bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 802: Synergistic effect of curcumin on FL118 efficacy in colon cancer
Authors: Ling Xiang , Gandhi Nishant , Jiao Boyang , Chandra Dhyan , Li Fengzhi
Published: May 2015

Colorectal cancer is the third most commonly diagnosed cancer in the United States and may cause about 50,830 deaths in 2013. Therefore, there is an unmet need for new therapeutic strategies. Combination of natural compounds with pharmacological small molecular inhibitors to increase anticancer efficacy while minimizing toxicity is an attractive approach for management of cancer. Curcumin, a natural dietary compound, has been shown to inhibit multiple cancer cell signaling pathways involved in survival, proliferation, apoptosis, angiogenesis and metastasis. FL118, a novel camptothecin derivative and an IAP (inhibitor of apoptosis) inhibitor, significantly attenuates colon cancer cell growth in vitro and tumor growth in vivo. In the current study, we report that curcumin enhances FL118 anti-cancer efficiency in colon cancer cell models. MTT and cell death detection ELISA assays were used for quantification of cell viability and apoptosis, respectively, in colon cancer HCT8 and SW620 cells. The synergistic effect of curcumin in combination with FL118 treatment on colon cancer growth inhibition was further analyzed by the Combination Index (CI) equation developed by Chou-Talalay using a CalcuSyn program (Biosoft, Cambridge, UK). Our data demonstrated that curcumin shows a synergistic growth inhibitory effect with FL118 in multiple colon cancer cells (p<0.05). Furthermore, combinational treatment can significantly enhance apoptotic cell death induced in comparison with either FL118 or curcumin treatment alone (p<0.05). In HCT8 colon cancer cells, a combination of 10µM curcumin with 0.3-20 nM FL118 treatment for 72 h showed a strong synergistic effect (CI < 0.5) in cell growth inhibition. Mechanistically, the combination treatment-enhanced cell growth inhibition and apoptosis are associated with alteration of the expression of cell death and cell cycle related genes. In conclusion, we propose that combination of curcumin with FL118 might provide a novel therapeutic strategy in colon cancer treatment.

Citation Format: Xiang Ling, Nishant Gandhi, Boyang Jiao, Dhyan Chandra, Fengzhi Li. Synergistic effect of curcumin on FL118 efficacy in colon 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 802. doi:10.1158/1538-7445.AM2014-802
Abstract 809: BRAF wild-type melanoma survival hinges upon AKT activity and adaptive autophagic reprogramming in response to chemotherapy
Authors: Rebecca Vito W. , Massaro Renato , Fedorenko Inna , Gibney Geoffrey T. , Sondak Vernon K. , Amaravadi Ravi K. , Jin Shengkan , Maria-Engler Silvya S. , Kudchadkar Ragini , Smalley Keiran S. M.
Published: May 2015

Strategies for patients whose melanomas are BRAF wild-type are completely lacking. We here report on the mechanisms underlying the long-term responses (>12 months) of 2 BRAF wild-type (WT) melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. A panel of 7 BRAF/NRAS-WT cell lines was leveraged to investigate strategies to overcome chemoresistance. Electron microscopy, western blotting and flow cytometry assays were integrated to simultaneously follow fluctuations in autophagic flux, reactive oxygen species levels and cytotoxicity caused from chronic treatment of cells with chemotherapy, MK-2206, lysomotropic agents and/or anti-oxidants. MK-2206 potently inhibited phospho-AKT signaling, but did not impact melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin induced little apoptosis following 3-day treatment, but led to cytotoxicity in long-term colony formation and 3D spheroid assays. Mechanistically the combination was noted to induce autophagy and disrupt reactive oxygen species homeostasis, as shown by increased LC3-II expression, the formation of LC3 punctae, acridine orange protonation, the accumulation of autophagosomes and increased ROS detection using DHR-123. At earlier time points, autophagy was protective with cytotoxicity enhanced following chloroquine and bafilomycin treatment as well as the increased cytotoxic effects seen in ATG5-/- MEFs. Although prolonged MK-2206/chemotherapy treatment (6-9 days) led to high levels of autophagy induction and a switch to caspase-dependent apoptosis, drug resistant clones still eventually emerged. The importance of autophagy for the escape process was suggested by the lack of ATG5-/- MEF colonies seen following combination therapy treatment. Autophagy inhibition enhanced the cell death response through increased generation of ROS and could be reversed by anti-oxidants. In summary, we demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma. We further show that the administration of an autophagy inhibitor may prevent resistance from emerging to this drug combination.

Citation Format: Vito W. Rebecca, Renato Massaro, Inna Fedorenko, Geoffrey T. Gibney, Vernon K. Sondak, Ravi K. Amaravadi, Shengkan Jin, Silvya S. Maria-Engler, Ragini Kudchadkar, Keiran S. M. Smalley. BRAF wild-type melanoma survival hinges upon AKT activity and adaptive autophagic reprogramming in response to chemotherapy. [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 809. doi:10.1158/1538-7445.AM2014-809
Abstract 843: Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination
Authors: Tedeschi Philip M. , Kathari Yamini K. , Farooqi Iqra , Bertino Joseph R.
Published: May 2015

In T-cell acute lymphoblastic leukemia (ALL), the genes CDKN2A (p16 and p14) and MTAP are homozygously co-deleted, with a frequency of ∼35 %. MTAP cleaves the natural substrate, 5′-deoxy-5′-methylthioadenosine, to adenine and 5-methylthioribose-1-phosphate, which are converted to adenine nucleotides and methionine. Cells lacking MTAP are unable to salvage adenine through this pathway and rely on the de novo pathway for purine synthesis. This variation between normal MTAP+ cells and tumor MTAP-/- cells led to several studies showing that MTAP -/- cells are more sensitive to inhibitors of de novo purine synthesis.

Pralatrexate (PDX) is a second generation antifolate that targets dihydrofolate reductase and via conversion to polyglutamylates, inhibits de novo purine synthesis. 6-Thioguanine (6TG), an antimetabolite analog of guanine, also target de novo purine synthesis. MTAP-deficient ALL cells should be more sensitive to these agents, remarkably so in combination. We tested single agent PDX and 6TG as well as a combination treatment in MTAP+ (Molt4) and MTAP-/- (CEM) ALL xenografts. CEM xenografts were more sensitive to PDX treatment than MOLT4 xenografts. CEM xenografts were also much more sensitive to 6TG, while Molt4 xenografts were resistant to 6TG. Early results of the combination of PDX and 6TG in vivo show promise as an effective therapy of MTAP-/- T-cell ALL.

Citation Format: Philip M. Tedeschi, Yamini K. Kathari, Iqra Farooqi, Joseph R. Bertino. Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination. [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 843. doi:10.1158/1538-7445.AM2014-843
Abstract 860: Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature
Authors: Chen Yingtai , Dong Feng , Tian Yantao , Wang Chengfeng , Cui Liang , Chen Xuezhong
Published: May 2015

Abstract

Background: Basal cell carcinoma (BCC) is the most common malignant skin carcinoma. Although mortality is low as BCC rarely metastasizes, this malignancy has a tendency for local recurrence. As such, it is of great practical utility to assess which is the best therapeutic choice in the management of BCC recurring after different treatments. Here, we describe six cases of recurrent BCC treated with carbon ion radiotherapy and review the cases previously reported in the literature.

Methods: Case records of six patients with biopsy-proved, recurrent BCC, who were given total doses of 60-70 GyE, administered in 6-11 fractions over 6-11 days, with a fraction dose of 7-10 GyE in the therapy terminal at Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences (IMP-CAS), China, were retrospectively reviewed.

Results: Tumor response rate was 100%, including 6 CR, at 12 months after completion of carbon ion radiation. In a minimum follow-up period of 55 months, overall survival and no recurrence were achieved. No grade 3 or higher toxicity and complication occurred.

Conclusions: Carbon ion radiotherapy is well tolerated and should be considered as a potential salvage modality for recurrent BCC in certain cases.

Note: This abstract was not presented at the meeting.

Citation Format: Yingtai Chen, Feng Dong, Yantao Tian, Chengfeng Wang, Liang Cui, Xuezhong Chen. Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature. [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 860. doi:10.1158/1538-7445.AM2014-860
Abstract 871: Clinical utility of a plasma microRNA biomarker within lung cancer screening
Authors: Boeri Mattia , Verri Carla , Sozzi Gabriella , Roz Luca , Conte Davide , Suatoni Paola , Marchiano Alfonso , Vecchia Carlo L. , Rossi Marta , Bravi Francesca , Negri Eva , Sverzellati Nicola , Pastorino Ugo
Published: May 2015

Recent screening trials indicate that low-dose computed tomography (LDCT) reduces lung-cancer mortality in high risk subjects. However, high false positive rates, costs and potential harms highlight the need for complementary biomarkers. MicroRNAs (miRNAs) are tissue and disease specific molecules, actively released by cells in the circulatory system, which are associated with protein complexes and/or packaged in exosomes and microvesicles. Circulating miRNAs are rather stable and easily detectable in body fluids suggesting the possibility of using miRNAs as a new promising class of biomarkers.

Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) of a non-invasive plasma miRNA signature classifier (MSC) to identify lung cancer occurrence and mortality was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicentre Italian Lung Detection (MILD) trial. Plasma samples from 939 subjects including 69 lung cancer patients and 870 disease-free individuals were analyzed using a Real-Time quantitative PCR (qRT-PCR) based assay for MSC. Combined sensitivity and specificity of plasma MSC and LDCT were assessed in a blinded validation study.

MSC correctly identified patients with lung cancer at 87% sensitivity, 81% specificity, and 99% NPV, and 18 of 19 lung cancer deaths at 95% sensitivity 81% specificity, and 99.86% NPV. MSC identified 43 of 49 (88%) LDCT-detected cancers, 8 of 9 (89%) interval cancers in the LDCT arm, and 9 of 11 (82%) cancers in the observational arm. Diagnostic performance of MSC was confirmed by time dependency analysis. MSC fell to negative after lung cancer resection in 16 of 22 evaluable subjects. In lung cancer patients, there was a trend in mortality across levels of MSC (p=0.0336) and survival rate significantly differed according to MSC in all subjects (X21=49.53, p<0.0001). Combination of MSC and LDCT resulted in a 5-fold reduction of LDCT false positive rate.

This large validation study highlights the clinical diagnostic and prognostic value of plasma MSC for lung cancer screening in high-risk populations. The combined use of LDCT and MSC could reduce the false positive rate of LDCT improving the efficacy of lung cancer screening.

Citation Format: Mattia Boeri, Carla Verri, Gabriella Sozzi, Luca Roz, Davide Conte, Paola Suatoni, Alfonso Marchiano, Carlo La Vecchia, Marta Rossi, Francesca Bravi, Eva Negri, Nicola Sverzellati, Ugo Pastorino. Clinical utility of a plasma microRNA biomarker within lung cancer screening. [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 871. doi:10.1158/1538-7445.AM2014-871
Abstract 889: MicroRNA-21-5p upregulation in urine samples serves as novel biomarkers for early stage renal cell carcinoma patients diagnosis
Authors: Meng Wei , Alder Hansjuerg , Maclean Kirsteen , Kirste Simon , Stegmaier Petra , Grosu Anca , Chakravarti Arnab , Lautenschlaeger Tim
Published: May 2015

Early prevention of renal cell carcinoma needs a reliable and robust bioassay to evaluate kidney cancer patients. As a novel class of regulatory molecules in cellular activity, the recent studies showed that microRNAs had tissue-specific patterns and were able to distinguish the cancer from benign disease. We explored the diagnostic value of urine microRNAs from a cohort of 160 individuals: 80 patients with renal clear cell carcinoma and 80 normal control individuals.

Material and methods: The renal clear cell carcinomas cohort included 63% stage I cases, 10% stage II cases, 19% stage III cases, 7% stage IV cases, 1% unknown cases. Normal control cohort included 34% diverticulosis cases, 15% bariatric surgery cases, 14% diverticulitis cases, 15% hernia surgery cases, 10% hemorrhoids cases and 12% other non-cancer conditions. Every 10 urine samples were pooled together and subjected to microRNA extraction. The Norgen Biotek urine microRNA purification kit was used for total microRNA extraction (including free floating microRNAs and microRNAs from exfoliated cells) in the pooled urine samples. Urine microRNA expression profiling was performed using nCounter miRNA Expression Assay. After ligation and purification, hybridized microRNAs sequences were label by specific color codes and quantified using nCounter Digital Analyzer, then the data were normalized to the sum of the microRNAs within each pooled sample before statistic analysis.

Result: comparing to normal control urine samples, microRNA-21-5p expression showed upregulation in kidney urine samples, which is consistent with TCGA kidney cancer tissue profiling results. Some recent studies also demonstrated that microRNA-21 may act as an oncomir in prostate, lung and colorectal cancers. We also observed that microRNA-1268a and microRNA-549 were highly expressed in urine samples from renal cell carcinoma patients.

Conclusion: These findings indicate that in urine microRNA-21-5p may serve as a potential molecular marker for renal cell carcinoma and provide a new approach in the diagnosis of kidney cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Wei Meng, Hansjuerg Alder, Kirsteen Maclean, Simon Kirste, Petra Stegmaier, Anca Grosu, Arnab Chakravarti, Tim Lautenschlaeger. MicroRNA-21-5p upregulation in urine samples serves as novel biomarkers for early stage renal cell carcinoma patients diagnosis. [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 889. doi:10.1158/1538-7445.AM2014-889
Abstract 901: Plasma proteins characterize second-line therapy response in progressive renal cell carcinoma
Authors: Hölters Sebastian , Bergmann Lothar , Grünwald Viktor , Keilholz Ulrich , Ohlmann Carsten , Staehler Michael , Schmerler Diana , Junker Kerstin
Published: May 2015

Introduction & Objectives: For patients with metastatic renal cell carcinoma (mRCC) vascular endothelial growth factor (VEGF)-targeted therapy represents a promising first-line therapy after tumour nephrectomy. For patients who progress during first-line therapy, inhibitors of mammalian target of rapamycin (mTOR) represent an option for second-line therapy. Within the framework of the MARC-2 clinical trial, the aim of our study is the identification and validation of marker proteins associated with second-line therapy (Everolimus) response.

Material & Methods: We included blood plasma samples from 19 mRCC patients receiving Everolimus. Therapy response was defined as stable disease and partial remission. We analysed the samples by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS) using CM10 and Q10 arrays. For the identification of potential marker proteins, 2-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and antibody array screening are on-going.

Results: We identified 20 mass peaks by SELDI-TOF MS with Q10 and 16 with CM10 chips for the discrimination between responders (defined as stable disease or partial remission after two month of therapy) and non-responders (defined as progressive disease after 2 month of therapy). With the Q10, but not with the CM10 chip, we obtained five peaks for the discrimination between both patient groups before the first drug application. These peaks could be useable to preselect patients for the second-line therapy with Everolimus. For therapy monitoring, we found seven mass peaks (four with Q10 and three with CM10 chips) after two weeks and 24 mass peaks (11 with Q10 and 13 with CM10 chips) after four weeks of therapy to differentiate between responders and non-responders. These mass peaks could be useful to estimate the therapy response for the patients.

Conclusion/Outlook: Our preliminary results argue for the presence of blood plasma proteins which potentially predict therapy response to Everolimus before as well as during therapy. The confirmation and identification of the SELDI-TOF MS outcomes by 2-dimensional gel electrophoresis and MALDI-TOF MS is on-going as well as the antibody array screening for angiogenesis related proteins.

Sponsored by: iOMEDICO AG

Citation Format: Sebastian Hölters, Lothar Bergmann, Viktor Grünwald, Ulrich Keilholz, Carsten Ohlmann, Michael Staehler, Diana Schmerler, Kerstin Junker. Plasma proteins characterize second-line therapy response in progressive renal cell carcinoma. [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 901. doi:10.1158/1538-7445.AM2014-901
Abstract 935: Exome sequencing reveals BRAF mutations in papillary craniopharyngiomas
Authors: Taylor-Weiner Amaro N. , Brastianos Priscilla K. , Manley Peter E. , Jones Robert T. , Dias-Sangata Dora , Thorner Aaron , Rodriguez Fausto , Bernardo Lindsay , Schubert Laura , Stewart Chip , Keiran Mark , Hahn William C. , Resnick Adam , Louis David , Sangata Sandro , Getz Gad
Published: May 2015

Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae both from extension of the tumors and from therapeutic interventions which damage the optic chiasm, the pituitary stalk, and the hypothalamic area. Using whole exome sequencing we identified mutations in beta-catenin (CTNNB1) in nearly all adamantinomatous craniopharyngiomas (11/12; 92%) and recurrent mutations in BRAF (V600E) in all papillary craniopharyngiomas (3/3; 100%). Targeted genotyping revealed BRAF V600E in 95% of papillary craniopharyngiomas (36 of 39 tumors) and CTNNB1 mutation in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype and no other recurrent mutations or genomic aberrations were detected in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.

Citation Format: Amaro N. Taylor-Weiner, Priscilla K. Brastianos, Peter E. Manley, Robert T. Jones, Dora Dias-Sangata, Aaron Thorner, Fausto Rodriguez, Lindsay Bernardo, Laura Schubert, Chip Stewart, Mark Keiran, William C. Hahn, Adam Resnick, David Louis, Sandro Sangata, Gad Getz. Exome sequencing reveals BRAF mutations in papillary craniopharyngiomas. [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 935. doi:10.1158/1538-7445.AM2014-935
Abstract 944: Translational implications of the 19q12 bladder cancer GWAS signal for aggressive bladder cancer
Authors: Fu Yi-Ping , Kohaar Indu , Moore Lee , Lenz Petra , Figueroa Jonine D. , Tang Wei , Porter-Gill Patricia , Chanock Stephen , Hewitt Stephen M. , Silverman Debra T. , Rothman Nathaniel ,   NCI-GWAS Bladder Cancer Consortium, Prokunina-Olsson Ludmila
Published: May 2015

Background: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein.

Methods: Genetic fine mapping analysis of the CCNE1 region was performed using data from two bladder cancer GWAS, which included a total of 5,942 cases and 10,857 controls. Cyclin E protein expression was evaluated by immunohistochemistry analysis in 265 bladder tumors in relation to CCNE1 genetic variants and tumor characteristics. Functional effects of cyclin E over-expression were evaluated with cell cycle assays.

Findings: The original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer (muscle-invasive or high-grade non-muscle-invasive cancer), with a per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10-5). Cyclin E protein expression was increased in aggressive bladder tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. Conclusions: Molecular mechanisms linking the CCNE1 GWAS signal and aggressive bladder cancer risk are related to cyclin E over-expression and cell cycle regulation. In combination with other genetic and clinical markers, CCNE1 genetic variants may be translationally useful for early prediction of aggressive bladder cancer.

Citation Format: Yi-Ping Fu, Indu Kohaar, Lee Moore, Petra Lenz, Jonine D. Figueroa, Wei Tang, Patricia Porter-Gill, Stephen Chanock, Stephen M. Hewitt, Debra T. Silverman, Nathaniel Rothman, NCI-GWAS Bladder Cancer Consortium, Ludmila Prokunina-Olsson. Translational implications of the 19q12 bladder cancer GWAS signal for aggressive bladder 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 944. doi:10.1158/1538-7445.AM2014-944
Abstract 968: β-catenin plays an important role in lung tumor development induced by EGFR mutations
Authors: Nakayama Sohei , Sng Natasha J. , Carretero Julian , Welner Robert , Hayashi Yuichiro , Yamamoto Mihoko , Alistair Tan J. , Yamaguchi Norihiro , Yasuda Hiroyuki , Danan Li , Soejima Kenzo , Ross Soo A. , Daniel Costa B. , Wong Kwok-Kin , Kobayashi Susumu S.
Published: May 2015

The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and the development of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have revolutionized treatment for non-small cell lung cancer (NSCLC). Resistance to TKIs emerges in almost all patients, but currently no effective treatment is available.Therefore, novel strategies to either prevent or overcome resistance are sorely needed. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. We found that β-catenin was upregulated, translocated to the nucleus, and subsequently activated in both EGFR mutated lung cancer cell lines and EGFR mutation driven lung tumors. We demonstrated that mutant EGFR preferentially bound to β-catenin and caused tyrosine-phosphorylation of β-catenin. Tyrosine-phosphorylation of β-catenin led to stabilization, nuclear translocation, and transcriptional activity particularly in cells harboring EGFR-L858R (LR)-T790M (TM). Pharmacological β-catenin inhibition using ICG-001, which specifically blocks the CBP-β-catenin interaction, suppressed growth of both H1975 cells harboring EGFR-LR-TM and lung tumors in EGFR-LR-TM transgenic mice. To further examine whether β-catenin plays an important role in lung tumorigenesis, we generated an EGFR-LR-TM lung cancer mouse model in which the β-catenin gene (Ctnnb1) can be conditionally deleted. Genetic deletion of Ctnnb1 dramatically reduced lung tumor formation and showed significantly longer survival. Taken together, our data suggest that β-catenin plays an important role in mutant EGFR-driven lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development and/or overcome resistance to EGFR TKIs.

Citation Format: Sohei Nakayama, Natasha J. Sng, Julian Carretero, Robert Welner, Yuichiro Hayashi, Mihoko Yamamoto, Tan J. Alistair, Norihiro Yamaguchi, Hiroyuki Yasuda, Li Danan, Kenzo Soejima, Soo A. Ross, Costa B. Daniel, Kwok-Kin Wong, Susumu S. Kobayashi. β-catenin plays an important role in lung tumor development induced by EGFR mutations. [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 968. doi:10.1158/1538-7445.AM2014-968
Abstract CS1-2: Contralateral prophylactic mastectomy: Patient preferences and risk perceptions
Authors: Partridge Ann
Published: May 2015

Recent studies have revealed increasing rates of contralateral prophylactic mastectomy (CPM) among women with unilateral early stage breast cancer. Bilateral mastectomy at diagnosis of unilateral breast cancer is particularly common among young women, with younger age consistently identified as a predictor of CPM. This trend for more surgery rather than less has raised concerns, given the lack of evidence for a survival benefit from CPM and the relatively low risk of contralateral breast cancer for most women in this setting. Although mastectomy is a safe procedure and major complications are rare, there are potential negative consequences including cosmetic concerns and clinically significant potential long-term sequelae such as numbness of the chest skin and chronic pain and decreased function. Given most women opt for reconstructive surgery, extended recovery time, additional surgical complications, and decreased strength or function due to muscles being moved or stretched are also additional risks. Recent data have revealed that some women who undergo CPM have misperceptions about their actual risks and the values of the prophylactic surgery. In a recent cross-sectional survey of young breast cancer survivors who had undergone bilateral mastectomy for unilateral breast cancer, most women indicated that desire to decrease their risk for contralateral breast cancer (98%) and improve survival (94%) were extremely or very important factors in their decision to have CPM. However, only 18% indicated that women with breast cancer who undergo CPM live longer than those who do not. BRCA1 or BRCA2 mutation carriers more accurately perceived their risk for contralateral breast cancer, whereas women without a known mutation substantially overestimated this risk. An increasing body of literature suggests that fear of recurrence and anxiety are strong predictors of undergoing CPM. Improved education and counseling about the risks and benefits of CPM, as well as increased awareness and management of anxiety surrounding breast cancer diagnosis and treatment, are likely to help patients to understand their risks more fully and to make decisions consistent with their preferences and values. Decision aids may be particularly useful in this setting.

Citation Format: Ann Partridge. Contralateral prophylactic mastectomy: Patient preferences and risk perceptions [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr CS1-2.
Abstract ES8-2: Circulating plasma tumor DNA as biomarkers for breast cancer therapy
Authors: Park Ben Ho
Published: May 2015

Currently, oncologists use prior clinical trials data to recommend therapies based upon features of the tumor and clinical stage of the patient. A limitation with this approach is that these data are averaged from large groups of patients that are then applied to each individual. This creates uncertainty as there is currently no reliable method to identify whether an individual patient truly is at risk for an unfavorable outcome and would benefit from a specific intervention. Recently, we and others have demonstrated the feasibility of detecting circulating plasma tumor DNA in metastatic breast cancer patients using digital PCR. We have now extended these studies to include early stage breast cancer patients using the second generation platform of droplet digital PCR (ddPCR). In this study the feasibility and accuracy of circulating plasma tumor DNA (ptDNA) detection was prospectively assessed by screening for the presence of tumor PIK3CA mutations in patients' plasma prior to and after breast surgery using ddPCR. We observed in early stage breast cancer patients that ddPCR could detect PIK3CA mutations preoperatively with 93.3% sensitivity (14 of 15 mutations detected) and 100% specificity (no false positives in 30 tumors). Moreover, 5 of 10 patients with PIK3CA mutation positive tumors continued to have mutant PIK3CA detected in their postoperative blood sample despite having no clinical evidence of disease. This work demonstrates that droplet digital PCR (ddPCR) can be used to accurately detect cancer DNA mutations in the blood of early stage breast cancer patients including those with minimal, clinically undetectable disease. Our results suggest that ddPCR provides an accurate and relatively non-invasive method for measuring residual disease and could be developed as a biomarker to identify early stage breast cancer patients at higher risk for recurrence to help make informed decisions regarding adjuvant therapies. Ongoing studies assessing mutational profiles from ptDNA from metastatic patients as well as patients undergoing neoadjuvant therapies will be discussed.

Citation Format: Ben Ho Park. Circulating plasma tumor DNA as biomarkers for breast cancer therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES8-2.
Abstract OT1-1-13: A Phase 2, randomized, open-label, multicenter, safety and efficacy study of oral lucitanib in patients with metastatic breast cancer with alterations in the FGF pathway
Authors: Abu-Khalaf Maysa , Mayer Ingrid , Litten Jason B , Raponi Mitch , Allen Andrew R , Pusztai Lajos , Arteaga Carlos L
Published: May 2015

BACKGROUND: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Aberrant FGF signaling, as defined as FGFR1 and/or 11q amplification, is a hallmark genomic alteration in breast cancer, observed at a combined frequency of up to 25% of patients. Breast cancer patients with measurable disease and aberrant FGF signaling treated in the ongoing Phase 1/2 clinical trial of lucitanib monotherapy experienced an ORR of 50% and a DCR of 100%. This compelling clinical activity has led to the initiation of a global clinical development program for lucitanib in breast cancer.

TRIAL DESIGN: The current study is comparing PFS for doses of lucitanib (10 or 15 mg daily) in patients with FGF-aberrant metastatic breast cancer after failure of currently available standard therapies. Approximately 160 patients will be randomized 1:1 to the 10 mg and 15 mg daily dosing groups and stratified by FGF pathway alteration (FGFR1 or 11q amplification) and prior anti-VEGF therapy (yes or no). FGFR1 and 11q (containing the FGF ligands 3, 4, and 19) amplification is determined locally for patient enrolment and confirmed by central laboratory fluorescent in situ hybridization (FISH) testing. A total of 130 PFS events provides 80% power at a 2-sided significance level of 0.05 to detect a hazard ratio of 0.60 for comparing the 10 mg and 15 mg dose groups. Secondary objectives are ORR, DoR, DCR, OS, PROs, safety and population PK. Exploratory endpoints include tissue and blood-based biomarkers that may be predictive of response or primary resistance to treatment with lucitanib.

ELIGIBILITY CRITERIA: Histologically or cytologically confirmed FGF-aberrant metastatic breast cancer relapsed or refractory to approved standard available treatment. ECOG 0 or 1. Normal organ function. Patients with uncontrolled hypertension are excluded.

Citation Format: Maysa Abu-Khalaf, Ingrid Mayer, Jason B Litten, Mitch Raponi, Andrew R Allen, Lajos Pusztai, Carlos L Arteaga. A Phase 2, randomized, open-label, multicenter, safety and efficacy study of oral lucitanib in patients with metastatic breast cancer with alterations in the FGF pathway [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-13.
Abstract OT3-1-07: MotHER: A US registry for women with breast cancer who have received trastuzumab, pertuzumab in combination with trastuzumab, or trastuzumab emtansine (T-DM1) during pregnancy or within 7 months prior to conception
Authors: Brown Vikki , Miller Richard K , Chu Laura , Chow Cheryl , Trudeau Caroline , Andrews Elizabeth B
Published: May 2015

Background: Trastuzumab (Herceptin) and pertuzumab (Perjeta) are HER2-targeted monoclonal antibodies, and T-DM1 (Kadcyla) is a HER2-targeted antibody–drug conjugate. These molecules are classified as FDA Pregnancy Category D, indicating evidence of fetal harm; there have been postmarketing reports of oligohydramnios in women who received trastuzumab during pregnancy; in non-clinical studies of pertuzumab, oligohydramnios, delayed renal development, and embryo-fetal death occurred in pregnant cynomolgus monkeys. Furthermore, maytansine, the parent molecule of DM1, has demonstrated embryotoxicity in mice. The MotHER pregnancy registry was established in 2008 as an FDA postmarketing commitment to evaluate the effects of trastuzumab on pregnancy outcome. Pertuzumab and T-DM1 were included in the registry following their respective FDA approvals in 2012 and 2013.

Study design: MotHER is a US pregnancy registry and uses a prospective, observational cohort design. Enrollment is voluntary and can be initiated by the patient or her healthcare provider. Women are followed up until pregnancy outcome; infants are followed up through the first year of life.

Eligibility criteria: Pregnant women ≥18 years of age and resident in the US are eligible if they have received at least one dose of trastuzumab, pertuzumab in combination with trastuzumab, or T-DM1 for breast cancer during pregnancy or within 7 months prior to conception. Enrollment must be initiated before pregnancy outcome is known.

Specific aims: The primary outcome measures are pregnancy outcomes and the incidence of pregnancy complications, such as oligohydramnios, congenital anomalies, and fetal/infant functional deficits. Information on potential birth defects, noted either at birth or during pediatric follow-up, is evaluated and classified by a birth defect evaluator/clinical geneticist.

Statistical methods: The study is descriptive and not designed for formal hypothesis testing; event rates with 95% confidence intervals will be calculated.

Accrual: There is no pre-specified sample size. Data collection is ongoing, from 2009 to 2019 for trastuzumab, from 2012 to 2022 for pertuzumab plus trastuzumab, and from 2013 to 2023 for T-DM1. Fourteen women have enrolled as of January 31, 2014.

Citation Format: Vikki Brown, Richard K Miller, Laura Chu, Cheryl Chow, Caroline Trudeau, Elizabeth B Andrews. MotHER: A US registry for women with breast cancer who have received trastuzumab, pertuzumab in combination with trastuzumab, or trastuzumab emtansine (T-DM1) during pregnancy or within 7 months prior to conception [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-07.
Abstract P1-07-06: Activation of oncogenic pathways by mitochondrial reprogramming in triple negative breast cancer
Authors: Park Jun Hyoung , Kumar Santhosh , Vithayathil Sajna , Arora Kavisha , Putluri Nagireddy , Tsouko Efrosini , Donti Taraka R , Frigo Daniel E , Creighton Chad J , Lewis Michael T , Sreekumar Arun , Wong Lee-Jun , Kaipparettu Benny Abraham
Published: May 2015

Triple negative breast cancer (TN BCa) Driver pathway is still poorly understood. Thus, it is important to identify the underlying mechanisms of triple negative breast cancer progression. Mitochondria, a semiautonomous organelle in cells, play an important role in cellular energy metabolism, free radical generation, and apoptosis. Mitochondria-nuclear crosstalk is a bidirectional pathway of communication between mitochondria and nucleus that influences many cellular and organismal activities. This crosstalk can regulate several oncogenic pathways involved in tumorigenesis. Using transmitochondrial cybrid (cybrid) technology, we generated different cybrid models under common nuclear background of TN BCa. Mitochondria from cells of different cancer potential including benign breast epithelium, moderately and highly metastatic breast cancer cell lines were used to understand cancer mitochondria regulated tumor pathways. Tumor and gene expression analysis suggested that among different cancer pathways, c-Src signaling pathway is one of the most consistently activated pathways in cybrids with TN BCa cancer mitochondria. Further analysis in parental cells and other tumor models suggested that autophosphorylation of c-Src is regulated by mitochondrial tumor characteristics. Our preliminary analysis also suggest that mitochondria targeted drugs are promising combination therapy for the management of Src-driven TN BCa. This finding is particularly important while considering the poor response rate observed after single drug therapy with Src family tyrosine kinase inhibitor Dasatinib in unselected TN BCa patients.

Citation Format: Jun Hyoung Park, Santhosh Kumar, Sajna Vithayathil, Kavisha Arora, Nagireddy Putluri, Efrosini Tsouko, Taraka R Donti, Daniel E Frigo, Chad J Creighton, Michael T Lewis, Arun Sreekumar, Lee-Jun Wong, Benny Abraham Kaipparettu. Activation of oncogenic pathways by mitochondrial reprogramming in triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-06.
Abstract P1-07-18: Loss of Rab1B promotes triple-negative breast cancer metastasis by activating TGF-β/Smad signaling
Authors: Jiang HongLin , Sun Hefen , Jin Wei
Published: May 2015

Background: Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype associated with poor prognosis. The onset of metastasis in organs such as the lung,bone and brain is a major cause of mortality in TNBC patients. Thus, identification of novel targets for the treatment of triple-negative breastcancer is urgent for improved outcomes in patients with this disease.

Methods and Results:Here we conducted quantitative proteomic analyses in breast cancer cell lines, which include a normal, primary tumor and a metastatic tumor that were isolated from a single patient. Stable isotope labeling of amino acid in cell culture followed by LC-MS/MS analysis was performed and deregulated proteins were identified using statistical analysis. We identified for the first time that Rab1B, a member of RAS oncogene family, was down-regulated in high metastatic human breast cancer cells. In a panel of breast tumor tissues, Immunohistochemical analysis demonstrated an inverse correlation between metastatic propensity and the expression of Rab1B. Compared with primary tumors, Rab1B expression was notably decreased in lymph node metastases. Low Rab1B expression also correlated with poorer survival in triple-negative breast cancer patients. Through in vitro assays, we confirmed that silencing of Rab1B expression by RNAi in MDA-MB-231 and MDA-MB-468 breast cancer cells, can potentiate the proclivity to metastasize in Transwell assay and enhance lung colonization by tail vain injection in mice. In a reverse-complimentary approach, we determined that elevated Rab1B expression in highly metastatic breast cancer cell lines (MDA-MB-231HM and MDA-MB-231Bo) can suppress the ability of invasion and metastasis in vitro and in vivo. Mechanistically, we establish that the metastatic behavior strongly correlates with increased phosphorylated Smad3 levels and overexpression of TGF-β type I receptor (TβRI). Conversely, restoration of Rab1B can inhibit the activation of this pathway in MDA-MB-231HM and MDA-MB-231Bo cells.

Conclusion:By utilizing a series of mammary tumor cell lines, animal models, and clinically sourced tissues, we demonstrate that Rab1B acts as a metastasis suppressor in triple-negative breast cancer through regulating TGF-β/Smad signaling pathway.

Citation Format: HongLin Jiang, Hefen Sun, Wei Jin. Loss of Rab1B promotes triple-negative breast cancer metastasis by activating TGF-β/Smad signaling [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-18.
Abstract P1-07-25: SSA, a novel sulindac sulfide derivative, inhibits tumor cell growth and invasion in breast cancer
Authors: Yi Bin , Feng Xiangling , Chang Hong , Ma Ruixia , Zhang Xiaoguo , Piazza Gary A , Xi Yaguang
Published: May 2015

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac sulfide (SS), have been reported for striking chemopreventive activities in various types of human malignances, including breast cancer. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for chemoprevention in human cancer. We recently developed a novel amine derivative of SS named as SSA, which lacks inhibitory effect on COX-1 or -2, yet shows 10 times greater suppressive effect than SS on growth of a panel of breast cells. Moreover, SSA treatment at sub-cytotoxic concentration (4μM) for 36 hr can significantly inhibit both migration and invasion of highly aggressive breast tumor MDA-MB-231cells. To understand the molecular mechanism accounting for this activity, we examined 4 oncogenic miRNAs, including mir-17-92, mir-9, mir-10b, and mir-21 that were previously reported by our group to be associated with SS anti-invasive activity in breast and colorectal cancer. We found SSA could significantly down-regulate these miRNAs; whereas their forced expression was able to counteract the anti-invasive activity of SSA in MDA-MB-231 cells. There results imply that significance of SSA with non-COX inhibitory properties in suppression of tumor cell invasion could provide novel insights into development of safer and more effective strategies for prevention of breast cancer progression and metastasis. In addition, after inducing mobility of non-invasive breast MCF-7 cells by using TGF-β1, we treated these invading cells with SSA and found that their mobility was significantly decreased. These results support anti-invasive activity of SSA in human breast cancer cells and inhibition of TGF-β1 as well as oncogenic miRNAs may be responsible for the mechanistic basis by which SSA prevents breast tumor cell invasion.

This study is supported by an American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC) and NIH/NCI R21 Grants (5R21CA160280 and 1R21CA182754) to Yaguang Xi.

Citation Format: Bin Yi, Xiangling Feng, Hong Chang, Ruixia Ma, Xiaoguo Zhang, Gary A Piazza, Yaguang Xi. SSA, a novel sulindac sulfide derivative, inhibits tumor cell growth and invasion in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-25.