tbuckley/cabot-search huggingface dataset:
Abstract LB-295: Food-based approach to cancer prevention: A phase I assessment of amorphous confections in modulating exposure and metabolism of black raspberry compounds in the oral cavity
Authors: Jennifer H. Ahn-Jarvis, Steven K. Clinton, Elizabeth M. Grainger, Christina Simpson, Junnan Gu, Matthew D. Teegarden, Kenneth M. Riedl, Thomas J. Knobloch, Christopher M. Weghorst, Steven J. Schwartz, Yael Vodovotz
Journal: Cancer Research (2016)

Abstract Background: Oral cancer remains a major global malignancy, largely due to persistence of tobacco use worldwide. Preventive strategies focusing upon high risk individuals due to long term tobacco use or presence of pre-malignancy are needed. Based upon strong epidemiologic and laboratory evidence we have developed a black raspberry food-based product targeting this population and have tested variations in a phase I trial. Objective: 1. To test three amorphous solids (glassy, elastic, and viscous) containing a bioactive rich black raspberry (BRB) fraction in a confectionary system for compliance. 2. To investigate the impact of amorphous structure in modulating oral exposure and metabolism of black raspberry compounds in the oral cavity as measured by differences in duration of black raspberry exposure and profile of black raspberry metabolites from saliva. Methods: A four week, phase I, randomized, parallel study design with 60 non-smoking adults was used to investigate three amorphous forms having different release rates (prolonged, intermediate, and rapid), each at two doses (4 or 8 g BRB/day). Salivary kinetics and changes in black raspberry composition among and within individuals were assessed. HPLC with Tandem MS/MS was used to quantify and characterize black raspberry compounds from the confections and profile them in the saliva. Results: All confections were well accepted having excellent adherence (94 ± 2%). Toxicities were limited to a grade I toxicity (NIH criteria). Oral residence time was 74% longer and saliva volume was 42% greater with glassy than the other two amorphous forms. Anthocyanin (cyanidin-3-glucoside) and ellagitannins were prevalent compounds in the saliva. Conclusions: Three amorphous confectionary forms of a BRB food-based delivery vehicle demonstrated excellent compliance, with the glassy form showing potential for greater oral distribution, suggesting the potential for greater bioactivity. Food science and technology provides many strategies to develop novel and fully characterized food products for cancer prevention trials. Citation Format: Jennifer H. Ahn-Jarvis, Steven K. Clinton, Elizabeth M. Grainger, Christina Simpson, Junnan Gu, Matthew D. Teegarden, Kenneth M. Riedl, Thomas J. Knobloch, Christopher M. Weghorst, Steven J. Schwartz, Yael Vodovotz. Food-based approach to cancer prevention: A phase I assessment of amorphous confections in modulating exposure and metabolism of black raspberry compounds in the oral cavity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-295.
Phase I evaluation of the PI3 kinase (PI3K) inhibitor taselisib (GDC-0032) in multiple locally advanced or metastatic PIK3CA mutant solid tumor types.
Authors: Komal L. Jhaveri, Philippe L. Bedard, Juan Miguel Cejalvo, Lowell L. Hart, Dejan Juric, Karen Kelly, A. Craig Lockhart, Anton Melnyk, Kathleen N. Moore, John J. Nemunaitis, Mafalda Oliveira, Manish R. Patel, Jasgit Sachdev, David Smith, Ari VanderWalde, Joseph A. Ware, Huan Jin, Timothy R. Wilson, Michael C Wei, Jose Baselga
Journal: Journal of Clinical Oncology (2016)

TPS11621 Background: The phosphoinositide 3-dependent kinase (PI3K) pathway is important for cancer growth, proliferation, and survival. PI3K is frequently activated in solid tumors due to amplification and/or gain-of-function mutations occurring in the PIK3CA gene that encodes the α-isoform of the catalytic subunit of PI3K, PI3Kα. Taselisib, a potent and isoform-selective PI3K inhibitor, displays greater selectivity for mutant PI3Kα isoforms than wild-type PI3Kα. Clinical data from the Phase Ia dose escalation study of single-agent taselisib suggest that taselisib has activity across multiple tumor types with PIK3CA mutations, including breast, lung, and gynecologic cancers. This trial has been designed as a “basket study” to provide preliminary evaluation of safety and response for single-agent taselisib in patients (pts) with a broad range of PIK3CA mutant solid tumors. Methods: This phase I study will enroll pts with PIK3CA mutant cancers who have had progression on, or did not respond to, at least one prior treatment regimen and are not candidates for regimens known to provide clinical benefit. Pts will be enrolled to receive single-agent taselisib (6 mg tablet, qd). This study comprises 11 sub-cohorts to evaluate the following tumor types: endometrial, bladder, head and neck squamous cell carcinoma, cervical, gastric/gastroesophageal junction, small cell lung, triple-negative breast, colorectal (excluding KRAS mutant tumors), squamous (excluding histologies in the other sub-cohorts), and ovarian; the final sub-cohort will include pts with PIK3CA mutant tumors that are not otherwise specified (excluding breast and lung cancers). The primary endpoint is tolerability and safety of single-agent taselisib. Other endpoints include response, pharmacokinetics, and pharmacodynamics. Target enrollment in each tumor-specific sub-cohort is approximately 10–20 pts, with 50 pts enrolled into the unspecified tumors cohort, from 25 sites and four countries. As of January 15, 2016, > 30 pts from the planned 150–250 pts have been enrolled (NCT01296555).
Clinical and Genetic Characteristics of Japanese Patients with Age-Related Macular Degeneration and Pseudodrusen
Authors: Sufian Elfandi, Sotaro Ooto, Naoko Ueda-Arakawa, Ayako Takahashi, Munemitsu Yoshikawa, Hideo Nakanishi, Hiroshi Tamura, Akio Oishi, Kenji Yamashiro, Nagahisa Yoshimura
Journal: Ophthalmology (2016)
Abstract 4410: ZEB2 drives cell motility and metastasis in ER+ breast cancer cells through a novel, E-cadherin independent pathway
Authors: Hope E. Burks, Lyndsay V. Rhodes, Elizabeth C. Martin, Van T. Hoang, Steven Elliott, Melody Badoo, Theresa Phamduy, Aaron Buechlein, Douglas Rusch, Douglas Chrisey, Erik Flemington, Kenneth Nephew, Bridgette Collins-Burow, Matthew E. Burow
Journal: Cancer Research (2016)

Abstract Breast cancer is the most commonly diagnosed cancer in women, with the second highest mortality rate. The overwhelming majority of breast cancer deaths are a direct result of distant metastatic spread to vital organs such as lung, bone, and brain. The zinc finger transcription factor ZEB2 has been implicated as a driver of cancer cell motility, tissue invasion and metastasis in a number of diverse malignancies, but its role in breast cancer is not completely understood. We chose to examine the effects of direct overexpression of ZEB2 in the MCF-7 cell line, a luminal and estrogen receptor positive (ER+) derived breast cancer line. MCF-7-ZEB2 cells demonstrated significantly increased migration and invasion as well as an altered morphology in vitro compared to that of vector. Additionally, MCF-7-ZEB2 cells exhibited increased lung metastasis in vivo when implanted in an orthotopic xenograft mouse model. ZEB2 function in metastasis has canonically been attributed to transcriptional repression of the cell junction protein E-Cadherin. Here we establish that in ER+ breast cancer cells, ZEB2 fails to repress E-cadherin and promotes cell motility and metastasis through the induction of an E-cadherin independent signaling cascade. Next generation RNA sequencing analysis of the MCF-7-ZEB2 cells compared to vector revealed alteration of the MAPK signaling cascade, evidenced by enhanced expression of key motility and MAPK associated genes, including PLAU, EGF, ACTA2, and MMP9. Pharmacological inhibition of MAPK pathway completely abrogated ZEB2 induced migration, cell morphology changes and expression of target motility genes, confirming a necessary role for MAPK signaling in ZEB2-driven cell motility in ER+ breast cancer. Together these results indicate that the ZEB2 transcription factor drives motility in breast cancer cells through a novel MAPK dependent pathway, warranting further investigation into the mechanisms involved in ZEB2 action. Elucidating the pathways involved in ZEB2 function which are specific to ER+ breast cancer is an important step in understanding the processes underlying metastasis and has the potential to yield new therapeutic targets. Citation Format: Hope E. Burks, Lyndsay V. Rhodes, Elizabeth C. Martin, Van T. Hoang, Steven Elliott, Melody Badoo, Theresa Phamduy, Aaron Buechlein, Douglas Rusch, Douglas Chrisey, Erik Flemington, Kenneth Nephew, Bridgette Collins-Burow, Matthew E. Burow. ZEB2 drives cell motility and metastasis in ER+ breast cancer cells through a novel, E-cadherin independent pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4410.
Abstract 4359: Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent
Authors: Alice O. Kamphorst, Andreas Wieland, Shu Yang, Tahseen Nasti, Ruan Zhang, Daniel L. Barber, Bogumila T. Konieczny, Lydia Koenig, Ke Yu, Gabriel Sica, Taofeek K. Owonikoko, Rathi Pillai, Suresh S. Ramalingam, Arlene H. Sharpe, Gordon J. Freeman, Laurence A. Turka, Koichi Araki, Rafi Ahmed
Journal: Cancer Research (2016)

Abstract T cell exhaustion was first described in mice during chronic lymphocytic choriomeningitis virus (LCMV) infection and later shown to occur in humans during persistent infections and cancer. Sustained expression of the inhibitory receptor programmed cell death-1 (PD-1) is a hallmark of T cell exhaustion. Therapeutic blockade of PD-1 rescues proliferation, cytokine production and cytotoxicity of exhausted T cells. PD-1 targeted therapies have shown efficacy for multiple cancer types and changed the landscape of cancer treatment, but the requirements for T cell rescue by blockade of the PD-1 pathway remain elusive. T cell activation ensues when positive signals overcome negative signals. CD28 is the most prominent positive co-receptor for T cell activation, and human CD8 T cells become CD28neg upon continuous stimulation. We analyzed tumor specimens from non-small cell lung cancer (NSCLC) patients by flow cytometry and found heterogeneous CD28 expression on tumor-infiltrating CD8 T cells. In most NSCLC patients, CD28neg cells were prevalent among CD8 T cells co-expressing inhibitory receptors (such as PD-1 and Tim-3). To address the role of the CD28/B7 pathway on CD8 T cell rescue by PD-1 targeted therapies, we used the LCMV chronic infection model. When B7 signals were impeded by CTLA-4-Ig or B7 blocking antibodies, blockade of the PD-1 pathway failed to rescue virus-specific CD8 T cells. To investigate a cell intrinsic requirement of CD28 on exhausted CD8 T cells, we used an adoptive transfer strategy of cells genetically deficient in CD28. We found that CD28-deficient LCMV-specific CD8 T cells do not expand after blockade of the PD-1 pathway. Furthermore, to ensure appropriate development and differentiation of CD8 T cells, we used mice in which the CD28 gene can be conditionally deleted. We confirmed that CD28neg exhausted CD8 T cells failed to proliferate after blockade of the PD-1 pathway even when CD28 gene deletion was induced on already exhausted T cells. These data demonstrate that CD28 engagement is required for CD8 T cell rescue, and CD28 status may constitute a predictive biomarker for PD-1 targeted therapies. Citation Format: Alice O. Kamphorst, Andreas Wieland, Shu Yang, Tahseen Nasti, Ruan Zhang, Daniel L. Barber, Bogumila T. Konieczny, Lydia Koenig, Ke Yu, Gabriel Sica, Taofeek K. Owonikoko, Rathi Pillai, Suresh S. Ramalingam, Arlene H. Sharpe, Gordon J. Freeman, Laurence A. Turka, Koichi Araki, Rafi Ahmed. Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4359.
Abstract 2835: Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition
Authors: Joyoti Dey, Joseph Casalini, Sally Ditzler, Matt Biery, Angela Merrell, Derek Thirstrup, Marc Grenley, Richard Klinghoffer
Journal: Cancer Research (2016)

Abstract Triple negative breast cancer (TNBC) is a highly heterogeneous disease, notoriously challenging to treat with standard chemotherapy options, and therefore is an area of intense focus for discovery of novel effective combination therapies. Here we used a previously described technology platform called CIVO, which enables assessment of multiple drugs and drug combinations simultaneously in living tumors, to identify drug combinations that result in synergistic anti-tumor activity in the HCC1187 model of TNBC. Our study focused on agents that combine with Voruciclib, a novel clinical stage oral CDK inhibitor with potent activity (&amp;lt;100 nM) against CDKs 1, 4, and 9. Among the drug combinations investigated, robust localized anti-tumor activity as measured by cleaved caspase 3 (CC3) positive apoptotic cells, was observed upon combined tumor exposure to Voruciclib and the proteasome inhibitor Bortezomib. In contrast, exposure to either Voruciclib or Bortezomib as single agents showed little anti-tumor activity. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies where tumor regression was induced by the Voruciclib/Bortezomib combination, but no significant impact on tumor progression was observed in xenografted subjects treated with either single agent. The ability of TNBC cells to withstand stressors such as chemotherapy may be due in part to activation of adaptive survival pathways including the unfolded protein (UPR) and endoplasmic reticulum (ER) stress responses. As observed in previous reports, exposure of HCC1187 cells to Bortezomib alone led to an increase in two markers of the cytoprotective arm of the UPR/ER stress pathway: XBP-1s and GRP-78/BIP. Consistent with the possibility that Voruciclib impedes the cytoprotective UPR/ER stress response induced by Bortezomib, exposure to the drug combination substantially reduced protein expression of both XBP-1s and GRP-78 with concomitant induction of cPARP. Voruciclib also neutralized upregulation of these same proteins by the classic ER stress inducing agent Tunicamycin. These studies provide a foundation for further investigation of breast cancer relevant anti-cancer agents that induce UPR/ER stress responses in combination with Voruciclib for treating TNBC patients. Citation Format: Joyoti Dey, Joseph Casalini, Sally Ditzler, Matt Biery, Angela Merrell, Derek Thirstrup, Marc Grenley, Richard Klinghoffer. Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2835.
248P GnRH antagonist plus bicalutamide might be an effective therapy as initial combined androgen blockade for patients with high grade prostate cancer
Authors: A. Kawashima, M. Uemura, A. Nagahara, Y. Yamamoto, S. Takada, Y. Inagaki, T. Kinouchi, O. Miyake, S. Nakazawa, K. Nishimura, H. Arai, M. Honda, K. Okada, M. Tsujihata, K. Tsutahara, S. Yamaguchi, T. Ujike, K. Fujita, N. Nonomura
Journal: Annals of Oncology (2015)
Abstract 3263: Dietary supplement 3, 3’-diindolylmethane (DIM) as an antiangiogenic agent in breast cancer
Authors: Ghada M. Ben Rahoma, Neha Y. Tuli, Robert B. Bednarczyk, Rachana R. Maniyar, Abraham Mittelman, Jan Geliebter, Raj Tiwari
Journal: Cancer Research (2016)

Abstract Tumor angiogenesis refers to the sprouting and cooption of proliferating endothelial cells (EC’s) from adjacent pre-existing host vasculature, and is a key target of cancer therapy. Tumor cells exploit their microenvironment by releasing cytokines and growth factors to promote and support angiogenesis. Within this complex tumor microenvironment, we and others have shown that tumors can recruit bone marrow derived endothelial progenitor cells that differentiate into mature bone marrow-derived endothelial cells and incorporate into sprouting tumor neovessels. Under pathological circumstances, such as breast cancer, a clear association between estrogen receptor expression by EC’s, angiogenic activity, and/or tumor invasiveness has been made. Approximately, 80% of breast cancers are hormone-receptor-positive cancers, thus enabling tamoxifen as the mainstay of breast cancer therapy. The roles of the anti-estrogens fulvestrant (ICI) and the dietary supplement 3, 3’-diindolylmethane (DIM) on cell-cell interaction and angiogenesis have not been fully elucidated. This study is designed to evaluate and compare the effect of these antiestrogens on angiogenesis at the cellular and molecular levels using tube formation of human umbilical vein endothelial cells (HUVEC) as an in vitro angiogenesis model. HUVEC cells were treated with serial dilutions of either DIM or ICI in presence and absence of (3nM) estrogen, and subjected to in vitro tube formation, proliferation, migration, and angiogenesis antibody array assays. We report that HUVEC cells are more sensitive to DIM than ICI. At 25 μM concentration, DIM significantly inhibited the crucial steps of angiogenesis including HUVEC cells proliferation, migration, cytokine release, and tube formation in an estrogen independent manner. On the other hand, at 1 μM concentration, ICI significantly exerted an antiangiogenic effects inhibiting HUVEC cells proliferation, migration, and tube formation, but this effect was totally dependent on the presence of estrogen. These results are validated by our observation that HUVEC cells express estrogen receptor beta (ER-β) and not estrogen receptor alpha (ER-α). A correlative effect between the antiangiogenic activity of DIM and ER-β upregulation was noted. We believe that the anti-estrogenic activity of DIM is mediated through the genomic and non-genomic activity of ER-β in endothelial cells predicting a new target for DIM to manifest its antiangiogenic effect. Citation Format: Ghada M. Ben Rahoma, Neha Y. Tuli, Robert B. Bednarczyk, Rachana R. Maniyar, Abraham Mittelman, Jan Geliebter, Raj Tiwari. Dietary supplement 3, 3’-diindolylmethane (DIM) as an antiangiogenic agent in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3263.
Abstract 723: Distinguishing macrophages by a unique gene signature to measure response to treatment
Authors: Yasmin A. Lyons, Sunila Pradeep, Jean M. Hansen, Rebecca A. Previs, Hui Yao, Keith A. Baggerly, Anil K. Sood
Journal: Cancer Research (2016)

Abstract Objectives: Tumor-associated macrophage infiltration is associated with poor prognosis, making macrophage depletion an ideal therapy. This study aims to identify a macrophage-specific gene signature to quantify macrophage content and measure response to treatment of high-grade serous cancer (HGSC) with colony stimulating factor-1 receptor (CSF1R) inhibitor. Methods: 39 murine genes were identified in the literature as being macrophage-specific. Corresponding human orthologous genes were identified using BioMart database. Expression levels (log-transformed normalized RSEM values) of human homologous genes were retrieved from The Cancer Genome Atlas (TCGA) portal. Principal component (PC) and hierarchical clustering (HC) analysis of 305 primary HGSC was performed. Q-PCR was performed on human macrophage cell line, endothelial cell line, and fibroblast cell line. Q-PCR was also performed on tumor tissue obtained from CD57Bl/6 mice injected with murine ovarian cancer and treated with CSF1R inhibitor. Results: 37 human homologous genes were identified for the macrophage specific murine genes. Of the 37 genes, 12 tracked together tightly and included the top 3 genes with greatest median absolute deviance of RSEM values, thus were chosen for further analysis. Q-PCR using human macrophage cell line revealed high expression in all 12 genes (delta CT &amp;lt;25), with TBXAS, CD14, and FCGR1A being the highest. All 12 genes showed greater expression in macrophages versus fibroblasts and endothelial cells, to varying degrees. Expression of CD14, TLR7, FCGR2C, and FCGR1B was significantly higher (p&amp;lt;0.0001) in macrophages compared to both fibroblasts and endothelial cells. Of these 12 human genes, 4 had homologous murine genes. These genes were used for Q-PCR on murine tumor tissue treated with CSF1R inhibitor. There was a statistically significant decrease in the level of CSF3R (p = 0.005), FCGR (p = 0.02), and PON3 (p = 0.002) between the control group and the group treated with CSF1R inhibitor. Conclusions: These data suggest that macrophage specific genes could be useful for quantifying macrophage content in tumor samples to monitor therapy-related changes. Citation Format: Yasmin A. Lyons, Sunila Pradeep, Jean M. Hansen, Rebecca A. Previs, Hui Yao, Keith A. Baggerly, Anil K. Sood. Distinguishing macrophages by a unique gene signature to measure response to treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 723.
Abstract 3444: Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population
Authors: Dong Hang, Yin Yin, Jing Han, Jie Jiang, Hongxia Ma, Shuanghua Xie, Xiaoshuang Feng, Kai Zhang, Zhibin Hu, Shen Hongbing, Gary M. Clifford, Min Dai, Ni Li
Journal: Cancer Research (2016)

Abstract HPV16 is the most carcinogenic HPV type, but only a minority of HPV16 infections progress to cancer. Intratype genetic variants of HPV16 have been suggested to confer differential carcinogenicity. To investigate risk implications of HPV16 variants among Chinese women, a case-control study was conducted with 298 cervical cancer patients and 85 controls (all HPV16-positive). HPV16 isolates were predominantly of the A variant lineage, and variants of A4 (previously named “Asian”) sublineage were common. A4/Asian variants were significantly associated with increased risk of cervical cancer compared to A1-3 (OR = 1.72, 95% CI = 1.04-2.85). Furthermore, a meta-analysis including 703 cases and 323 controls from East Asia confirmed the association (OR = 2.82, 95% CI = 1.44-5.52). In conclusion, A4 variants appear to predict higher risk of cervical cancer among HPV16-positive women, which may provide clues to the genetic basis of differences in the carcinogenicity of HPV16 variants. Citation Format: Dong Hang, Yin Yin, Jing Han, Jie Jiang, Hongxia Ma, Shuanghua Xie, Xiaoshuang Feng, Kai Zhang, Zhibin Hu, Shen Hongbing, Gary M. Clifford, Min Dai, Ni Li. Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3444.