bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 23: Chemotherapy and tau interplay facilitates breast-to-brain metastasis
Authors: Saatian Behnaz , Deshpande Krutika , Julian Alex , Nakamura Brooke Naomi , Shao Ling , Neman Josh 
Published: August 2018

Abstract
Breast cancer represents the second most common cause of brain metastasis with the rate of 10-16% after lung cancer. The overall survival in brain metastatic patients is very short ranging from 2 to 25 months. Considering the high incidence of brain metastasis and the limitation of available therapies, developing preventive strategies and early detection methods are required to improve the survival rate in the patients. Many primary and brain metastatic breast cancer patients represent cognitive deficits. Besides, chemo-treated breast cancer patients show memory problems before brain metastases diagnosis. Although the cause of cognitive impairments after chemotherapy have not been explored, a recent study revealed that chemotherapy promotes breast cancer metastasis. Correspondingly, our mRNA expression analysis showed downregulation of the tight junction markers in chemo-treated choroid plexus cells (CPs), suggesting that chemotherapy is likely to cause an increase in the blood-cerebral spinal fluid barrier (BCSFB) permeability. Chemotherapy also induces upregulation of tau expression in CP cells. Tau is known as a pathological hallmark of Alzheimer's disease (AD) and neurodegenerative disorders. The abnormally phosphorylated and aggregated form of tau play critical role in neurodegenerative diseases as of AD. Tau expression, both at the mRNA and protein level, is significantly elevated in breast to brain metastases (BBMs). Therefore, we hypothesized that chemotherapy upregulates tau expression in breast cancer cells leading to the BCSFB and blood-brain barrier (BBB) permeability, and consequently, breast to brain metastasis and neurodegeneration. To test our hypothesis, the effect of chemotherapy on the BCSFB and BBB permeability were investigated using the trans endothelial electrical resistance (TEER) and migration assays in the in vitro models. Our results show an increase in abnormal tau expression in chemo-treated primary breast cancer cells. BBM-derived tau is abnormal and forms paired helical filaments (PHFs), similar to Alzheimer's. We conclude that breast to brain metastasis is facilitated through an interplay between chemotherapy, and tau expression and release from breast cancer cells. Additionally, we suggest that tau plays a key role in neurodegeneration defects in brain metastatic patients. This study opens a new path towards prevention and early detection of breast cancer metastasis to the brain, cognitive decline and neurodegeneration in metastatic patients.
Citation Format: Behnaz Saatian, Krutika Deshpande, Alex Julian, Brooke Naomi Nakamura, Ling Shao, Josh Neman. Chemotherapy and tau interplay facilitates breast-to-brain metastasis [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 23.
Abstract 2301: Dual targeting of CDK4/6 and MET in metastatic uveal melanoma
Authors: Ohara Masahiro , Saito Kengo , Kageyama Ken , Terai Mizue , Cheng Hanyin , Aplin Andrew E. , Sato Takami 
Published: August 2018

Abstract
Uveal melanoma (UM) is the most common cancer of the eye in adults. Up to 50% of UM patients subsequently develop metastases, especially in the liver, for which no effective treatment has been identified. It has been reported that the retinoblastoma (RB) pathway is deregulated in more than 90% of UM despite the rarity of mutations in the RB1 gene itself. Cyclin D1 over-expression and inactivation of p16INK4a in UM are frequently present and make the RB protein constitutively hyperphosphorylated and functionally inactivated; therefore, CDK4/6 inhibition (CDK4/6i) is a rational strategy for treatment of UM. In this report, we investigated the antiproliferative activity of a selective CDK4/6 inhibitor on metastatic UM. A CDK4/6 inhibitor induced G0-G1 arrest in all three metastatic UM cell lines and suppressed their growth in in vitro and in vivo experiments. Interestingly, hepatocyte growth factor (HGF) decreased the effect of CDK4/6 inhibitor on metastatic UM cell lines and protected the metastatic UM cells from CDK4/6 inhibitor-induced cellular senescence. When CDK4/6i was combined with MET inhibitor, enhanced growth suppression was observed in metastatic UM tumors grown in human-HGF knock-in xenograft mouse models. HGF is enriched in the liver and the majority of liver metastases from UM express activated forms of MET; therefore, signaling through MET could contribute to the resistance mechanisms against CDK4/6i, especially in UM patients with hepatic metastasis. Together, these results provide a rationale for the use of MET inhibitor in combination with a CDK4/6 inhibitor for the treatment of metastatic UM.
Citation Format: Masahiro Ohara, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin, Takami Sato. Dual targeting of CDK4/6 and MET in metastatic uveal 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 2301.
Abstract 2308: Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer
Authors: Sankaranarayanan Ranjini , Dachineni Rakesh , Kumar D. Ramesh , Callegari Eduardo , Kesharwani Siddharth S. , Seefeldt Teresa , Tummala Hemachand , Gunaje Jayarama B. 
Published: August 2018

Abstract
Aspirin's potential as a drug continues to be evaluated for the prevention of colorectal cancer (CRC). Although multiple targets for aspirin and its metabolite, salicylic acid, have been identified, no unifying mechanism has been proposed to clearly explain its chemopreventive effects. Our goal here was to investigate the ability of salicylic acid metabolites, known to be generated through cytochrome P450 (CYP450) enzymes, and also its derivatives as cyclin dependent kinase (CDK) inhibitors to gain new insights into aspirin's chemopreventive actions. Using in vitro kinase assays, for the first time, we demonstrate that salicylic acid metabolites, 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), as well as derivatives 2,4-dihydroxybenzoic acid (2,4-DHBA), 2,6-dihydroxybenzoic acid (2,6-DHBA), inhibited CDK1 enzyme activity. 2,3-DHBA and 2,6-DHBA did not inhibit CDK2 and 4; however, both inhibited CDK-6 activity. Interestingly, another derivative, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) was highly effective in inhibiting CDK1, 2, 4 and 6 activity. Molecular docking studies showed that these compounds potentially interact with CDK1. Immunoblotting experiments showed that aspirin acetylated CDK1, and preincubation with salicylic acid and its derivatives prevented aspirin-mediated CDK1 acetylation, which supported the data obtained from molecular docking studies. We suggest that intracellularly generated salicylic acid metabolites through CYP450 enzymes within the colonic epithelial cells, or the salicylic acid metabolites generated by gut microflora may significantly contribute to the preferential chemopreventive effect of aspirin against CRC through inhibition of CDKs. This novel hypothesis and mechanism of action in aspirin's chemopreventive effects opens a new area for future research. In addition, structural modification to salicylic acid derivatives may prove useful in the development of novel CDK inhibitors in cancer prevention and treatment.
Citation Format: Ranjini Sankaranarayanan, Rakesh Dachineni, D. Ramesh Kumar, Eduardo Callegari, Siddharth S. Kesharwani, Teresa Seefeldt, Hemachand Tummala, Jayarama B. Gunaje. Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal 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 2308.
Abstract 231: Identification of susceptible loci and enriched pathways for post-radiotherapy pain in breast cancer patients
Authors: Lee Eunkyung , Takita Christina , Wright Jean L. , Martin Eden , Slifer Susan , Hu Jennifer 
Published: August 2018

Abstract
Pain is one of the most prevalent symptoms among breast cancer survivors, which negatively impact on their quality of life (QOL). Adjuvant radiotherapy (RT) can increase the risk of development or persistence of pain; however, little is known about the mechanisms of RT-related pain or genetic susceptibility. The current study aimed to identify susceptible loci and enriched pathways for clinically relevant pain, which is defined as pain score ≥ 4, at the completion of RT (post-RT pain). We conducted a genome-wide association study (GWAS) of 1,112 breast cancer patients with 1,344,832 tagging SNPs, gene-based analysis using PLINK set-based tests for 19,621 genes, and functional enrichment analysis of a gene list (875 genes having p &lt; 0.05) using NIH DAVID functional annotation module with KEGG pathways and GO terms (n=380). About 29% of patients reported post-RT pain, and 4 SNPs showed suggestive associations; rs16970540 in RFFL or near to LIG3 gene (p=1.7x10-6), rs4584690 and rs7335912 in ABCC4/MPR4 gene (p=5.5x10-6 and p=7.8x10-6, respectively), and rs73633565 in EGFL6 gene (p=8.1x10-6). Gene-based analysis suggested the importance (involvement) of neurotransmitter, olfactory receptor, and cytochrome P450 in post-RT pain, and functional analysis suggested glucuronidation and olfactory receptor activity as the most enriched biological processes/features. With a limited size of sample, this is the first GWA study showing (confirming) that post-RT pain is a complex polygenic trait influenced by many biological processes and functions. If validated in a larger population, the results can provide biological targets for pain management to improve cancer survivor's QOL. Additionally, these findings may be used as predictive biomarkers of personalized pain management.
Citation Format: Eunkyung Lee, Christina Takita, Jean L. Wright, Eden Martin, Susan Slifer, Jennifer Hu. Identification of susceptible loci and enriched pathways for post-radiotherapy pain in breast cancer patients [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 231.
Abstract 2311: Determinants of CDK4 target engagement by palbociclib, ribociclib and abemaciclib
Authors: Green Jennifer L. , Nomanbhoy Tyzoon 
Published: August 2018

Abstract
Palbociclib, ribociclib and abemaciclib compose a class of ATP-competitive CDK4 and CDK6 inhibitors that have demonstrated preclinical and clinical efficacy against various tumor types. While these inhibitors have favorably altered the landscape of cancer therapeutics, identification of patients likely to respond to CDK4/6 inhibition remains a challenge. Previously, we used our chemoproteomics platform (KiNativ), which measures competition of an ATP- or ADP-acyl-phosphate probe, to profile lysates generated from cells that were treated with palbociclib. We showed that palbociclib-CDK4 target engagement is cell line specific and that engagement correlates with sensitivity of the cell line to palbociclib-mediated growth inhibition. However, the circumstances that determine whether target engagement is achieved were not understood. In an effort to understand the molecular mechanisms that influence CDK4 target engagement, we used the same proteomics platform to interrogate the contribution of various known CDK regulators. We identified a family of proteins that prevents palbociclib target engagement upon overexpression and whose lack of expression correlates with palbociclib sensitivity. This interaction is specific for CDK4/6 as modulation of the drug's interaction with off-target kinases was not affected by overexpression of these proteins. Furthermore, we found that these proteins similarly prevent CDK4 target engagement by ribociclib and abemaciclib. Incorporation of the proteins identified here into a biomarker strategy should help to enrich for patients likely to respond to CDK4/6 inhibition therapy and expand the utility of these inhibitors.
Citation Format: Jennifer L. Green, Tyzoon Nomanbhoy. Determinants of CDK4 target engagement by palbociclib, ribociclib and abemaciclib [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 2311.
Abstract 2317: Palbociclib monotherapy exhibits potent activity in cervical cancer cell lines
Authors: Dam Peter Van , Wouters An , Dirix Luc , Rolfo Christian 
Published: August 2018

Abstract
Background: Over the last decades, little progress has been made in the systemic treatment of patients with advanced or recurrent cervical cancer. We recently performed an silico analysis to identify potential driver pathways of cervical carcinogenesis and candidate targets for treatment.1 Expression2Kinases (E2K) analysis revealed a protein-protein interaction (PPI) network of 162 nodes (including 20 druggable kinases) consisting of 5 signaling modules associated with MYC signaling (module 1), cell cycle deregulation and cyclin signaling (module 2), TGFβ-signaling (module 3), a PI3K - MAPK signaling (module 4) and chromatine modeling (module 5).
Methods: The cervical cancer cell lines included in the study were CaSki, SiHa and HeLa. Cells were incubated for 24 or 72 hours with the PI3K pathway inhibitor BYL719 (Novartis), the multiple pathway inhibitor INC280 (inhibits cMET-dependent PI3K and RAS signaling, Novartis), or the CDK4/6 inhibitor PD-0332991 (palbociclib, Selleck Chemicals) in monotherapy. Sensitivity to drug treatment (0 - 10 μM) was investigated using the colorimetric sulforhodamine B (SRB) assay. IC50 values were calculated using WinNonlin Software.
Results: Incubation with BYL719 or INC280 for 24 or 72 hours in concentrations up to 10 μM was not able to establish a distinct cytotoxic effect in the three cervical cancer cell lines included in the study. Incubation with 10 μM BYL719 for 72h resulted in only 20% cell kill, while 10 μM INC280 for 72h caused around 30% cell kill in all three cell lines. However, incubation with palbociclib for 72 hours clearly induced a concentration-dependent cytotoxic effect, with IC50 values of 5.32 ± 0.03 μM, 7.69 ± 0.02 μM and 5.68 ± 0.12 μM for HeLa, SiHa and CaSki cells, respectively.
Conclusion: CDK4/6 inhibition seems effective in cervical cancer cell lines and should be further evaluated alone and in combination with chemotherapy for the treatment of advanced and recurrent cervical cancer.
References:
Van Dam P, van Dam PJ, Rolfo C, Giallombardo M, Van Berckelaer C, Trin XB, Altintas S, Huizing M, Papadimitriou K, Tjalma W, Van Laere S. In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment. Oncotarget 2016;7(3):2780-2795
Citation Format: Peter Van Dam, An Wouters, Luc Dirix, Christian Rolfo. Palbociclib monotherapy exhibits potent activity in cervical cancer cell lines [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 2317.
Abstract 2322: Ferroptosis induced by erastin in RAS mutant ovarian cancer cells
Authors: Takenaka Motoki , Suzuki Noriko , Mori Minako , Aoki Hitomi , Hirayama Tasuku , Nagasawa Hideko , Morishige Ken-ichirou 
Published: August 2018

Abstract
Although apoptosis has been thought as the principal mechanism of programed cell death in chemotherapy, other forms of non-apoptotic death also has been noted. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of cell death termed ferroptosis. This mechanism is expected to induce eradication of chemotherapeutic (e.g. platinum) resistant cancer cells. In this study we demonstrate this new form of cell death in ovarian cancer cells. The clear cell epithelial ovarian cancer cell lines, TOV-21G (KRAS_G13C) and KOC-7C (RAS wild type) were used in this study. Erastin dose-dependently inhibited growth in TOV-21G cells, but not KOC-7C cells. Treatment of TOV-21G cells with erastin resulted in increase of ROS. Iron chelator deferoxamine (DFO) rescued growth inhibition induced by erastin in TOV-21G cells. Although cisplatin inhibited growth in TOV-21G cells, this inhibition was not rescued by DFO. The GSH level was reduced by erastin, but this reduction was not rescued by DFO. In addition, the basal GSH level was higher and the basal ROS level was lower in KOC-7C cells than those in TOV-21G cells. Erastin induced ferroptosis by reducing the GSH level in RAS mutant ovarian cancer cells. Although DFO rescued growth inhibition induced by erastin, the pathway was not on System Xc-. The sensitivity to erastin might depends on the basal level of GSH in cells. Ferroptosis had great potential to become a new approach in anti-tumor therapies in ovarian cancer.
Citation Format: Motoki Takenaka, Noriko Suzuki, Minako Mori, Hitomi Aoki, Tasuku Hirayama, Hideko Nagasawa, Ken-ichirou Morishige. Ferroptosis induced by erastin in RAS mutant ovarian 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 2322.
Abstract 2323: Involvement of glutamine in tolerance of human pancreatic cancer cell to inhibition of fatty acid synthesis
Authors: Nishi Koji , Suzuki Mina , Yamamoto Noriko , Iwase Yumiko , Yumita Nagahiko 
Published: August 2018

Abstract
Pancreatic cancer (PC) is the fifth leading cause of cancer-related mortality in Japan. Although the standard chemotherapy regimens, FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin), gemcitabine and nab-paclitaxel, are widely used to treat patients with advanced pancreatic cancer, their antitumor effects (progression and survival rates) are less potent against this cancer type than other solid tumors. Previously, we found that inhibition of acetyl-CoA carboxylase (ACC), a major rate-controlling enzyme of fatty acid synthetic pathway, suppressed the proliferation of PC cells. However, in this study, we found the tolerance to the inhibition in a part of PC cells. Therefore, we investigated the mechanism of the tolerance to ACC inhibition in PC cells. The human PC cell lines, AsPC-1, BxPC-3 and PANC-1 were obtained from the American Type Culture Collection. Live and apoptotic cell numbers were determined using the MUSE Annexin V and Dead Cell Kit according to the manufacturer's instructions. PANC-1 cells showed the tolerance to inhibition of fatty acid synthesis by ACC inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), whereas TOFA induced apoptosis in AsPC-1 and BxPC-3 cells. In addition, PANC-1 did not show autophagy even under the condition of fatty acid starvation. Next, we investigated whether PANC-1 has the tolerance to nutrient starvation in nutrient-depletion medium, Earle's Balanced Salt Solution (EBSS) and serum-free medium respectively. PANC-1 showed the survival even in such mediums, whereas AsPC-1 and BxPC-3 almost dead. This result suggests that the tolerance of fatty acid starvation of PANC-1 are related to that of nutrient starvation. Interestingly, proliferation of PANC-1 cultured in glutamine-depletion medium dramatically was suppressed, even though low glucose medium did not affect. BPTES, a selective inhibitor of glutaminase, also suppressed the proliferation and induced apoptosis in PANC-1, whereas there are little effects of 2-dexy-glucose, inhibitor of glycolysis, on them. These results suggest that the TCA cycle plays an important role on the tolerance to inhibition of fatty acid synthesis and nutrient starvation of PANC-1, and can be novel therapeutic target of PC cells which have the tolerance to nutrient starvation like PANC-1.
Citation Format: Koji Nishi, Mina Suzuki, Noriko Yamamoto, Yumiko Iwase, Nagahiko Yumita. Involvement of glutamine in tolerance of human pancreatic cancer cell to inhibition of fatty acid synthesis [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 2323.
Abstract 2330: CaV1.3 calcium channel expression in prostate cancer cells during androgen-deprivation conditions
Authors: McKerr Niamh , Breen Conor , Srivastava Kirtiman , Mills Ian G. , McCloskey Karen D. 
Published: August 2018

Abstract
Background Prostate cancer (PCa) remains one of the most frequently diagnosed cancers in males in the western world. Despite efforts to reduce tumour burden through treatments including androgen-deprivation therapy (ADT), patients often relapse 2 years post-therapy due to emergence of castration-resistant disease. The importance of ion channels including calcium channels in cancer biology is increasingly recognized. CACNA1D encodes the calcium channel, CaV1.3, which is overexpressed in PCa biopsies. In addition to canonical ion transport, the c-terminal region of CaV1.3 may modulate gene expression. The purpose of this study was to elucidate the expression of CaV1.3 during PCa progression and explore the effects of calcium channel blockers. Methods A cell line panel comprising normal prostate epithelium (RWPE-1), androgen-sensitive PCa (LNCaP, VCaP) and castration-resistant PCa (C4-2B, DU145 and PC3) were used. LNCaP were cultured in charcoal-stripped serum-containing media to mimic ADT or with the anti-androgen enzalutamide (10μM) for 4-14 days. qPCR, Western blotting and immunofluorescence imaging were performed. Cell viability assays were performed in the absence/presence of ADT, enzalutamide and the CaV1.3 blocker nifedipine (1μM). Apoptosis was measured with flow cytometry in cells stained with Annexin V/Propidium Iodide (AV/PI). Results CACNA1D mRNA had higher expression in LNCaP, VCaP and C4-2B vs. RWPE-1 (p≤0.05; N=3). Western blotting/densitometry showed higher protein expression of CaV1.3 in LNCaP, VCaP and C4-2B relative to RWPE-1 (P≤0.05; N=3). Immunofluorescence indicated cytoplasmic and perinuclear localisation of CaV1.3 in the majority of cell lines and diffuse cytoplasmic staining in VCaP (N=2). ADT and enzalutamide-treated LNCaP displayed time-dependent increased CACNA1D expression over 14 days however, CaV1.3 protein expression peaked at 4 days (N=3). Cell viability assays of LNCaP treated with ADT or enzalutamide (4 days) showed significant reduction in viability when nifedipine was combined with the treatment (N=3; P≤0.05). Similarly, increased % of apoptotic LNCaP cells were observed when nifedipine was added to treated LNCaP vs. ADT or enzalutamide alone (N=2). Conclusion CaV1.3 expression is differentially expressed in cells lines modelling PCa progression and enhanced during ADT. Blockade of CaV1.3 in combination with ADT treatments further reduced cell viability and increased the apoptotic population.
Citation Format: Niamh McKerr, Conor Breen, Kirtiman Srivastava, Ian G. Mills, Karen D. McCloskey. CaV1.3 calcium channel expression in prostate cancer cells during androgen-deprivation conditions [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 2330.