bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1940: Thymine DNA glycosylase (TDG) as a novel target for melanoma
Authors: Tricarico Rossella , Mancuso Pietro , Bhattacharjee Vikram , Cosentino Laura , Nicolas Emmanuelle , Einarson Margret , Beeharry Neil , Devarajan Karthik , Katz Rich , Dorjsuren Dorjbal G. , Simeonov Anton , Kadariya Yuwaraj , Davidson Guillaume , Testa Joseph R. , Davidson Irwin , Larue Lionel , Sobol Robert W. , Yen Timothy , Bellacosa Alfonso 
Published: August 2018

Abstract
Melanoma is an aggressive neoplasm with increasing incidence that bears the infamous distinction of being a recalcitrant cancer, i.e. a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signal transduction pathway and immune checkpoints; however, advanced therapeutic approaches based on novel targets are urgently needed. We reasoned that the base excision repair enzyme Thymine DNA Glycosylase (TDG) could be such a target for its dual role in safeguarding genome stability and in effecting active DNA demethylation downstream the Ten-Eleven Translocation (TET) dioxygenases. TDG knockdown in melanoma cell lines causes cell cycle arrest, senescence and death by mitotic alterations, and impairs xenograft formation. Importantly, untransformed melanocytes are not affected by TDG knockdown, and adult mice with conditional knockout of TDG are viable. Candidate TDG inhibitors, identified through a high-throughput screen, reduced viability and clonogenic capacity of melanoma cell lines. Candidate TDG inhibitors increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA demethylation, which is specifically removed by TDG, indicating successful targeting. These findings suggest that TDG may provide critical functions in cancer cells, but not in normal cells, that make it a highly suitable anti-melanoma drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy.
Citation Format: Rossella Tricarico, Pietro Mancuso, Vikram Bhattacharjee, Laura Cosentino, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan, Rich Katz, Dorjbal G. Dorjsuren, Anton Simeonov, Yuwaraj Kadariya, Guillaume Davidson, Joseph R. Testa, Irwin Davidson, Lionel Larue, Robert W. Sobol, Timothy Yen, Alfonso Bellacosa. Thymine DNA glycosylase (TDG) as a novel target for melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1940.
Abstract 1942: Synthetic lethal interaction between SETD2 loss and inhibition of PI3Kβ in clear cell renal cell carcinoma (ccRCC)
Authors: Terzo Esteban , Chiang Yun C. , Chytil Anna , Jansen Valerie M. , Rathmell Kimryn 
Published: August 2018

Abstract
Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer for which several new targeted therapies exist. However, responses of primary clear cell RCC (ccRCC) tumors and metastases to these targeted agents are variable, and complete responses are relatively uncommon underscoring the need to identify reliable biomarkers to predict tumor behavior. Bi-allelic inactivation of the tumor suppressor gene SETD2, encoding a lysine methyltransferase, occur in approximately 20% of ccRCC tumors while the SETD2 protein deficiency rate has been reported to be as high as 34%. The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies, including ccRCC. Here, we show that genetic and pharmacologic inhibition of the PI3Kβ isoform results in inhibition of SETD2 deficient (-/-) ccRCC-derived 786-O and A498 cells, which exhibit increased sensitivity to PI3Kβ-specific inhibitors TGX221 (IC50 = 2.3 - 4.5 µM, respectively) and AZD8186 (IC50 = 1.79 - 0.24 µM, respectively) as compared to SETD2 proficient (+/+) 786-O cells (IC50 = &gt;10 µM). Inhibition of the p110δ isoform alone had a modest effect on ccRCC cell growth and migration. Importantly, genetic (with siRNA) and pharmacologic (with BYL719) inhibition of p110α had no effect on the ccRCC cell lines. Inhibition of AKT with the small molecule inhibitor MK2206 recapitulated the effects seen with AZD8186 in ccRCC cell lines with SETD2 loss, suggesting PI3Kβ mediates the synthetic lethality via AKT signaling in the context of SETD2 loss in ccRCC. Our work strongly suggests a synthetic lethal-type of interaction between PI3Kβ inhibition and SETD2 loss and offers a rationale for further translational and clinical investigation of small molecule inhibitors of PI3Kβ in RCC. Xenograft studies are ongoing to investigate the in vivo efficacy of AZD8186.
Citation Format: Esteban Terzo, Yun C. Chiang, Anna Chytil, Valerie M. Jansen, Kimryn Rathmell. Synthetic lethal interaction between SETD2 loss and inhibition of PI3Kβ in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1942.
Abstract 195: Electrochemical treatment produces pH changes in the tumor microenvironment that are toxic to cancer cells
Authors: Perkons Nicholas , Stein Elliot , Nwaezeapu Chike , Wildenberg Joseph , Ackerman Daniel , Nadolski Gregory , Hunt Stephen , Gade Terence 
Published: August 2018

Abstract
Background: Locoregional therapy is playing an increasingly central role in the management of hepatocellular carcinoma (HCC), where ablation is distinguished among these techniques by its capacity to effect cure. Electrochemical treatment (EChT), a technique that facilitates necrosis via the application of direct current at low voltages shows promise; however, widespread use has been limited as studies of the underlying biology and the mechanism of action have been limited.
Methods: A novel assay for the study of EChT mechanism was designed, wherein HCC cells (2.5e5 cells/mL) were embedded in low-melting temperature agarose (1.5%). EChT was performed on these assays between nitinol cathodes (d = 0.5 mm) and platinum anodes (d = 0.5 mm) in a variety of geometries. Buffering capacity of the encapsulation assay was varied via the addition of HEPES buffer at final concentrations of 10mM, 50mM, or 200mM. Either during or immediately following EChT, the following measurements were recorded: cell viability, pH, ROS burden, transmembrane potential, and temperature.
Results: Following EChT, acidic pH was appreciated surrounding the anodes and basic pH surrounding the cathodes in regions where cell death was observed by fluorescence microscopy. Upon increasing the buffering capacity of the assay, the total area of cell death decreased (p &lt; 10-6). There was not sufficient heat generation nor transmembrane potential to account for the observed cell death. A pH-threshold was identified, where a pH &gt; 10.8 or &lt; 4.4 was found to cause cell necrosis in the three different buffer conditions studied. By varying the number of electrodes, their spacing, and length of ablation, it was possible to shape the zone of cell death observed to an arbitrary geometry.
Conclusions: The mechanism of EChT-induced cancer cell death is through the spread of acidic and basic species generated by hydrolysis of water upon electron transfer at the electrodes. The diffusion of these species leads to cell death in a predictable, pH dependent manner. These results suggest that an electrochemical ablation device could treat complex HCC tumor geometries with appropriate electrode placement and charge delivery.
Citation Format: Nicholas Perkons, Elliot Stein, Chike Nwaezeapu, Joseph Wildenberg, Daniel Ackerman, Gregory Nadolski, Stephen Hunt, Terence Gade. Electrochemical treatment produces pH changes in the tumor microenvironment that are toxic to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 195.
Abstract 1965: Biologic evaluation of chalcone derivatives as ABCG2- and ABCB1-mediated drug resistance reversal agents
Authors: Cai Chaoyun 
Published: August 2018

Abstract
The overexpression of ATP-binding (ABC) transporters, including ABCG2 and ABCB1, has been shown to be related to multidrug resistance (MDR). In this work, we investigated a series of chalcones and bis-chalcones as ABCG2- and ABCB1-mediated resistance reversal agents. The results revealed that methoxyl chalcones have better reversal activities than hydroxyl chalcones toward ABCG2-mediated resistance. One methoxyl chalcone has good reversal activities in both ABCG2 and ABCB1 overexpressing cell lines. The compound can increase the accumulation of anticancer drugs in ABCG2 or ABCB1 overexpressing cell lines while combined with anticancer drugs, due to its inhibition of ABCG2 and ABCB1 (IC50 (ABCB1) =1.54 μM, IC50 (ABCG2) = 1.15 μM). In addition, this compound did not significantly alter the expression and localization of ABCG2 or ABCB1 in ABCG2 or ABCB1 overexpressing cell lines.
Citation Format: Chaoyun Cai. Biologic evaluation of chalcone derivatives as ABCG2- and ABCB1-mediated drug resistance reversal agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1965.
Abstract 1980: S116836 overcomes BCR-ABL T315I mutation mediated imatinib resistance in chronic myeloid leukemia
Authors: Gupta Pranav , Zhang Guannan , Barbuti Anna Maria , Ding Ke , Pan Jingxuan , Druker Brian J. , Chen Zhe-Sheng 
Published: August 2018

Abstract
Chronic Myeloid Leukemia (CML) is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer activity against BCR-ABL expressing BaF3 cells. S116836 shows potent activity against wild-type and T315I mutated BaF3 cells as compared with imatinib. S116836 inhibited the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. S116836 inhibited the mRNA expression of BCR-ABL in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 increased the cell population in the G0/G1 phase of the cell cycle, induced apoptosis and elevated ROS production in both BaF3/WT and BaF3/T315I cells. Moreover, S116836 inhibited tumor growth in BaF3/WT and BaF3/T315I tumor xenografts. Taken together, our results indicate that S116836 exhibits anti-proliferative effects and inhibits the imatinib-resistant T315I BCR-ABL mutation. S116836 may be a novel drug candidate for overcoming the resistance to imatinib in CML patients.
Keywords: S116836, Chronic myeloid leukemia, BCR-ABL, T315I, Resistance
Citation Format: Pranav Gupta, Guannan Zhang, Anna Maria Barbuti, Ke Ding, Jingxuan Pan, Brian J. Druker, Zhe-Sheng Chen. S116836 overcomes BCR-ABL T315I mutation mediated imatinib resistance in chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1980.
Abstract 1982: Obesity reversibly enhances mammary epithelial estrogen receptor alpha expression and progenitor activity
Authors: Chamberlin Tamara , D'Amato Joseph V. , Arendt Lisa M. 
Published: August 2018

Abstract
Obesity has been identified as an important risk factor for breast cancer in post-menopausal women and is significantly correlated with poor prognosis in breast cancer patients. Women with an increasing body mass index (BMI) are more likely to develop estrogen receptor alpha (ERα) positive tumors that are larger at the time of diagnosis and demonstrate an increased risk for metastasis. Given that obesity is becoming a global epidemic, understanding how obesity alters the biology of the normal breast is of significant clinical relevance. To examine the effects of obesity on mammary tissue, mice were fed a high fat diet to induce obesity and compared with mice fed a control diet. We also examined reduction mammoplasty tissue from women with a known BMI. In both obese female mice and women, mammary epithelial cell populations demonstrated significant decreases in basal/myoepithelial cells, when examined using either flow cytometry or cell type-specific markers (SMA and p63) in tissue. ERα expression was significantly increased in luminal cells in obese mammary tissue, compared with control mice or breast tissue from lean women. Functional assays demonstrated significantly enhanced mammary epithelial progenitor activity in obese mammary epithelial cells as well as elevated numbers of ERα positive epithelial cells that were co-labeled with markers of proliferation. Weight loss in a group of obese mice reversed increases in progenitor activity and ERα expression observed in obese mammary tissue. Obesity enhances the percentage of ERα positive epithelial cells and reduces the number of basal/myoepithelial cells within normal mammary tissue in both women and female mice. Both aspects of this phenotype have been linked to breast tumor susceptibility. These changes may contribute to lifetime risk for the development of ERα positive tumors in postmenopausal women. However, the changes in epithelial cell populations induced by obesity are reversible with weight loss, suggesting that weight loss interventions in obese women may effectively reduce breast cancer risk by decreasing the number of potential tumor progenitor cells in the breast epithelium.
Citation Format: Tamara Chamberlin, Joseph V. D'Amato, Lisa M. Arendt. Obesity reversibly enhances mammary epithelial estrogen receptor alpha expression and progenitor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1982.
Abstract 1985: Upregulation of miR-328 contributes to ovarian cancer stem cell maintenance by downregulating DDB2
Authors: Srivastava Amit K. , Cui Tiantian , Han Chunhua , Banerjee Ananya , Cai Shuri , Liu Lu , Zhang Xiaoli , Li Zaibo , Karuppalyah Selvendiran , Wani Altaf A. , Wang Qi-En 
Published: August 2018

Abstract
Cancer stem cells (CSCs) are considered to play a central role in the cancer progression, metastasis and the development of drug resistance. MicroRNAs (miRNAs) have important roles in regulating CSC properties and are considered to be potential therapeutic targets. Diverse aberrantly expressed miRNAs have been reported in ovarian cancer cells. However, there have been few reports about miRNAs that were associated with stemness and progression of ovarian cancer. In this study, miRNA Nanostring profiling analysis was performed to screen crucial miRNAs associated with characteristics and maintenance of CSCs in ovarian cancer. We found that miR-328-3p was remarkably upregulated in ovarian CSCs isolated from both ovarian cancer cell lines and primary ovarian tumors compared to their corresponding bulk cancer cells. We further demonstrated that enforced expression of miR-328-3p in ovarian cancer cell lines expanded the population of ALDH+ cells, enhanced their sphere formation ability, as well as increased their tumorigenicity. While inhibition of miR-328-3p limited the ALDH+ cell population, reduced their sphere formation capacity, and decreased their tumorigenicity. The orthotopic ovarian xenograft assay also demonstrated that inhibition of miR-328-3p impedes tumor growth and metastasis. The mechanistic investigation revealed that repressed ERK1/2 phosphorylation in ovarian CSCs, mainly due to reduced level of reactive oxygen species (ROS), contributes to the enhanced expression of miR-328-3p, and the maintenance of CSCs. Finally, we identified DDB2 as a direct target of miR-328-3p. Given our previous finding that DDB2 is capable of limiting the CSC population in ovarian cancers, we conclude that highly expressed miR-328-3p in ovarian CSCs, probably due to repressed ERK1/2 activity, inhibits DDB2 expression, resulting in the expansion of these CSCs. Thus, targeting miR-328 could be exploited to a novel strategy to eradicate CSCs in ovarian cancer.
Citation Format: Amit K. Srivastava, Tiantian Cui, Chunhua Han, Ananya Banerjee, Shuri Cai, Lu Liu, Xiaoli Zhang, Zaibo Li, Selvendiran Karuppalyah, Altaf A. Wani, Qi-En Wang. Upregulation of miR-328 contributes to ovarian cancer stem cell maintenance by downregulating DDB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1985.
Abstract 1988: The pivotal roles of adipocytes on regulation of cancer stemness and drug resistance in hepatocellular carcinoma
Authors: Gurung Shilpa , Lee Terence Kin-Wah 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world with less than 10% 5-year survival rate. Liver cancer stem cells (CSCs) are sub-populations of the cancer cells that have been found to play a crucial role in tumor relapse and therapeutic resistance. Increasing reports showed the significant correlation between non-alcoholic fatty liver disease (NAFLD) and HCC development. Based on this evidence, we hypothesize adipocytes, one of the key cellular factors within the tumor microenvironment, play a crucial role in HCC development and progression via regulation of liver CSCs. To verify this, we have employed a co-culture system to dissect the potential cross-talk between fully differentiated adipocytes and HCC cells. Our pilot data showed that adipocytes enhanced the self-renewal ability of HCC cells through indirect paracrine secretion. Based on this finding, we examined the effect of the conditioned medium of adipocytes on regulation of liver CSC. Consistently, we found that HCC cells pre-incubated with conditioned medium of adipocytes showed enhanced in vivo tumorigenicity and chemo-resistance to doxorubicin and sorafenib. Furthermore, conditioned medium of adipocytes promoted the migration and invasion abilities of HCC cells. To delineate the molecular mechanism of how adipocytes, exert its CSC enhancing effect on HCC cells, we have collected the conditioned medium derived from adipocytes and analyzed their secretome profiles using Orbitrap Liquid Chromatography-Mass spectrometry. Upon analysis, we identified 209 proteins, among which we have focused on two proteins (CSF1 and FABP4) for further analysis as these are preferentially secreted from adipocytes. Respective inhibitors of the proteins are used to study the specificity of the protein in the medium and the downstream studied with the help of RNA sequencing which has been performed on conditioned medium treated HCC cells. Collectively, we demonstrated the pivotal role of adipocytes on regulation of liver CSCs through paracrine secretion. Thus, targeting adipocytes-derived signaling cascade may be a novel therapeutic strategy for treatment of fatty liver induced HCC.
Citation Format: Shilpa Gurung, Terence Kin-Wah Lee. The pivotal roles of adipocytes on regulation of cancer stemness and drug resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1988.
Abstract 1993: Rapid clonal evolution of dormant micrometastatic disease in head and neck cancer
Authors: Lagunas Angelica M. , Wu Jianchun , Crowe David L. 
Published: August 2018

Abstract
Head and neck cancer (HNC) is prone to locoregional recurrence which results in poor clinical outcome. Recent HNC clinical studies demonstrated that cervical lymph node dissection results in improved patient outcome even in early disease. These results suggest that dormant micrometastatic cancer occurs early in head and neck carcinogenesis. We used our established in vivo chemical carcinogenesis model of head and neck cancer to characterize dormant micrometastatic disease using genetic lineage tracing and null mutant mice. Histopathology was analyzed by hematoxylin and eosin staining. Telomere DNA damage response was determined by immunofluorescent 53BP1 localization at telomeres, and by ATM/ATR western blotting. Keratin expression and proliferation index were determined by immunohistochemistry. Apoptotic cells were determined by TUNEL analysis. Telomerase activity was determined by telomere repeat amplification protocol. Alternative lengthening of telomeres was determined by PML localization at telomeres, telomere circular DNA analysis, and chromosome orientation fluorescence in situ hybridization. Genomic instability was determined by high throughput sequencing. Cancer stem cells were sorted by flow cytometry and transplanted subcutaneously in Matrigel. Advanced HNC exhibited significant metastatic disease in the majority of lymph nodes. Early HNC and even premalignant lesions exhibited micrometastatic disease in most lymph nodes. These micrometastatic lesions contained multiple HNC clones that were dependent for proliferation on paracrine chemokine signaling from a tumorigenic keratin 15+ cancer stem cell population. In situ, the micrometastatic K15+ cancer stem cell population exhibited increased telomere DNA damage response including activated ATM and ATR which correlated with low proliferation index. Clonal evolution of K15+ micrometastatic cancer stem cells was dependent on extremely short telomeres. These cells expressed both telomerase and recombination-based alternative lengthening of telomeres (ALT) activities. K15+ micrometastatic cancer stem cells exhibited high levels of genomic instability resulting from telomere fusions and expressed metastasis-specific gene expression programs. These patterns of micrometastatic gene expression revealed targeted therapeutic vulnerabilities. These results indicate that dormant micrometastatic disease develops rapidly during head and neck carcinogenesis from normal epithelial cells with short telomeres and is sensitive to targeted therapies.
Citation Format: Angelica M. Lagunas, Jianchun Wu, David L. Crowe. Rapid clonal evolution of dormant micrometastatic disease in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1993.