells and virtually zero killing of normal cells. This is an obvious goal that seems to have been lost in most of the current targeting strategies for treating cancer. For instance, one well-known strategy employs drugs that kill or inhibit cancer cells through their generally higher metabolic rate and uptake of nutrients. A second strategy uses drug conjugates and/or carrier systems that target cell surface receptors or antigens. Another strategy now gaining rapid acceptance is using cancer genomics and/or proteomics to more “specifically” inhibit various up-regulated metabolic targets in cancer cells. The use of inhibitors and/or the current limitations of toxic drugs result in incomplete killing of the cancer, which frequently results in resistance. Another purpose of this work is to redirect some of the massive resources of industry and academia back to the harder task of specifically killing cancer instead of just inhibiting it. If all cancer cells are killed during treatment, there is no opportunity for resistant cells to grow back. Therefore, the ideal goal is to produce a drug and/or drug delivery system that is virtually 100% specific for killing cancer. This 100% specificity must be based on properties that only cancer cells possess. This eliminates normal cell surface receptors or metabolic pathways that are simply up-regulated or down-regulated compared to normal cells. Cancer is caused by one or more mutations in DNA. Therefore, all cancers have at least one or more mutations that are not found in normal cells. These unique mutations are the truly specific targets that should be used for killing cancer cells. The methods in this work identify mutations inside live cancer cells through specific binding to mutated DNA, (or the resulting mutated proteins). By employing a unique delivery system, a highly toxic compound is released into the cancer cell only when specific binding occurs. This feasibility study will show that nearly 100% of cancer cells can be killed through cancer-specific, intracellular targets while normal cells are not.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 886. doi:1538-7445.AM2012-886
Abstract 888: In vitro selection of prostate cancer cell-specific molecular recognition elements
Authors: Williams Ryan M. , Nayeem Sara , Sooter Letha J. 
Published: August 2012

Abstract
Among males in the United States, prostate cancer is the most-diagnosed cancer and is the second leading cause of cancer-related deaths. Current detection and therapeutic methods are not specific for the disease. The current standard in detection, prostate specific antigen (PSA) levels in the blood, was recently given a “D” grade by the U.S. Preventative Services Task Force. To address this problem, molecular recognition elements (MREs) that bind with high affinity and specificity to a molecule displayed on the surface of prostate cancer cells but not benign prostate cells are being developed. MREs are obtained through the in vitro selection process, which is the iterative enrichment of a large pool of random biomolecules for those that bind to a target of interest but not closely related targets. Seven rounds of in vitro selection have been completed, enriching a yeast-displayed single-chain variable fragment (scFv) antibody library with an initial diversity of 10^9 molecules. First, three rounds of biopanning were performed. In the positive panning selections, yeast-displayed scFv molecules were incubated with the LNCaP prostate cancer cell line. Those that bound to the LNCaP cells were amplified and subjected to a negative panning selection, in which the scFv's were incubated with benign prostate cell lines. These cell lines represented high grade prostatic intraepithelial neoplasia, benign prostate hyperplasia, and normal prostate cells. Those that did not bind to the benign cells were amplified. Then, four rounds of fluorescent activated cell sorting (FACS) were completed with increasing stringency. Binding of selected scFv MREs is being characterized. This work will produce a prostate cancer cell-specific MRE useful in specific detection and therapeutic targeting of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 888. doi:1538-7445.AM2012-888
Abstract 892: Angiotensin II /angiotensin II type I receptor (AGTR1) promotes cell growth in epithelial ovarian cancer
Authors: Lee Jeong-Won , Park Young-Ae , Choi Chel Hun , Lee Yoo-Young , Choi Jung-Joo , Kim Byoung-Gie , Bae Duk-Soo , Jeon Hye-Kyung , Kim Ha-Jeong , Cho Young Jae , Ryu Jee-Yun 
Published: August 2012

Abstract
Background: Angiotensin and its receptor, AGTR (Anigiotensin receptor) are known as main effectors molecules of renin-angiotensin system in regulating the physiological processes of the cardiovascular system. Not only do they function as an endocrine system, but they have recently reported to regulate cell proliferation, angiogenesis, invasiveness, and viabilities via inducing intercellular signaling pathways. The aim of this study is to evaluate the role of angiotensin II and AGTR1 on cell survival and proliferation in epithelial ovarian carcinoma cells. Methods: Expressions of AGTR1 were evaluated by immunohistochemistry in epithelial ovarian carcinoma tissues and analyzed the correlation between AGTR1 expression and clinicopathological characteristics of patients. For in vitro test, we checked the level of expression for angiotensin II and AGTR1 in human ovarian cancer cell lines by Western blot. A recombinant angiotensin II and its blocker losartan were treated into the cells. For cell viabilities and proliferations were estimated by MTT assay. Results: Through checking the expression of AGTR1 in human ovarian cancer cells, we selected A2780 and HeyA8 cells for in vitro tests because these cells have relatively high expression. Exogenous treatment of angiotensin II resulted in increased cell growth of both cells. Losartan, specific blocker of AGTR1, diminished the angiotensin II-induced increased cell growth. Moreover, we identified that angiotensin II activated Akt and STAT signaling through AGTR1 and pretreatment of losartan inhibited those activations. Conclusion: In this study, we inquired into the role of angiotensin II-AGTR1 interaction in ovarian cancer. They positively regulate cell survivability and proliferation and activate intercellular signaling involving Akt and STAT via suggesting their oncogenic mechanisms. Moreover, treatment of losartan, showed antiproliferative effect by inhibiting the activations of AGTR1 mediated signaling. These results suggest that AGTR1 inhibitor like as losartan could be a novel therapeutic strategy treating this cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 892. doi:1538-7445.AM2012-892
Abstract 894: Targeting ROS1 receptor tyrosine kinase gene fusions in non-small cell lung cancer
Authors: Davies Kurtis D. , Le Anh T. , Skokan Margaret C. , Theodoro Mariana F. , Varella-Garcia Marileila , Camidge D. Ross , Doebele Robert C. 
Published: August 2012

Abstract
Genomic rearrangements that fuse kinase domain-containing 3′ regions of tyrosine kinase genes with 5′ regions of unrelated genes are well characterized in cancer. The resulting fusion proteins often drive proliferation and invasion of tumor cells and thus represent attractive targets for therapeutic intervention. One such kinase that has been demonstrated to be involved in various genomic rearrangement events in non-small cell lung cancer (NSCLC), glioblastoma, and cholangiocarcinoma is the ROS1 receptor tyrosine kinase (also known as c-ROS and ROS). To date, three different 5′ fusion partners for ROS1 have been identified. In this study, we examined the frequency of ROS1 gene rearrangement in a panel of 428 patient-derived NSCLC tumor samples using a break-apart FISH assay. We found that approximately 1.2% of samples were positive. In positive samples, the expression of the fusion gene and the identity of the fusion partner were examined. HCC78 is a NSCLC cell line that has been demonstrated by us and others to express the SLC34A2-ROS1 gene fusion. In order to assess the cellular consequences of ROS1 inhibition, we treated HCC78 cells with two distinct small molecule kinase inhibitors that have activity against ROS1 (crizotinib and TAE684). We found that both drugs inhibited proliferation of HCC78 cells, down-regulated signaling pathways known to control cellular growth and survival, and disrupted normal cell-cycle progression. Finally, we report clinical data from a NSCLC patient with a ROS1 gene rearrangement, as detected by the FISH break-apart assay, who demonstrated tumor shrinkage when treated with crizotinib. This patient's tumor exhibited a novel ROS1 gene fusion partner. In conclusion, genomic rearrangements involving the ROS1 receptor tyrosine kinase are present in a small subset of NSCLC patients, and drugs that target ROS1 may be an effective treatment strategy for these patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 894. doi:1538-7445.AM2012-894
Abstract 940: Inhibition of androgen receptor activity in refractory prostate cancer cells by the novel Millennium-Takeda compound T-1759243
Authors: Schmidt Lucy J. , Nacusi Lucas P. , Sun Zhifu , Tindall Donald J. 
Published: August 2012

Abstract
Purpose. Prostate cancer (PCa) continues to be a leading cause of cancer death in males worldwide. In the prostate, androgens play a crucial role in both normal and cancerous growth by acting through the androgen receptor (AR), a member of the nuclear receptor super-family; hence, the AR has become a target of therapeutic intervention. The standard treatment for advanced PCa is androgen ablation therapy, initially leading to tumor regression through inhibition of AR activity. However, the success of androgen ablation therapy is often terminated by the emergence of castration- recurrent PCa (CRPC), for which there is still no cure. CRPC remains dependent on a functional AR-axis for proliferation and drugs targeting this network are continually being developed. We have examined the effects of Millennium-Takeda investigational compound T-1759243 on both androgen-responsive and androgen-refractory PCa cells in order to assess its therapeutic potential. Methods. We used PCa cell lines LNCaP, LNCaP-C42 and 22RV1 and assessed effects on cell viability and proliferation using MTS and BrdU assays. AR activity was measured using PSA-luciferase reporter constructs and protein levels by western blot. Microarray analysis with the Illumina HT-12 platform was used to identify genes affected by treatment with T-1759243, followed by real-time PCR confirmation. Pathway analysis was performed using MetaCoreTM software. Results. Our studies have revealed that T-1759243 reduces viability in all cell lines examined, regardless of androgen responsiveness. Treatment resulted in decreased proliferation in androgen-responsive cells and increased apoptosis in refractory cells. AR activity, as measured by PSA-luciferase assay, was greatly decreased in all cell lines by 10uM T-1759243 and T-1759243 abrogated the ability of synthetic androgen R1881 to increase AR activity by inhibiting nuclear translocation of the AR in refractory cells. Pathway analysis revealed changes in genes involved in cell-cycle, cell adhesion and cytoskeletal remodeling in addition to genes in androgen target pathways. Conclusions. T-1759243 is a novel AR antagonist that inhibits AR activity in both androgen-dependent and androgen-refractory prostate cancer cells. Additionally, it inhibits the ability of androgen to promote nuclear translocation of the AR and thus stimulate AR activity in castrate-resistant prostate cancer cells. Pathways affected by treatment with T-1759243 are cell-specific and dependent on AR status and may reveal novel gene targets in PCa treatment. This work was supported in part by Grant #35 from Millennium Pharmaceuticals, Inc the Takeda Oncology Company.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 940. doi:1538-7445.AM2012-940
Abstract 942: CYP3A4 epoxygenase mediates hypoxia-induced biosynthesis of epoxyeicosatrienoic acids (±)-11,12- and (±)-14,15-EET in breast cancer cells
Authors: Guo Zhijun , Mitra Ranjana , Luo Xiangghua , Capdevila Jorge , Lipscomb JohnL , David Potter A. 
Published: August 2012

Abstract
Introduction: CYP3A4 has recently been implicated in the growth of breast cancer cell proliferation but whether it promotes cell proliferation under conditions of hypoxia is unknown. This autocrine/paracrine growth promoting mechanism is dependent on epoxygenase activity, requires epoxygenation of arachidonic acid and can be complemented by add back of (±)-14,15-EET. Ambient tissue oxygen concentrations in tumors range from sub-microM to 50 microM. Methods: Human recombinant CYP3A4 SupersomesTM(BD Bioscience)-catalyzed epoxygenation of arachidonic acid (AA, 100 μM) reaction was performed at 37°C in the presence of a NADPH regenerating system. Oxygen concentration of the reaction solution was varied and rates of oxygen consumption were recorded with an oxygen electrode. Lineweaver Burke analysis was performed to calculate the oxygen Michaelis-Menten constant (Km). MCF7 breast cancer lines stably expressing two different CYP3A4 shRNA expression constructs were exposed to hypoxic conditions ([O2]=50 μM) and EET levels were quantified. Results: The oxygen Km for CYP3A4 was 21 μM. Under hypoxic incubation ([O2]=50 μM), (±)-8,9-EET levels were unaffected but (±)-11,12-EET and (±)-14,15-EET levels were induced 1.5 and 1.3-fold (P&lt;0.05; Student t-test). The MCF7 CYP3A4 knock down line 3-18 line, which exhibits 80% knock down of CYP3A4, exhibited no response to hypoxia compared to the MCF7 non-target (NT) line, which exhibited 1.25 and 1.33 fold increase of (±)-11,12- and (±)-14,15-EET respectively. Remarkably, (±)-8,9-EET exhibited no induction under hypoxic conditions. Conclusions: These results indicate that CYP3A4, which is known to promote breast cancer cell proliferation, is responsive to oxygen under ambient conditions comparable to those found in hypoxic tissues, exhibiting a Km of 21 μM. These results also indicate that hypoxia induces EETs in the breast cancer line, in a fashion dependent on CYP3A4. CYP3A4 therefore provides the majority of EETs induced in breast cancer cells under conditions of hypoxia and may contribute to autocrine and paracrine breast cancer growth signals under these conditions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 942. doi:1538-7445.AM2012-942
Abstract 944: Down-regulation of CAMKK2 by androgen deprivation induces castration-resistant prostate cancer
Authors: Mizokami Atsushi , Shima Takashi , Miyagi Toru , Kawai Keiichi , Izumi Kouji , Kumaki Misako , Jian Zhang , Keller Evan T. , Namiki Mikio 
Published: August 2012

Abstract
One of the mechanisms through which prostate cancer (PCa) relapses after androgen deprivation therapy (ADT) is to become androgen-hypersensitive and adapt to the low concentration of androgen during ADT. cDNA microarray analysis between PCa tissues before ADT and normal prostate tissues revealed that the level of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) mRNA was overexpressed 6 times in PCa more than in normal prostate. Immunohistochemical analysis of CAMKK2 protein using prostate tissue microarray showed that CAMKK2 protein was expressed well in PCa compared with normal tissue. However, the expression of CAMKK2 for the high grade PCa diminished compared with the low grade PCa. Moreover, we confirmed that the narrowness of a positive regional area of the CAMKK2 expression before ADT was a poor prognostic factor. Expression of CAMKK2 mRNA was up-regulated in the presence of DHT in LNCaP cells. Stable overexpression of CAMKK2 in LNCaP cells (LNCaP/GFP-CAMKK2), however, attenuated androgen-sensitivity. Tumorigenesis of LNCaP/GFP-CAMKK2 cells by subcutaneous injection in male SCID mice was also inhibited compared with control cells irrespective of castration. In contrast, knockdown of CAMKK2 mRNA in LNCaP cells induced androgen-hypersensitivity and stimulated LNCaP cell proliferation without DHT. Overexpression and knockdown of CAMKK2 in the presence of DHT were correlated with activation and inactivation of AMP-activated protein kinase (AMPK) that is a key kinase important for regulating cell proliferation, respectively. AMPK activation inhibited LNCaP cell proliferation. Taken together, induction of androgen-hypersensitivity after ADT may be involved in down-regulation of CAMKK2. This result may provide new therapeutic approach to keep androgen-sensitivity of PCa after ADT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 944. doi:1538-7445.AM2012-944