bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA21: Combination treatments that include PI3K-inhibitors for the treatment of triple-negative breast cancer
Authors: Wulf Gerburg M. , Juvekar Ashish , Lyssiotis Costas M. , Hu Hai , Baek Kim , Yadegarynia Sina , Scully Ralph , Winer Eric , Asara John , Cantley Lewis C. , Matulonis Ursula 
Published: October 2015

Abstract
Alterations in the PI3K pathway are highly prevalent in triple-negative breast and high grade ovarian cancer, including BRCA1- and BRCA2-related disease. On the cellular level, loss of BRCA1 increases genomic instability and reliance on single strand break repair, hence creating an opportunity to treat BRCA-related TNBC or OC with PARP-inhibitors. In addition, loss of BRCA1 and/or p53 lead to relaxation of negative feed-back loops in mitogenic signaling, resulting in highly proliferative malignancies. For these reasons PARP-inhibitor Olaparib and PI3K-inhibitor NVP-BKM120 were tested in combination and found to be synergistic in mouse models of BRCA1-related BC. Surprisingly, PI3K-inhibition enhanced a DNA damage phenotype, caused by a profound decrease in DNA synthesis that could be observed after treatment with NVP-BKM120 in vivo and in vitro. The decrease in DNA synthesis was due to reduced Nucleoside synthesis resulting from a block in glycolysis that led to a drop in flux through the non-oxidative pentose phosphate pathway. In a preclinical mouse model (K14-Cre BRCA1f/fp53f/f), the combination of NVP-BKM120 and Olaparib could induce complete remissions, while PI3K-inhibitor alone marginally slowed disease progression and PARP-inhibitor alone stabilized the disease. This concept was translated into a clinical trial: BKM120/Olaparib for Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer (NCT01623349; PI: Ursula Matulonis). Dose escalation for this study and accrual to an extension cohort at the MTD (NVP-BKM120 50 mg once a day in combination with Olaparib 300 mg twice a day) have been completed and a second dose escalation arm with NVP-BYL719 and Olaparib is ongoing.
Citation Format: Gerburg M. Wulf, Ashish Juvekar, Costas M. Lyssiotis, Hai Hu, Kim Baek, Sina Yadegarynia, Ralph Scully, Eric Winer, John Asara, Lewis C. Cantley, Ursula Matulonis. Combination treatments that include PI3K-inhibitors for the treatment of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA21.
Abstract IA25: Autophagy: A potentially druggable resistance mechanism to PI3K/mTOR inhibitors
Authors: Amaravadi Ravi 
Published: October 2015

Abstract
Inhibition of PI3K/mTOR signaling in cancer cells activates autophagy. Numerous preclinical models have demonstrated therapy-induced autophagy in advanced cancer promotes tumor cell survival and is a targetable resistance mechanism. Clinical trials involving the lysosomal autophagy inhibitor hydroxychloroquine (HCQ) have been launched for patients with refractory malignancies. Currently there are nearly 30 early phase clinical trials involving HCQ for a variety of malignancies in development or actively accruing patients in the United States and abroad. The results of the first 6 HCQ clinical trials (5 in humans, 1 in dogs) that represent the first deliberate attempt to modulate autophagy therapeutically in patients will be presented. This includes a phase I trial of the mTOR inhibitor temsirolimus, and hydroxychloroquine in patients with advanced melanoma which produced a low rate of grade 3-4 toxicities and a 74 % stable disease rate. The development of novel translatable pharmacodynamic assays to characterize autophagy modulation in peripheral blood cells and tumor tissue using electron microscopy, and newer serum-based approaches based on a proteomics discovery effort will be highlighted. Our efforts to synthesize a more potent second generation autophagy inhibitor Lys05, and our plans to move a Lys05 derivative into the clinic will be discussed.
Citation Format: Ravi Amaravadi. Autophagy: A potentially druggable resistance mechanism to PI3K/mTOR inhibitors. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA25.
Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Premenopausal Women
Authors: Fabian Carol J. , Kimler Bruce F. , Phillips Teresa A. , Box Jessica A. , Kreutzjans Amy L. , Carlson Susan E. , Hidaka Brandon H. , Metheny Trina , Zalles Carola M. , Mills Gordon B. , Powers Kandy R. , Sullivan Debra K. , Petroff Brian K. , Hensing Whitney L. , Fridley Brooke L. , Hursting Stephen D. 
Published: October 2015

AbstractHigher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore the effects of high-dose EPA and DHA on blood and benign breast tissue risk biomarkers before design of a placebo-controlled phase IIB trial. Premenopausal women with evidence of hyperplasia ± atypia by baseline random periareolar fine needle aspiration were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase prestudy and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility, which was predefined as 50% uptake, 85% retention, and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77% to 38% (P = 0.002), and Ki-67 from a median of 2.1% to 1.0% (P = 0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo-controlled trial in premenopausal women is warranted. Cancer Prev Res; 8(10); 912–21. ©2015 AACR.See related article, p. 922.
Abstract A07: Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer
Authors: Rybicki Benjamin , Jankowski Michelle , Do Kieu , Chitale Dhananjay , Trudeau Sheri , Rundle Andrew , Belinsky Steven , Tang Deliang 
Published: October 2015

Abstract
We previously reported results from a case-control study nested in a large hospital-based cohort of men identified over a 12-year period (1990-2002) that gene promoter hypermethylation in histopathologically benign prostate specimens is a marker of prostate cancer risk (Tang et al. J Urol 2013). Whether methylation in pre-diagnostic benign prostate tissue can also predict subsequent disease prognosis has not been studied. Therefore, we estimated hazard ratios (HRs) for biochemical recurrence (BCR), defined as two successive prostate-specific antigen increases after definitive treatment, associated with methylation status of the two genes we found associated with prostate cancer risk: retinoic acid receptor-β (RARB) and adenomatosis polyposis coli (APC). Follow-up data were from a subset of the cases (n=394) that were part of our aforementioned nested prostate cancer case-control study of gene promoter methylation status of five genes measured in pre-diagnostic benign biopsy specimens. Overall, after adjusting for known clinical risk factors for prostate cancer progression (advanced grade, advanced stage, high prostate-specific antigen (PSA)), neither methylation of the APC or the RARB genes was associated with a significantly increased risk of BCR, but risk associated with RARB methylation was elevated (HR=1.30; 95% CI= 0.93-1.83). This risk was higher in Whites (HR=1.44; 95% CI= 0.92-2.25) compared with African Americans (HR=1.22; 95% CI= 0.71-2.12), but differences by race were not significant. In additional stratified analyses, we found that while associations with APC methylation did not differ between strata, RARB methylation showed significantly increased risk of BCR in specific substrata; specifically men with high PSA at time of diagnosis (HR=1.73; 95% CI=1.13–2.64) and men in whom methylation did not occur in the four other genes under study (HR=1.82; 95% CI=1.14–2.93). In conclusion, we show for the first time that methylation events occurring before onset of prostate cancer may predict the course of subsequent cancer in defined patient groups. These findings may have important clinical decision making implications in terms of both identifying aggressive prostate cancer at its earliest stages and also avoiding unnecessary additional diagnostic biopsies.
Citation Format: Benjamin Rybicki, Michelle Jankowski, Kieu Do, Dhananjay Chitale, Sheri Trudeau, Andrew Rundle, Steven Belinsky, Deliang Tang. Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A07.
Abstract A24: Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer
Authors: Lord Simon R. , Patel Nilay , Liu D. , Fenwick J. , Frezza C. , Costa S. Henriques da , Gaude E. , Zhang Q. , Wakelam M. , Gleeson F. , Haider S. , Buffa F. , Harris A. L. 
Published: October 2015

Abstract
There is great interest in the effects on cancer metabolism of the diabetes drug, metformin and its potential as a cancer treatment. Despite intense investigation it is still not clear as to its metabolic effects on primary human cancer in vivo. 41 patients with primary breast cancer were recruited to a ‘window of opportunity study’ prior to neoadjuvant chemotherapy. Before and after 2 weeks of metformin, dynamic 18F-FDG PET-CT scans were carried out, breast core biopsies of the primary tumour taken for RNASeq, metabolomics and immunohistochemistry analysis and host serum metabolic markers assessed.
Metabolomic mass spectrometry analysis revealed an increase in the ADP/ATP and AMP/ATP ratio (fold change 8.6 and 24.9, respectively, p = 0.07 and p = 0.14) after metformin treatment.
RNA sequencing of the first 21 paired samples showed upregulation of many genes encoding components of complex 1, and the TCA cycle, glutaminolysis, and glycolysis pathways. Several genes encoding for glucose and glutamine transport were amongst those most consistently upregulated, including GLUT1, SLC38A1 and SLC7A5 (all p&lt;0.0001).
Dynamic PET-CT analysis of the first 17 paired scans demonstrated a trend toward a decrease in the variable K2 post-metformin (an estimate of 18F-FDG efflux from tumour intracellular pool back to blood), but with much variability between paired scans (0.70±0.11 vs 0.51±0.05 (p=0.14)).
There was a decrease in serum C-peptide (0.56±0.04nmol/L vs 0.48±0.02nmol/L, pre- and post-metformin, p=0.003) consistent with reduced host insulin secretion. This is the first study in the clinical setting to show that metformin can cause an energy stress in cancer cells. The effect on mRNA expression was compatible with direct mitochondrial effects on the cancer cell leading to upregulation of the glutaminolysis and glycolysis pathways. The decrease in efflux of radiolabelled glucose may indicate retention of glucose possibly secondary to changes in blood glucose availability. We expect this study will help define biomarker development and future treatment strategies for metformin, in particular potential combination therapy.
Note: This abstract was not presented at the conference.
Citation Format: Simon R. Lord, Nilay Patel, D. Liu, J. Fenwick, C. Frezza, S. Henriques da Costa, E. Gaude, Q. Zhang, M. Wakelam, F. Gleeson, S. Haider, F. Buffa, A. L. Harris. Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A24.
Abstract B11: An efficient resource to accelerate research into the cause and prevention of breast cancer: The Army of Women
Authors: Love Susan M. , Eshraghi Leah D. 
Published: October 2015

Abstract
Background: It is well established that more research into the cause and prevention of breast cancer is needed. While studies are done in cell lines and lab animals, translation of findings to women is often delayed due to difficulty in recruitment. To address this problem, the Dr. Susan Love Research Foundation formed the Army of Women® (AOW); an online recruitment resource designed to partner women with researchers in order to accelerate breast cancer research.
Methods: Researchers submit a proposal to the Dr. Susan Love Research Foundation's Scientific Advisory Committee. If a study is accepted, a mass e-mail describing the study procedures and inclusion/exclusion criteria is sent to the entire AOW database. Women sign up at www.armyofwomen.org to join and receive AOW e-mails about breast cancer research studies. Women self-select based on interest and study criteria, and undergo a secondary online screening before contact information is passed on to the researcher for the enrollment process.
Results: Over 376,000 women have signed up, including survivors and women without a history of breast cancer, ranging from ages 18 to 100, representing all 50 US states and 49 countries. To date, the AOW has recruited for 87 studies. The diversity of the AOW members has proved beneficial for many studies, such as those needing to enroll racial/ethnic minorities, women of varying sexual orientations, or young survivors.
A secondary goal of the AOW is to assist researchers new to research with human subjects. The AOW has successfully helped researchers cross the chasm, coaching them on what it takes to transition their research from animal models to human subjects.
Conclusions: The AOW has proved to be a successful resource for scientists to accelerate accrual, expand the number and diversity of their subject population and to obtain exactly the type of specimens they need when they need it. This partnership between women and scientists has revolutionized research and accelerated efforts to eradicate breast cancer. The public is ready and willing to partner with the research community to find the answers to urgent clinical problems.
Citation Format: Susan M. Love, Leah D. Eshraghi. An efficient resource to accelerate research into the cause and prevention of breast cancer: The Army of Women. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B11.
Abstract B45: A pilot trial of dietary fish and ω-3 fatty acid supplements in women at high risk for breast cancer
Authors: Straka Shana , Lester Joanne L. , Puchala Sarah , Rose Angela , Cole Rachel , Andridge Rebecca R. , Clinton Steven K. , Belury Martha A. , Yee Lisa D. 
Published: October 2015

Abstract
Background: The type of fat consumed in the diet may influence mammary tissue biology and breast cancer risk, with preclinical evidence for inhibitory effects of n-3 versus n-6 polyunsaturated fatty acids (PUFAs) on mammary carcinogenesis. Fish consumption and fish oil supplements are two strategies to increase dietary n-3 fatty acids.
Objective: To determine the effects of increased fish consumption on breast adipose tissue fatty acids, we conducted a study of dietary fish versus an n-3 fatty acid supplement in women at increased risk for developing breast cancer.
Design: In this three month randomized study, women at high risk for breast cancer received either (a) dietary fish in the form of canned salmon and albacore tuna at a dose of four 6 ounce servings/week or (b) two n-3 fatty acid capsules (1.68 g EPA+DHA)/day for three months. Subjects underwent fasting blood draws monthly and breast adipose tissue samples at baseline and three months for fatty acid profiling by gas chromatography.
Results: Both study interventions of dietary fish and n-3 PUFA capsule yielded increased EPA and DHA content in plasma (p&lt;0.0001), erythrocyte membranes (p&lt;0.0001), and breast adipose tissue samples (p &lt;0.01) at 3 months, with also significantly increased total ω-3 PUFAs and decreased n-3/n-6 ratios (p&lt;0.0001). Women taking n-3 PUFA capsules had a greater rise in plasma and erythrocyte membrane EPA relative to those consuming fish (p=0.002), without significant differences in DHA. BMI attenuated the incremental increase in EPA and DHA. Adherence was excellent in both groups at 93.9%, and higher in the dietary fish arm (p=0.01).
Conclusions: Dietary fish and n-3 PUFA capsules significantly increase breast adipose tissue EPA and DHA content and represent two well tolerated strategies for future clinical trials of dietary n-3 PUFAs for breast cancer prevention.
Citation Format: Shana Straka, Joanne L. Lester, Sarah Puchala, Angela Rose, Rachel Cole, Rebecca R. Andridge, Steven K. Clinton, Martha A. Belury, Lisa D. Yee. A pilot trial of dietary fish and ω-3 fatty acid supplements in women at high risk for breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B45.
Abstract B53: Predicting efficacy of chemopreventive agents in animal tumor assays by statistical modeling
Authors: Dunn Barbara K. , Steele Vernon E. , Fagerstrom Richard M. , Topp Carol F. , Ransohoff David , Ford Leslie G. , Kramer Barnett S. 
Published: October 2015

Abstract
NCI's Division of Cancer Prevention has over 25 years entered some 800 agents into a program designed to test cancer preventive efficacy. Early in the testing pathway are 2 sequential critical steps: (1) in vitro/in vivo morphologic assays and, (2) for agents successful in step 1, cancer-preventive testing (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. The ultimate intention is to follow successful testing in animals with entry into clinical trial testing in humans. To facilitate the optimal selection of appropriate morphologic tests for specific disease-site animal tumor models, we undertook the current project. We evaluated the success of our strategy by determining how accurately the earlier stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays. Focusing on 210 agents that were tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the 6 most commonly used morphologic assays predicted drug efficacy in animal tumor models. Using multimodel inference, three statistical models were generated to evaluate the ability of these 6 morphologic assays to predict tumor outcomes in 3 different sets of animal tumor assays: (1) all tumor types, (2) breast cancer only, and (3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the 3 different sets of animal tumor assays. The goal is to use predictive models such as these to guide our future decision-making with respect to selection of preventive agents as well as morphologic and animal tumor assays. In this manner, we hope to improve the efficiency of our overall approach to chemoprevention agent development.
Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, David Ransohoff, Leslie G. Ford, Barnett S. Kramer. Predicting efficacy of chemopreventive agents in animal tumor assays by statistical modeling. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B53.
Abstract CN01-02: Instrumenting the healthcare enterprise for discovery research
Authors: Murphy Shawn N. 
Published: October 2015

Abstract
It is critical for us to leverage healthcare technology to find ways to meet our goals in clinical research. The Informatics for Integrating Biology and the Bedside (i2b2) project is used to accrue patients for clinical trials using data from a hospital's medical record. It is also valuable as a platform for generally validating disease phenotypes as part of in-silico studies that explore associations of phenotypes with the information gathered from biologic samples such as the genotypes of the patients and their tissues. The software can adapt to Patient Surveys and Reported Outcomes as well as routine Electronic Medical Record data. The software can be used to support multisite trials across institutions using the Shared Healthcare Research Informatics Network (SHRINE).
Citation Format: Shawn N. Murphy. Instrumenting the healthcare enterprise for discovery research. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN01-02.