bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5483: Implications of the type of BRCA1 germline mutation in the treatment of patients with hereditary breast cancer
Authors: Vaclova Tereza , Woods Nicholas T. , Setién Fernando , Bueno José María García , Macías José Antonio , Barroso Alicia , Urioste Miguel , Esteller Manel , Monteiro Alvaro N.A. , Benítez Javier , Osorio Ana 
Published: May 2015

Abstract
Carrying an inherited mutation in BRCA1 or BRCA2 genes significantly increases individual´s lifetime risk to develop breast or ovarian cancer. However, there are considerable differences in disease manifestation among mutation carriers, suggesting the existence of other factors which could modify the risk of cancer development.
Since BRCA1 is an important component of DNA repair, BRCA1-deficient cells have to rely on other members of the DNA repair machinery. This makes them sensitive to drugs which target specific repair pathways, such as inhibitors of poly (ADP-ribose) polymerase (PARP). Several PARP inhibitors are currently being tested in preclinical or clinical trials, either as a monotherapy or in combination with chemo- or radiotherapy. Taking into account the promising results in patients with germline mutation in BRCA1 or BRCA2 genes, we aimed to investigate which BRCA1 mutation carriers, depending on the mutation type, might benefit from treatment with PARP inhibitors the most. In addition, we were also interested in identifying markers of sensitivity/resistance to PARP inhibitors.
We have used lymphoblastoid cell lines (LCLs) derived from lymphocytes of healthy women heterozygous for different BRCA1 mutations and healthy women from the same families with no mutation. In total, 23 LCLs were characterized according to their DNA repair capacity, growth rate, gene/miRNA expression and sensitivity to PARP inhibitors. Our preliminary results have shown significantly higher sensitivity to PARP inhibitor olaparib in cells harbouring missense mutation in comparison to cells with truncating or no mutation. The ongoing functional studies on these BRCA1 missense variants indicate that these mutations could act in a dominant negative manner. Importantly, the observed differences in sensitivity to olaparib among mutation carriers could be also relevant for recently proposed use of PARP inhibitors as prophylactic agent for mutation carriers.
Our ongoing work may help us to better understand the mechanisms of action of PARP inhibitors and lead to improvement of therapeutic strategies for BRCA1-associated cancers with extension to other tumors.
Citation Format: Tereza Vaclova, Nicholas T. Woods, Fernando Setién, José María García Bueno, José Antonio Macías, Alicia Barroso, Miguel Urioste, Manel Esteller, Alvaro N.A. Monteiro, Javier Benítez, Ana Osorio. Implications of the type of BRCA1 germline mutation in the treatment of patients with hereditary breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2014-5483
Abstract 5484: Dehydroleucodine: A potential sesquiterpene lactone for targeting castration-resistant prostate cancer
Authors: Banerjee Souresh , Munirathinam Gnanasekar 
Published: May 2015

Abstract
Prostate cancer (PCa) patients undergoing standard androgen deprivation therapy eventually develop aggressive castration-resistant prostate cancer (CRPC) for which there is no effective treatment currently available. Hence, there is an urgent need to identify effective treatment strategy for lethal CRPC. Previous studies have shown naturally occurring sesquiterpene lactones (SLs) are promising anti-cancer agents and few SLs are under clinical trials for cancer treatment. Evaluation of additional SLs may prove to be valuable as an adjunct or stand alone treatment especially for CRPC. Dehydroleucodine (DhL), a sesquiterpene lactone isolated from Artemisia douglasiana has several pharmacological benefits such as anti-inflammatory, anti-ulcer and anti-oxidant effects. However, the anti-cancer effects of DhL are not well known. In this study, we have evaluated the effects of DhL against castration-sensitive (LNCaP) and CRPC (PC-3) cells in a pre-clinical study. Our cell viability assay results showed that DhL had pronounced inhibition on PC-3 cell proliferation compared to that of LNCaP cells. Therefore, our subsequent studies focussed on elucidating the effects and mechanism of action of DhL using PC-3 CRPC cells. Our investigations showed that in addition to inhibiting the cell proliferation of PC-3 cells, DhL also abrogated the clonogenic potential of PC-3 cells by activating apoptotic markers such as caspase-3 and PARP-1 and cell cycle inhibitors p21 and p27 respectively. Furthermore, our mechanistic study has identified DhL downregulates the expression of NF-kB (p65) in PC-3 cells which may be contributing to the anti-cancer effects of DhL in these cells. Interestingly, our studies also showed that DhL inhibited the osteoclastogenesis mediated by PC-3 in vitro as determined by tartarate-resistant acid phosphatase (TRAP) assay suggesting that DhL may be beneficial in preventing the bone destruction caused by metastatic CRPC. Taken together, our study warrants further investigation of DhL as a promising natural agent for effective treatment and management of CRPC.
Citation Format: Souresh Banerjee, Gnanasekar Munirathinam. Dehydroleucodine: A potential sesquiterpene lactone for targeting castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5484. doi:10.1158/1538-7445.AM2014-5484
Abstract 5488: Everolimus inhibits the proliferation of aromatase inhibitor-resistant breast cancer cells
Authors: Lui Asona , Lewis-Wambi Joan 
Published: May 2015

Abstract
Aromatase inhibitors (AIs) are currently the standard treatment for estrogen receptor positive breast cancer in postmenopausal women. Unfortunately, the majority of patients treated with AIs eventually develop resistance to these drugs. The mechanism by which AI resistance occurs is still not known, however, there is strong evidence that upregulation of the PI3K/Akt/mTOR pathway might play an important role. As such, mTOR inhibition is now under study in clinical trials as a breast cancer treatment. The newest mTOR inhibitor, Everolimus (Afinitor®), has been FDA approved for the treatment of metastatic breast cancer. We have previously reported the development of two AI-resistant breast cancer cell lines (MCF-7:5C and MCF-7:2A) which were clonally derived from parental MCF-7 cells following long term estrogen deprivation. Both MCF-7:5C and MCF-7:2A cells have been shown to overexpress members of the PI3K/Akt/mTOR pathway. In this study, we examined the therapeutic benefits of everolimus in AI-resistant MCF-7:5C and MCF-7:2A cells compared to endocrine sensitive MCF-7 breast cancer cells and normal breast epithelium MCF10A cells. Results from cell viability assay showed that everolimus markedly inhibited the proliferation of endocrine sensitive MCF-7 cells and AI-resistant MCF-7:5C and MCF-7:2A cells in a time-dependent and concentration-dependent manner with IC50s of 30 nM, 40 nM and 10 nM, respectively. Notably, the MCF-7:2A cells were the most sensitive to everolimus which caused a 70% reduction in proliferation at 24 hours whereas in MCF-7 and MCF-7:5C cells only 30% inhibition was observed at the same time point. The inhibitory effect of everolimus was due primarily to G1 arrest and was associated with significant downregulation of phospho-mTOR, phospho-p70S6K, phospho-Akt, GSK3β, cyclin D1 and p21. Colony formation assay in soft agar indicated that AI-resistant MCF-7:5C and MCF-7:2A cells formed significantly more colonies than MCF-7 cells and that treatment with everolimus notably reduced the size and number of colonies for all three cell lines. Finally, we found that exposure of AI-resistant MCF-7:5C and MCF-7:2A cells to a single dose of gamma-irradiation (6 Gy) significantly enhanced the anti-proliferative effect of everolimus on these cells. In summary, these studies showed that everolimus significantly inhibited the proliferation and tumorigenicity of AI-resistant breast cancer cells and that everolimus might be an effective treatment option for patients with AI-resistant breast cancer.
Citation Format: Asona Lui, Joan Lewis-Wambi. Everolimus inhibits the proliferation of aromatase inhibitor-resistant breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5488. doi:10.1158/1538-7445.AM2014-5488
Abstract 5493: Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) sensitivity in breast cancer stem cells and non-stem breast cancer cells
Authors: Soo Sian Siu , Ng Char Hong , Malik Rozita Abdul , Teh Yew Ching , Tan Boon Shing , Ho Gwo Fuang , See Mee Hoong , Taib Nur Aishah Mohd , Yip Cheng Har , Teo Soo Hwang , Leong Chee Onn 
Published: May 2015

Abstract
Incorporating cancer stem cells (CSCs)-targeting therapies into current therapies could prevent cancer progression, recurrence and metastasis. An anti-diabetic, AMPK-activating drug, metformin has been shown to kill CSCs and reduces cancer incidence and cancer related death. This study aimed to evaluate the combination treatment of metformin or other AMPK/mTOR-acting drugs with chemotherapy on breast CSCs and non-CSCs in the pre-clinical and clinical settings. We investigated the combination effect of metformin, AICAR, A-769662, or rapamycin with doxorubicin, cisplatin, paclitaxel, or FEC on breast CSCs (mammospheres) and non-CSCs in vitro. The study was extended clinically in a pilot study of ten non-diabetic locally advanced breast cancer patients treated with metformin and neoadjuvant FEC chemotherapy. Nine patients treated with FEC only were identified as historical controls. ESA+/CD44+/CD24-/low (CSCs) population of the tumor samples and tumor response were evaluated. In contrast to other drugs, metformin exhibited higher sensitivity in CSCs compared to attached cell lines. Metformin combined with FEC demonstrated a synergistic effect on breast CSCs and non-CSCs. Patients receiving metformin/FEC neoadjuvant therapy showed a significant reduction in CSCs proportion (P=0.008). Proportion of CSCs after treatment with metformin/FEC was significantly lower compared with the FEC-only neoadjuvant group (P=0.008). Five out of nine patients (56%) receiving metformin/FEC therapy showed a clinical response versus one out of eight (13%) patients in the FEC-only group. In conclusion, metformin synergizes FEC sensitivity in both CSCs and non-CSCs in breast cancer cell lines. Combination treatment of metformin and FEC reduces CSCs in primary tumor from non-diabetic locally advanced breast cancer patients. These results indicate that neoadjuvant metformin/FEC may be a potential treatment option for breast cancer patients and warrants further clinical investigations.
Citation Format: Sian Siu Soo, Char Hong Ng, Rozita Abdul Malik, Yew Ching Teh, Boon Shing Tan, Gwo Fuang Ho, Mee Hoong See, Nur Aishah Mohd Taib, Cheng Har Yip, Soo Hwang Teo, Chee Onn Leong. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) sensitivity in breast cancer stem cells and non-stem breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2014-5493
Abstract 5496: Mechanisms of anti-tumurogenic activity of the brown seaweed, F. vesiculosus
Authors: Riby Jacques E. , Conde Lucia , Cui Xiangqin , Zhang Jianqing , Skibola Christine F. 
Published: May 2015

Abstract
Introduction. We previously reported significant anti-estrogenic effects related to the consumption of the brown seaweed, F. vesiculosus. The present study aimed to further characterize the mechanisms involved and to investigate other actions of F. vesiculosus that may be biologically relevant.
Methods. Activation of the estrogen receptor was determined using a luciferase reporter assay (CALUX assay) in six breast, ovarian and endometrial cancer cells lines (MCF7, T47D, MDA-MB-231, OVCAR-3 and HEC-1-B) treated with an F. vesiculosus extract. Cell proliferation and apoptosis were determined by the MTT assay and the AnnexinV affinity assay, respectively. Gene expression profiling for 248 genes in pathways including tumor suppression, apoptosis, autophagy, hormonal regulation, cell cycling, proliferation, angiogenesis, inflammation and oxidative stress were analyzed using the nCounter Analysis System (NanoString Technologies, Seattle, WA), and validated by real-time quantitative RT-PCR. A two-way ANOVA model, with cell line effect and treatment dose effect, was fitted to the normalized expression data for each gene. The permutation based F-test was used to identify genes differentially expressed between treatment doses.
Results. In co-treatments with 12.5 pM β-estradiol (EC50), F. vesiculosus reduced ER activity by ∼50% at the 1mg/mL dose, showing a potent ER antagonist effect. All cells showed a progressive decrease in proliferation rates, as measured by the MTT assay over 3 days, with increasing concentrations of the seaweed extract, but the sensitivity of individual cell lines was variable. The two endometrial cell lines were most responsive, with up to a 50% reduction in cell number, whereas the MDA-MB-231 breast cancer cell line was least responsive with a 30% overall reduction. Transcription levels of multiple genes were affected by the treatments in all cell lines, with more notable effects in apoptosis, proliferation, and several receptor-mediated signaling pathways.
Conclusion. Our results provide new insights into the anti-estrogenic activity of F. vesiculosus through direct inhibition of estrogen receptor activation that may be particularly relevant in the pathogenesis and progression of female cancers. We also found that the F. vesiculosus extract reduced cell proliferation, induced apoptosis and up-regulated genes in signaling pathways that have anti-tumorigenic potential.
Citation Format: Jacques E. Riby, Lucia Conde, Xiangqin Cui, Jianqing Zhang, Christine F. Skibola. Mechanisms of anti-tumurogenic activity of the brown seaweed, F. vesiculosus. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2014-5496
Abstract 5498: Changes in expression of DNA repair genes in human leukemia cells treated with laromustine
Authors: Robinson Kristen N. , Coe Kathryn A. , Owumi Justin E. , Rice Kevin P. 
Published: May 2015

Abstract
The anticancer prodrug laromustine induces cytotoxic DNA damage and has had clinical success against acute myelogenous leukemia and glioblastoma multiforme. The causative DNA damage is principally a G-C interstrand crosslink preceded by 2-chloroethylation of guanine O6 by a subspecies of laromustine generated in situ upon base-catalyzed activation. Another cogenerated electrophile, methylisocyanate, contributes synergistically with the DNA alkylating activity towards cytotoxicity. Given this synergism, DNA repair enzymes are considered likely targets of methylisocyanate, which can carbamoylate amines and sulfhydryls. The inhibition of O6-alkylguanine-DNA alkyltransferase (AGT) and DNA polymerase beta by laroumustine's carbamoylating activity, observed in vitro, may contribute to cytotoxicity. To further investigate the relationship between laromustine and DNA repair, drug-induced changes in the transcription of 88 DNA repair genes were measured in cultured human promyelocytic (HL-60) cells using quantitative real-time reverse transcriptase PCR. Cells were treated with laromustine or vehicle for six hours before harvesting mRNA for analysis. The expression of a subset of the tested genes emerged as significantly different in cells treated with laromustine as compared to control cells. Included among those genes with significantly increased expression were: NTHL1 (17 fold), PARP1 (8 fold), and AGT (5 fold). Included among those genes with significantly decreased expression were: PARP2 (-5 fold) and MSH6 (-74 fold). Increased expression of NTHL1, which encodes for an N-glycosylase that can remove damaged guanine bases, may reduce the effectiveness of laromustine's alkylation of guanine O6. A strong negative correlation between the level of AGT activity in patient samples and the efficacy of laromustine has already been established. Some of the gene products identified in this study, such as NTHL1, may emerge as possible cotherapeutic targets or markers for clinical screening.
Citation Format: Kristen N. Robinson, Kathryn A. Coe, Justin E. Owumi, Kevin P. Rice. Changes in expression of DNA repair genes in human leukemia cells treated with laromustine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5498. doi:10.1158/1538-7445.AM2014-5498
Abstract 5501: Combined effects of docetaxel-magnetic nanoparticles with different surface modifications on prostate cancer cells
Authors: Furuta Nao , Yamaguchi Sou , Iwasaki Ayumi , Okamoto Daiki , Sato Akiko , Endo Yoshihiro , Kurioka Daisuke , Nittami Tadashi , Ishiguro Hitoshi , Uemura Hiroji , Kunota Yoshinobu , Watanabe Masatoshi 
Published: May 2015

Abstract
Docetaxel-based chemotherapy prolongs life and relieves symptoms in patients with castration resistant prostate cancer. However, this needs to be improved because of limitations by lack of specificity, systemic toxicity, and progression of docetaxel-resistance. Nanotechnology has served a new role in medical sciences by a variety of nanotechnology platforms, leading to theranostics. Among these platforms, Fe3O4 magnetic nanoparticles (MgNPs) have potential applications in drug delivery, cancer diagnosis and hyperthermia. We have already shown that MgNPs would modify the effect of chemotherapy in prostate cancer cells based on the observations that MgNPs increased reactive oxygen species (ROS) production and induced oxidative DNA damage in prostate cancer cell lines. Combined treatment of docetaxel and MgNPs has also shown to suppress nuclear transcription factor kappa B expression in DU145 cells. In this study, we analyzed the combined effects of docetaxel-MgNPs with different surface modifications on a prostate cancer cell line, DU145 and their mechanisms. The combination treatment of docetaxel and carboxylic acid-modified MgNPs (MgNPs-COOH) more effectively inhibited cancer cell growth and induced apoptosis compared with docetaxel-MgNPs combination. While MgNPs produced ROS in a dose-dependent manner and inhibited cancer cell growth slightly, MgNPs-COOH did exert no ROS production, however cell membrane damage in a dose-dependent manner. In addition, MgNPs-COOH showed the involvement of the endoplasmic reticulum (ER) stress. These results suggest that MgNPs-COOH may induce different responses compared with MgNPs, and result in favorable development of current chemotherapy for the advanced disease and leading to new theranostics.
Citation Format: Nao Furuta, Sou Yamaguchi, Ayumi Iwasaki, Daiki Okamoto, Akiko Sato, Yoshihiro Endo, Daisuke Kurioka, Tadashi Nittami, Hitoshi Ishiguro, Hiroji Uemura, Yoshinobu Kunota, Masatoshi Watanabe. Combined effects of docetaxel-magnetic nanoparticles with different surface modifications on prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5501. doi:10.1158/1538-7445.AM2014-5501
Abstract 5508: Bromodomain and hegdehog pathway targets in small cell lung cancer
Authors: Kaur Gurmeet , Reinhart Russell A. , Monks Anne , Evans David , Morris Joel , Teicher Beverly A. 
Published: May 2015

Abstract
Small cell lung cancer (SCLC) is an extremely aggressive cancer that frequently recurs after conventional cytotoxic chemotherapy. SCLC is a neuroendocrine lung malignancy for which there is no effective treatment that affects &gt;200,000 people world-wide every year with a very high mortality rate (&lt;5% of patients survive five years). SCLC cells are, indeed, small with limited cytoplasm surrounding the nuclei. The cells tend to grow as floating clusters or spheroids which are often difficult to disaggregate. Twenty-four human SCLC lines were assessed for response to bromodomain inhibitors and hedgehog pathway inhibitors. Gene expression determined from Affymetrix Exon ST1 arrays and protein expression determined by western blotting confirmed that 6 SCLC lines expressed high levels of c-Myc, 5 lines expressed high levels of L-Myc and 3 lines expressed high levels of n-Myc. The c-Myc over-expressing lines expressed very low levels of ASCL1 and high levels of SMO. The L-Myc over-expressing lines expressed high ASCL1 and moderate SMO, and the n-Myc over-expressing lines had variable expression of ASCL1 and moderate expression of hedgehog pathway genes. Gene expression data is being correlated with the protein expression in 24 human SCLC cell lines using western blot analysis. Nine point concentration response experiments were performed with the bromodomain inhibitors JQ1 and I-BET-15. In general, the Myc over-expressing SCLC lines were more sensitive to the Bromodomain inhibitors than were the lines without Myc amplification. At the IC50 concentrations, the c-MYC over-expressing lines were &gt;-4-fold more sensitive to JQ1 than the lines without Myc amplification while the L-Myc over-expressing lines were &gt;-3-fold more sensitive and the n-Myc over-expressing lines were &gt;-9-fold more sensitive to JQ1 than the lines without Myc amplification. Concentration response experiments with the same 24 SCLC lines were carried out with the Hedgehog pathway inhibitors HPI1, SEN-450, LDE225 (erismodegib; clinical Cmax = 9 uM) and GDC0049 (vismodegib; clinical Cmax = 34 uM). The SCLC lines which over-express Myc were more sensitive to the 4 hedgehog pathway inhibitors than were the lines without Myc amplification. Although the 6 c-Myc over-expressing lines had higher levels of SMO gene expression than the other SCLC lines, they were not different in sensitivity to the SMO inhibitors than the other Myc over-expressing lines. Further studies of SCLC lines response to investigational agents are underway.
Citation Format: Gurmeet Kaur, Russell A. Reinhart, Anne Monks, David Evans, Joel Morris, Beverly A. Teicher. Bromodomain and hegdehog pathway targets in small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5508. doi:10.1158/1538-7445.AM2014-5508