bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2825: Identification of CDK4/6-response biomarkers using estrogen receptor-positive breast cancer patient-derived xenografts (PDX)
Authors: Serra Violeta , Palafox Marta , Herrera Maria-Teresa , Rivas Martin A , Guzmán Marta , Rodriguez Olga , Grueso Judit , Bellet Meritxell , Oliveira Mafalda , Saura Cristina , di Tomaso Emmanuelle , Camponigro Giordi , Turner Nicholas C. , Cortés Javier , Baselga José 
Published: July 2016

Abstract
Endocrine resistance is a clinical challenge for the treatment of estrogen receptor positive (ER+) breast cancer (BC). CDK4/6 blockade in combination with endocrine therapy has shown clinical activity in metastatic ER+ BC refractory to anti-hormonal treatment. However, there is a need for biomarkers that can predict the response to this treatment and improve patient stratification. We aimed to address this issue using xenograft models established from samples of ER+ BC patients.
Six ER+ PDXs were treated with continuous doses of a CDK4/6 inhibitor (LEE011, 75mg/kg, 6IW) and a PI3K-alpha inhibitor (BYL719, 35mg/kg, 6IW) as single agents and in combination, and intrinsic sensitivity to these agents was evaluated. The models were then genomically characterized using a capture-based sequencing panel and by digital PCR.
One PDX model was intrinsically sensitive to single-agent CDK4/6 inhibition and experienced tumor regression, but all individual tumors eventually escaped therapy after 50 days of treatment. This particular model harbored an ESR1-mutation and concomitant losses of CDKN2A/B. At relapse, we identified the acquisition of an RB1 frameshift mutation. Interestingly, upfront combined treatment with a PI3K-alpha inhibitor delayed the onset of tumor progression. Two out of the remaining five CDK4/6-resistant PDXs harbored either a frameshift mutation in RB1 (plus loss of heterozygosity) or had low pRb protein expression. Two other resistant models harbored CCND1 and MYC amplifications. The remaining one harbored a TSC1 loss. In all the CDK4/6-resistant PDX, however, the combination of CDK4/6 and PI3K-alpha inhibition resulted in tumor regression.
From our results, we conclude that loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 and CCND1-amplification, is associated with lack of response to CDK4/6 blockade in ER+ BC PDX. The addition of a PI3K-alpha inhibitor results in improvement of disease control in all experimental models tested.
Citation Format: Violeta Serra, Marta Palafox, Maria-Teresa Herrera, Martin A Rivas, Marta Guzmán, Olga Rodriguez, Judit Grueso, Meritxell Bellet, Mafalda Oliveira, Cristina Saura, Emmanuelle di Tomaso, Giordi Camponigro, Nicholas C. Turner, Javier Cortés, José Baselga. Identification of CDK4/6-response biomarkers using estrogen receptor-positive breast cancer patient-derived xenografts (PDX). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2825.
Abstract 2826: Sustained melanoma regression is achieved with continuous palbociclib and PLX4720 treatment but not with intermittent or sequential dosing
Authors: Sheppard Karen E. , Cullinane Carleen , Martin Claire , Kirby Laura , Haynes Nicole , Waldeck Kelly , Young Richard , VanArsdale Todd , McArthur Grant 
Published: July 2016

Abstract
In melanoma the development of resistance to BRAF inhibitors limits clinical responses. Thus the search for novel single agent and combination therapies as well as sequencing strategies that overcome or delay the emergence of resistance is needed. The p16-CDK4- cyclinD-RB1 pathway (CDK4 pathway) is deregulated in approximately 90% of melanomas and most melanoma cell lines are sensitive to palbociclib a specific CDK4/6 inhibitor. We hypothesized that dual targeting the MAPK/ERK and CDK4 pathways would lead to robust inhibition of the CDK4/Cyclin D complex and consequently induce greater tumor regression than single agent treatment. Proliferation and colony formation assays demonstrated that sequential and intermittent treatment with PLX4720 and palbociclib was not as effective as continuous combinational dosing. Only the combination of PLX4720 and palbociclib overcame the development of resistance leading to sustained inhibition of proliferation, cell death and induction of senescence. In A375 and HT144 human tumor xenograft models, palbociclib and PLX4720 initially induced tumor regression and tumor stasis, respectively, however resistance eventually developed to both agents. In contrast, the combination treatment induced rapid and sustained tumor regression. Biomarker studies indicate resistance to single agent PLX4720 was due to reactivation MAPK/ERK pathway and resistance to palbociclib to partial restoration of phosphorylated RB1. Tumor regression in the combination treatment was associated with the infiltration of leukocytes including activated natural killer cells indicating that these cells were involved in tumor clearance. These data demonstrate that dual targeting CDK4/6 and mutant BRAF evades resistance to single agents and leads to sustained tumor regression
Citation Format: Karen E. Sheppard, Carleen Cullinane, Claire Martin, Laura Kirby, Nicole Haynes, Kelly Waldeck, Richard Young, Todd VanArsdale, Grant McArthur. Sustained melanoma regression is achieved with continuous palbociclib and PLX4720 treatment but not with intermittent or sequential dosing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2826.
Abstract 2837: The CDK4/6 inhibitor has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma
Authors: Ku Bo Mi , Koh Jiae , Bae Yeon-Hee , Sun Jong-Mu , Lee Se-hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju 
Published: July 2016

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a rare lethal human malignancy with no effective therapy. It is critical to identify new therapeutic strategies for NHSCC. Deregulation of CDKN2A (p16) or CCND1 (cyclin D1) occurs commonly in HNSCC and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. The selective CDK4/6 inhibitor, LY2835219 inhibited CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induced cell cycle arrest and growth inhibition. In an animal xenograft model of HNSCC, LY2835219 treatment led to reduced tumor growth. However, because single-agent treatment with LY2835219 showed a limited effect in HNSCC, a combinational strategy is necessary for effective therapy. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combination treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.
Citation Format: Bo Mi Ku, Jiae Koh, Yeon-Hee Bae, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn. The CDK4/6 inhibitor has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2837.
Abstract 2847: Phenyl 2-pyridyl ketoxime induces cellular senescence-like alterations via NO production in human diploid fibroblasts
Authors: Jang Hyun-Jin , Jo Eunbi , Chung Young-Ho , Park JunSoo , Park Sung-Jun , Jang Ik-Soon 
Published: July 2016

Abstract
Phenyl-2-pyridyl ketoxime (PPKO) was found to be one of small molecules enriched in the extracellular matrix of near-senescent human diploid fibroblasts (HDFs). Treatment of young HDFs with PPKO reduced the viability of young HDFs in a dose and time-dependent manner, and resulted in senescence-associated β-galactosidase (SA-β-gal) staining and G2/M cell cycle arrest. In addition, the levels of some senescence-associated proteins, such as phosphorylated ERK1/2, caveolin-1, p53, p16ink4a, and p21waf1, were elevated in PPKO-treated cells. To monitor the effect of PPKO on cell stress responses, reactive oxygen species (ROS) production was examined by flow cytometry. After PPKO treatment, ROS levels transiently increased at 30 min but then returned to baseline at 60 min. The levels of some antioxidant enzymes, such as catalase, peroxiredoxin II, and glutathione peroxidase I, were transiently induced by PPKO treatment. SOD II levels increased gradually, whereas the SOD I and III levels were biphasic during the experimental periods after PPKO treatment. Cellular senescence induced by PPKO was suppressed by chemical antioxidants, such as N-acetylcysteine, 2,2,6,6-tetramethylpiperidinyloxy and L-buthionine-(S,R)-sulfoximine. Furthermore, PPKO increased nitric oxide (NO) production via inducible NO synthase (iNOS) in HDFs. In the presence of NOS inhibitors, such as L-NG-nitroarginine methyl ester and L-NG-monomethylarginine, PPKO-induced transient NO production and SA-β-gal staining were abrogated. Taken together, these results suggest that PPKO induces cellular senescence in association with transient ROS and NO production and the subsequent induction of senescence-associated proteins.
Citation Format: Hyun-Jin Jang, Eunbi Jo, Young-Ho Chung, JunSoo Park, Sung-Jun Park, Ik-Soon Jang. Phenyl 2-pyridyl ketoxime induces cellular senescence-like alterations via NO production in human diploid fibroblasts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2847.
Abstract 2852: CITED2, an emerging regulator in hypoxia- and anoikis- mediated cancer cell growth
Authors: Kuo Ming-Han , Chan Chia Ee , Chou Yu-Ting 
Published: July 2016

Abstract
In solid tumors, hypoxia and anoikis are two common phenomena occurred in the central of region, inducing a series of genes to switch metabolic pathways, prevent apoptosis and promote continuous growth of cancer cells. Herein, we reported that CITED2 (CBP/p300-interacting transactivators with glutamic acid (E)/aspartic acid (D)-rich C-terminal domain 2) responded to hypoxia and anoikis induction, preventing lung cancer cells from cell cycle arrest. We found that hypoxia induced CITED2 through a HIF2α dependent pathway; moreover, three-dimensional (3D) growth of lung cancer cells induced the expression of CITED2. 3D growth condition elicited anoikis-mediated cell cycle arrest, which was further potentiated by hypoxia stimulation. Knockdown of CITED2 or HIF2α in lung cancer cells enhanced anoikis, causing G1/S cell cycle arrest. Soft agar analysis displayed that both HIF2α and CITED2 are necessary for anchorage-independent cell growth under the hypoxic condition. Spheroid assay indicated that HIF2α-CITED2 signaling axis plays an important role in spheroid formation. Pearson correlation analysis showed that CITED2 was associated with HIF2α expression in lung adenocarcinoma. Kaplan Meier analysis revealed that CITED2 expression was correlated with poor survival outcomes in patients with lung adenocarcinoma. Thus, our findings support the notion that CITED2 plays a critical role in hypoxia- and anokis- mediated cancer cell growth with the potential as a prognostic biomarker for predicting lung cancer progression.
Citation Format: Ming-Han Kuo, Chia Ee Chan, Yu-Ting Chou. CITED2, an emerging regulator in hypoxia- and anoikis- mediated cancer cell growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2852.
Abstract 2853: Apoptosis and proliferation in micropapillary structures of colorectal polyps and carcinomas
Authors: Patankar Madhura , Vayrynen Sara , Tuomisto Anne , Makinen Markus , Karttunen Tuomo 
Published: July 2016

Abstract
Background: Micropapillary structures (MIP) can be defined as focal piles of epithelial cells in columnar epithelium. MIP's are found in many cancers, but they are characteristic for serrated colorectal carcinomas. Suprabasal cells of MIP show no contact with extracellular matrix (unpublished).
Objective: To evaluate whether MIP cells in colorectal polyps and cancers would show evidence for anoikis inhibition we assessed proliferation and apoptosis indexes (PI and AI, respectively) in MIP and non-MIP epithelium.
Materials and methods: We stained human colorectal lesions: non-serrated adenomas (n = 15), serrated polyps (n = 29), conventional adenocarcinomas (n = 32), and serrated adenocarcinomas (n = 30) with antibodies to Ki67 and M30. To obtain PI and AI two independent observers counted proportions of positive cells separately in the cells of MIP and in non-MIP epithelium.
Results: In carcinomas, AI was lower in the cells of MIP (M30; median 0, range 0-40) than in the non-MIP cells (median 2, range 0-40; p&lt;0.001, Wilcoxon). Similarly, PI was lower in the MIP cells (Ki67; MIP: median 17, range 0-93; non-MIP: median 30, range 1-93; p&lt;0.001). Similar patterns were evident in subsets of serrated lesions, in both carcinomas (p&lt;0.001) and polyps (p&lt;0.001), and in non-serrated carcinomas (p&lt;0.004). Apoptosis/proliferation (AI/PI) ratio was lower in the MIP cells than in the non-MIP epithelium in both cancers and their precursor lesions (P&lt;0.01).
Conclusion: Apoptosis rate was lower in MIP's than in other tumor epithelium indicating ability of these cells to survive without matrix contact, i.e. Anoikis is inhibited in them. Lower PI could suggest that cells in the MIP are in some kind of quiescent stage. However, significantly lower AI/PI ratio in the MIP infers that these structures may form a fast growing subpopulation of tumor cells. Further studies are in progress to dissect mechanism of formation of MIP and matrix independent survival of tumor cells in them.
Citation Format: Madhura Patankar, Sara Vayrynen, Anne Tuomisto, Markus Makinen, Tuomo Karttunen. Apoptosis and proliferation in micropapillary structures of colorectal polyps and carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2853.
Abstract 2867: Functional role of FHL2 in the splicing machinery of liver cells
Authors: Cao Ye , Liu Minghua , Yang Yi , Zhang Yinfeng , Tsui Kwok Wing 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing worldwide incidence. The four-and-a-half LIM domain protein 2 (FHL2) has been identified as an oncogene / tumor suppressor gene in a tissue/cell specific manner by acting as an adaptor protein to form different complexes and involving in various signaling pathways. To clarify the intriguing functions of FHL2, we have identified a batch of interacting partners of FHL2 by immunoprecipitation and liquid chromatography coupling with mass spectrometry. Many of these proteins, including SNRNP70, DAZAP1, SFPQ, TIAL1 and so on, are involved in spliceosome components and mRNA surveillance. The interaction among several proteins and FHL2 has been confirmed by co-immunoprecipitation. To further elucidate the functional role of FHL2 in the splicing process in liver cancer cells, we have studied the transcriptomes of FHL2 overexpression and FHL2 knockdown liver cells, whereas empty vector and scrambled siRNA were used as controls respectively. Followed by bioinformatics analysis, we found significant concordance between the immunoprecipitation and transcriptome datasets. Selected genes were further validated by real-time PCR such as FGFR4. In summary, FHL2 is probably regulating the mRNA splicing by interacting with components of the splicing machinery and modulating splicing related genes at the transcriptional level.
Citation Format: Ye Cao, Minghua Liu, Yi Yang, Yinfeng Zhang, Kwok Wing Tsui. Functional role of FHL2 in the splicing machinery of liver cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2867.
Abstract 2874: Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development
Authors: Zhang Xiaowen , Nair Sreejith J. , Chiang Huai-Chin , Wang Yao , Jahid Md Jamiul , Ruan Jianhua , Jin Victor X. , Hu Yanfen , Li Rong 
Published: July 2016

Abstract
Breast cancer susceptibility gene BRCA1 is well known for its function in double strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. Cofactor of BRCA1 (COBRA1) is a BRCA1-binding protein and an important regulator of transcription elongation. Here we used mouse genetics to interrogate functional interaction between BRCA1 and COBRA1 during mammary gland development. Tissue-specific deletion of Cobra1 reduced mammary epithelial compartments and blocked ductal morphogenesis, alveologenesis, and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout were largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restored developmental transcription at puberty, altered luminal epithelial homeostasis, yet remained deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription program during mammary gland development.
Citation Format: Xiaowen Zhang, Sreejith J. Nair, Huai-Chin Chiang, Yao Wang, Md Jamiul Jahid, Jianhua Ruan, Victor X. Jin, Yanfen Hu, Rong Li. Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2874.
Abstract 2875: Genes associated with neuronal development, including splicing regulatory factors, increase in expression across epithelial-mesenchymal transition
Authors: Khodor Yevgenia L. , Riquelme Daisy , Gertler Frank , Burge Christopher B. 
Published: July 2016

Abstract
The program by which epithelial cells lose their polarity and close contacts with neighboring cells and acquire migratory and invasive properties is known as epithelial-mesenchymal transition (EMT). Initially identified as a critical developmental process, EMT is now understood to occur during cancer, where it has been shown to confer resistance to senescence and apoptosis. Previous work indicates that cancer cells that escape the site of the primary tumor hijack at least a portion of the EMT program to increase their invasive properties and metastasize. Earlier work in the field has focused on cell signaling and transcriptional regulation changes that lead to EMT, but changes in the gene expression and post-transcriptional regulation of the cell have only recently become the focus of study. We characterized gene expression and splicing across EMT in the luminal epithelial MCF7ras SLUG+SOX9 breast cancer cell line by collecting samples at 2-day intervals across its 6-day transition and profiling the RNA by RNA-seq. We found over 4,000 significantly changing genes, and that the majority of gene expression and splicing changes occurred in the first two days of the transition, with few changes noted between days 4 and 6. Genes that changed could be broadly categorized into those whose expression decreased, increased, or peaked in the middle of the transition before decreasing. Intriguingly, genes whose expression increased during EMT were enriched for gene ontology terms related to cell signaling and neuronal development. We specifically observed increased expression of mRNAs encoding splicing factors and other RNA-binding proteins (RBPs) associated with neuronal development, in contrast to the majority of RBPs whose expression decreases in EMT. We are currently exploring various aspects of this program, including effects of increased expression of the neuronal-associated splicing regulatory factor quaking (QKI). These may include downregulation of the Notch pathway via effects on splicing of NUMB, a Notch inhibitor. We are currently validating the role of QKI on this and other RNA processing changes and will report our findings.
Citation Format: Yevgenia L. Khodor, Daisy Riquelme, Frank Gertler, Christopher B. Burge. Genes associated with neuronal development, including splicing regulatory factors, increase in expression across epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2875.
Abstract 288: Low-dose cabazitaxel inhibits the growth of prostate cancer cells and enhances the anti-tumor properties of PEDF with greater efficacy than docetaxel
Authors: Jarvis Courtney L. , Nelius Thomas , Martinez-Marin Dalia , Cheerla Srirupa , Filleur. Stéphanie 
Published: July 2016

Abstract
Despite recently approved novel agents, taxane-based chemotherapy remains the major therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC). Still mCRPC continues to be incurable. Furthermore, patients often experience severe side effects, prompting a re-evaluation of conventional regimen. Past studies have demonstrated promise for Low-Dose Metronomic (LDM) chemotherapy; schedule defined as the frequent administration of low doses of chemotherapeutic drugs with no prolonged drug-free breaks. Yet relative activities of LDM taxanes and combinations with known anti-neoplasic agents have to be investigated. Using CRPC cell lines (PC3, Du145 and the LNCaP-derivative CL1), we have shown that cabazitaxel-treated cells have a significantly lower EC50 compared to docetaxel, with Du145 cells presenting the greatest differences. In cell cycle analysis, both low-dose taxanes increased the sub-G1 cells population. However, the sub-G1 increase was significantly greater in cabazitaxel- than in docetaxel-treated Du145 cells, but not in PC3 and CL1. Accordingly, plasma membrane Annexin V elevation occurred in Du145 cells at lower doses of cabazitaxel than docetaxel validating a higher efficacy due to increased apoptosis. As other possible cell death mechanisms, autophagy and necrosis were investigated. Beclin1 expression levels remain unchanged in all three cell lines. In contrast, necrosis was stimulated in all the taxanes-treated cell lines in a dose dependent manner. In vivo, LDM cabazitaxel was significantly more efficient in delaying tumor growth than docetaxel. This effect was markedly increased when cabazitaxel was combined with the angio-inhibitor and anti-tumor Pigment Epithelium-Derived Factor (PEDF). Other results showed that PEDF and LDM chemotherapy combination induces more phagocytosis of CRPC cells when compared to single treatments. In conclusion, our data demonstrate a higher efficacy of cabazitaxel on CRPC both in vitro and in vivo, and suggest that LDM taxane chemotherapy/PEDF combination could be used as a novel therapeutic strategy for CRPC.
Citation Format: Courtney L. Jarvis, Thomas Nelius, Dalia Martinez-Marin, Srirupa Cheerla, Stéphanie Filleur. Low-dose cabazitaxel inhibits the growth of prostate cancer cells and enhances the anti-tumor properties of PEDF with greater efficacy than docetaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 288.