bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-97: Aurora kinase inhibition suppresses colon cancer cell growth through NF-κb-mediated PUMA induction.
Authors: Sun Jing , He Kan , Yu Jian , Zhang Lin 
Published: August 2014

Abstract
Aurora kinases are a group of highly conserved protein kinases that play a key role in mitosis. It has been shown that aurora kinases are overexpressed in a variety of tumors, and their overexpression contributes to aneuploidy in cancer cells. Inhibitors of aurora kinases have been developed and showed promises in recent studies. However, the mechanisms by which aurora kinase inhibitors suppress tumor cell growth have remained unclear. In this study, we found that ZM-447439, an aurora B inhibitor that has been tested in a number of preclinical studies, suppressed colon cancer cell growth by inducing apoptosis through PUMA, a p53 downstream target and a BH3-only Bcl-2 family protein. Treatment with ZM-447439 strongly induced PUMA in a variety of colon cancer cells irrespective of their p53 status. The induction of PUMA by ZM-447439 is mediated by IκB-dependent activation of NF-κB, which directly binds to the PUMA promoter to activate its transcription. Deficiency in PUMA abrogated ZM-447439-induced apoptosis and caspase activation, and rendered ZM-447439 resistance in vitro and in vivo. Furthermore, chemosensitization by ZM-447439 was also found to be PUMA-dependent. Together, these results demonstrate a key role of PUMA-dependent apoptosis in mediating the therapeutic effect of aurora kinase inhibition. They provide a rationale for manipulating the apoptotic machinery to improve sensitivity and overcome resistance to aurora kinase inhibitors.
Citation Format: Jing Sun, Kan He, Jian Yu, Lin Zhang. Aurora kinase inhibition suppresses colon cancer cell growth through NF-κb-mediated PUMA induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-97. doi:10.1158/1538-7445.AM2013-LB-97
Abstract SY01-03: The obesity-inflammation connection: Implications for breast carcinogenesis.
Authors: Dannenberg Andrew J. 
Published: August 2014

Abstract
Obesity is a risk factor for the development of several malignancies including hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. Chronic inflammation increases the risk of multiple malignancies. A link between obesity, breast inflammation and hormone receptor-positive breast cancer was previously unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead adipocytes forming crown-like structures (CLS). The synthesis of estrogen is catalyzed by aromatase, which is encoded by CYP19. Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators (TNF-α, IL-1β, PGE2) and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity→inflammation →aromatase axis is important for breast carcinogenesis. Importantly, these findings have now been translated to women. Breast tissue was obtained from women who underwent mastectomy. CLS of the breast (CLS-B) were found in nearly 50% of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index and adipocyte size. Consistent with our preclinical findings, increased NF-κB binding activity, increased levels of pro-inflammatory mediators and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, these results suggest that the obesity→inflammation →aromatase axis is present in the breast tissue of most overweight and obese women and is likely to contribute to the increased risk of hormone receptor-positive breast cancer. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis. The discovery of the connection between obesity, breast inflammation and changes in the expression of genes linked to breast cancer provides a mechanistic rationale for the development of behavioral, dietary and pharmacological strategies to reduce the risk of breast cancer. Recently conducted preclinical experiments provide proof-of-principle evidence that obesity-related mammary gland inflammation can be rapidly reversed with caloric restriction.
Citation Format: Andrew J. Dannenberg. The obesity-inflammation connection: Implications for breast carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY01-03. doi:10.1158/1538-7445.AM2013-SY01-03
Abstract SY02-01: Regulators of in situ to invasive breast carcinoma progression.
Authors: Polyak Kornelia 
Published: August 2014

Abstract
A major clinical diagnostic criterion that differentiates in situ from invasive breast carcinoma is the presence of a continuous myoepithelial cell layer and basement membrane. In pre-invasive lesions such as DCIS, a relatively intact myoepithelial cell layer and basement membrane are still observed, but we have found that the molecular profiles of DCIS-associated myoepithelial cells are distinct from those from normal breast. The mechanisms underlying the loss of myoepithelial cells during the in situ to invasive breast carcinoma transition are unknown.
We hypothesized that the differentiation of breast epithelial progenitors into myoepithelial cells is progressively inhibited by signals from tumor epithelial cells and cells composing the microenvironment such as fibroblasts and leukocytes. As a consequence, the myoepithelial cell layer is progressively lost and eventually disappears resulting in progression to invasion.
We have been testing this hypothesis by characterizing myoepithelial cells from normal human breast tissues from nulliparous and parous women, including BRCA1 and BRCA2 mutation carriers. To dissect the functional properties of different types of myoepithelial cells, we have been using the MCFDCIS xenograft model. Our results will not only improve the current understanding of the role of myoepithelial cells but also have the potential to provide new prognostic markers to predict risk of invasive progression in DCIS. Furthermore, our results may help identify new targets for chemoprevention aimed at decreasing the risk of invasive breast tumors.
Citation Format: Kornelia Polyak. Regulators of in situ to invasive breast carcinoma progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY02-01. doi:10.1158/1538-7445.AM2013-SY02-01
Abstract SY02-04: Inhibition of Hedgehog signaling for prevention and treatment of basal cell carcinomas.
Authors: Epstein Ervin H. 
Published: August 2014

Abstract
Basal cell carcinomas, the most common of human cancers, differ from many other cancers not only in their frequency but also in the great rarity with which they metastasize and their routinely high cure rate following surgery. Because all BCCs are driven by mutational activation of the hedgehog signaling pathway in the tumor cells, small molecule hedgehog inhibitors are a “natural” approach. Indeed, not only the rare metastatic and locally advanced BCCs but also the high number of smaller individually less aggressive BCCs in patients with the Gorlin syndrome respond extremely well to small molecule Hedgehog inhibitors. This illustrates that interfering with critical pathways not only can treat existing tumors but also can prevent even the development of new tumors.
Citation Format: Ervin H. Epstein. Inhibition of Hedgehog signaling for prevention and treatment of basal cell carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY02-04. doi:10.1158/1538-7445.AM2013-SY02-04
Abstract SY10-02: Breast cancer subtypes have selective kinome reprogramming in response to kinase inhibitors.
Authors: Johnson Gary 
Published: August 2014

Abstract
Multiplexed Inhibitor Beads coupled with quantitative Mass Spectrometry (MIB/MS) allows study of over 60-70% of the expressed kinome simultaneously using lysates from cell lines, mouse tumors and human specimens. Cells or tumors are assessed before and after addition of agonists or inhibitors. Results show a systems kinome reprogramming in response to highly selective inhibitors that creates inhibitor resistance. The activation signatures and changes in the kinome activation profile (kinome reprogramming) are unique for each breast cancer subtype (Luminal, HER2+, Basal-like, Claudin-low) in response to highly selective, clinically relevant kinase inhibitors (MEKinh, mTOR/PI3Kinh). Window trials in patients with TNBC have shown kinome reprogramming in response to MEKinh, suggesting understanding kinome resiliency is necessary for rational design of effective combination therapies to treat cancer in individual patients.
Citation Format: Gary Johnson. Breast cancer subtypes have selective kinome reprogramming in response to kinase inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY10-02. doi:10.1158/1538-7445.AM2013-SY10-02
Abstract SY11-01: Plasma tumor DNA: Changing the paradigm for administering systemic therapies.
Authors: Beaver Julia A. , Valda Patricia , Jelovac Danijela , Higgins Michaela J. , Park Ben H. 
Published: August 2014

Abstract
The ability to accurately detect somatic cancer DNA alterations from cell free circulating plasma tumor DNA (ptDNA) using next generation genomic technologies has many potential applications for clinical oncology. The initial use of this technology has been to detect point mutations in peripheral blood that could serve as predictors of response to various targeted therapies. Thus the development of a “liquid biopsy” that could easily match the mutational status of a given cancer with a specific therapy had great therapeutic implications. For example, the ability to assess certain epidermal growth factor receptor (EGFR) mutations via blood versus an invasive lung biopsy would allow for the rapid determination of whether a patient would be a candidate for small molecule EGFR inhibitors such as gefitinib or erlotinib. We initially sought to evaluate the feasibility of detecting PIK3CA mutations in circulating ptDNA from patients with metastatic breast cancer using a novel technique of digital polymerase chain reaction (PCR) called BEAMing (for Beads, Emulsions, Amplification, Magnetics). We demonstrated that BEAMing is both sensitive and specific for identifying PIK3CA mutations in metastatic breast cancer patients, though we also confirmed the work of other groups that PIK3CA mutation status can change with progression to metastatic disease. An overview of these data will be presented. While these studies demonstrated the feasibility of using ptDNA in metastatic patients as a liquid biopsy for detecting specific cancer mutations, we are now focusing efforts to exploit the quantitative nature of digital PCR technology. Specifically, by analyzing the amount of ptDNA before and after primary breast surgery in early stage breast cancer patients, we will identify which patients truly have residual microscopic disease post surgery and therefore would be the most appropriate candidates for additional systemic therapies. Thus, in contrast to the current paradigm of “over” treating breast cancer patients in the adjuvant setting, detection of ptDNA using next generation digital PCR technologies will enable us to make rational decisions regarding which patients truly have need for adjuvant systemic therapies. Preliminary data and ongoing studies will be discussed as well as the implementation of these technologies in future clinical trials.
Citation Format: Julia A. Beaver, Patricia Valda, Danijela Jelovac, Michaela J. Higgins, Ben H. Park. Plasma tumor DNA: Changing the paradigm for administering systemic therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY11-01. doi:10.1158/1538-7445.AM2013-SY11-01
Abstract SY24-03: Targeting IAP proteins in cancer: From molecular mechanism to therapeutic application.
Authors: Fulda Simone 
Published: August 2014

Abstract
Evasion of apoptosis is a hallmark of human cancers and contributes to tumor formation and progression as well as resistance to current cancer therapies, which largely rely on intact cell death pathways in cancer cells. Apoptosis resistance can be caused by aberrant expression of antiapoptotic proteins, for example, Inhibitor of Apoptosis“ (IAP) proteins, which are expressed at high levels in many human cancers. Since IAP proteins block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases, they present promising therapeutic targets.
Among the therapeutic approaches that have been developed to target IAP proteins, the most widely used strategy is based on mimicking the IAP-binding motif of second mitochondria- derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. Current and future perspectives on neutralizing IAP proteins for therapeutic intervention in human cancers will be discussed.
Citation Format: Simone Fulda. Targeting IAP proteins in cancer: From molecular mechanism to therapeutic application. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY24-03. doi:10.1158/1538-7445.AM2013-SY24-03
Abstract SY28-01: Is mitosis the target of “anti-mitotic” cancer drugs.
Authors: Mitchison Timothy J. 
Published: August 2014

Abstract
Cytotoxic drugs, which mostly target DNA or microtubules, can be curative in some cancers, but how they kill tumor cells selectively compared to normal cells has long been mysterious. The textbook view holds that cytotoxic drugs gain efficacy and selectivity by targeting different phases of the cell cycle, mitosis in the case of anti-microtubule drugs such as paclitaxel. However, the proliferation rate in tumors is slow compared to bone marrow and gut, and drugs that target cells only during cell division have shown little tumor efficacy. It is thus unclear whether mitosis is really a druggable process for cancer treatment. We have investigated the cytotoxic actions of anti-mitotic drugs in cell culture and using intravital imaging in a xenograft tumor model. Comparing the same cell line growing in culture and xenografts, we find that paclitaxel kills via mitotic arrest in culture, but by a non-mitotic mechanism in tumors. Candidate cell-killing mechanisms and their implications for improving chemotherapy will be discussed.
Citation Format: Timothy J. Mitchison. Is mitosis the target of “anti-mitotic” cancer drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY28-01. doi:10.1158/1538-7445.AM2013-SY28-01
Abstract SY30-01: Molecular characterization of single circulating tumor cells.
Authors: Haber Daniel A. , Yu Min , Ozkumar Emre , Ting David , Miyamoto David , Lee Richard , Shah Ajay , Bardia Aditya , Stott Shannon , Toner Mehmet , Maheswaran Shyamala 
Published: August 2014

Abstract
Circulating Tumor Cells (CTCs) are present at extraordinarily low levels in the blood of patients with advanced epithelial cancers. Our group has developed and tested three generations of microfluidic devices for the isolation of CTCs, each with further improvements in automation, processing throughput and downstream analytical capabilities. Isolation and molecular analyses of these cells has a number of significant potential clinical applications: rising or declining numbers of CTCs are well correlated with tumor progression or therapeutic response. Furthermore, CTCs bear genetic hallmarks of the primary cancer, offering a noninvasive “liquid biopsy” to enable initial and serial monitoring of tumor genotypes during cancer therapy. Most significantly, CTCs hold the key to understanding the process of blood-borne metastasis. Using next generation RNA sequencing strategies, we have initiated studies of expression profiles within CTCs. These have identified cellular pathways implicated in resistance of epithelial cells to anoikis in the circulation and in epithelial-mesenchymal transition - a phenomenon implicated in cancer invasion. The heterogeneity of CTC populations is evident in single cell imaging analyses and sequencing studies, with implications for understanding the complexity of therapeutic responses. Taken together, the application of novel bioengineering technologies to the isolation and analysis of CTCs across multiple different cancer types offers a unique window into the properties of cancer cells that invade into the bloodstream and give rise to metastases.
Citation Format: Daniel A. Haber, Min Yu, Emre Ozkumar, David Ting, David Miyamoto, Richard Lee, Ajay Shah, Aditya Bardia, Shannon Stott, Mehmet Toner, Shyamala Maheswaran. Molecular characterization of single circulating tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY30-01. doi:10.1158/1538-7445.AM2013-SY30-01
Abstract A18: The role of histone demethylase JARID1C in tumorigenesis of clear cell renal cell carcinoma
Authors: Ler Lian Dee , Allen George Edward , Myint Swe Swe , Teh Bin Tean 
Published: August 2014

Abstract
Clear cell renal cell carcinoma (ccRCC) constitutes 75% of all RCC. It is characterized by inactivation of the tumor suppressor Von Hippel Lindau gene (VHL) in ~70% of sporadic ccRCC cases. Recent large scale screen of ~3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX, JARID1C and SETD2. These genes encode enzymes that demethylate and methylate key lysine residue of histone H3. In particular, JARID1C is a histone 3 lysine 4 (H3K4) demethylase involved in the demethylation of gene activating trimethyl H3K4 (H3K4me3) mark and was found to be mutated in 3-9% of ccRCC, independent of the mutation status of VHL. Using gene expression profiling, we revealed that major down-regulated pathways in primary RCCs harboring JARID1C inactivating mutation are pointing towards changes involving metastatic properties. The highlighted pathways include ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton, cell junction organization and cell junction assembly. Therefore, we focused on elucidating the role of JARID1C in ccRCC invasive properties. From in vitro assay, depletion of JARID1C by introducing JARID1C shRNA in ccRCC cells did not result in significant changes in cell migration. By contrast, in consistent with the findings from gene expression profiling, we showed that such depletion of JARID1C significantly enhances the invasiveness of ccRCC cells regardless of their VHL gene status. In summary, our findings establish the role of JARID1C in potentiating the invasive capabilities of ccRCC.
Citation Format: Lian Dee Ler, George Edward Allen, Swe Swe Myint, Bin Tean Teh. The role of histone demethylase JARID1C in tumorigenesis of clear cell renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A18.
Abstract A28: Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers
Authors: Brien Gerard L. , Jerman Emilia , Campbell Matthew , Adrian Bracken P. 
Published: August 2014

Abstract
The Polycomb Repressive Complex 2 (PRC2) is emerging as an attractive therapeutic target for the treatment of cancer. Several functional protein domains that are amenable to small-molecule inhibition exist within the complex and the recent development of chemical inhibitors of the EZH1/2 SET domain now offers a means to therapeutically target the complex. Here we explore the potential of targeting the sub-stoichiometric PRC2 component, PCL3/PHF19, as an alternative to EZH1/2 inhibition. We show, both in normal fibroblasts and in SNF5 deficient malignant rhabdoid sarcoma cells, that targeted depletion of PCL3/PHF19 leads to proliferative defects, owing, at least in part, to a loss of Polycomb binding at and de-repression of the tumour suppressor p16INK4A. Significantly, we show that ectopic expression of PCL3/PHF19 leads to p16INK4A repression and a bypass of cellular senescence. This correlates with increased recruitment of EZH2, accumulation of H3K27me3 and PRC1 components on the INK4A promoter, suggesting a potential oncogenic role for PCL3/PHF19. Consistent with this, PCL3/PHF19 is over-expressed in many cancers. Previously we demonstrated that the TUDOR domain of PCL3/PHF19 is required for the ability of the protein to read epigenetic modifications and facilitate the recruitment of EZH2 to chromatin. Taken together with the data presented here, we propose that the TUDOR domain of PCL3/PHF19 represents a viable alternative functional domain within the PRC2 complex for small-molecule inhibition.
Citation Format: Gerard L. Brien, Emilia Jerman, Matthew Campbell, Bracken P. Adrian. Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A28.