tbuckley/cabot-search huggingface dataset:
Abstract 4994: SEA-CD40: from bench to bedside
Authors: Shyra J. Gardai, Haley Neff-LaFord, Angela Epp, Jing Yang, Thomas Manley, Che-Leung Law
Journal: Cancer Research (2016)

Abstract SEA-CD40 is a non-fucosylated, humanized IgG1 monoclonal antibody directed against human CD40, a co-stimulatory receptor of the TNF receptor superfamily. The consequence of enhanced SEA-CD40/FcγRIIIa binding is potent immune stimulatory activity. CD40 receptor ligation induces multiple pathways; to pave the road for identification of a specific activity signature in the clinical setting, in vitro preclinical assays were developed to monitor the immune modulatory activity of SEA-CD40. Human PBMCs stimulated with increasing concentrations of SEA-CD40 were assessed for immune changes including cytokine production, cellular activation, and modulation of cellular subsets. SEA-CD40 PBMC stimulation elicited a unique set of cytokines including MIP-1β, MCP-1, and IL-8. In addition to inducing cytokines, specific immune cell changes were also observed including up-regulation of stimulatory molecules on monocyte/ macrophages, activation of NK cells, and changes in cellular subsets such as deletion of B-cells. While some of these changes were common across the other CD40 therapeutic antibodies being tested in the clinic, SEA-CD40-specific changes were identified. These changes included a reduction in the immune dampening cytokine IL-10, induction of Th1 CXCR3 positive cells, and reduction of T-regulatory cells, all potentially contributing to an antitumor immune response. The specific in vitro SEA-CD40 signature was also observed in vivo in cynomolgus monkeys. SEA-CD40 treatment induced the same signature cytokines observed in vitro and elicited the same cellular changes including depletion of B-cells, and activation of CD8+ T-cells. A CD40 receptor occupancy assay was also created to correlate receptor engagement with activity. Interestingly, while SEA-CD40 is rapidly cleared from plasma, it is detectable on the surface of antigen-presenting cells for up to 3 weeks. The initial starting dose for SEA-CD40 clinical trials was calculated using the minimal anticipated biological effect level (MABEL). SEA-CD40 cytokine induction was the most sensitive preclinical marker of biologic activity and was, therefore, used for MABEL dose calculation. In the ongoing phase 1 First-In-Human clinical trial, this preclinical SEA-CD40 activity signature is being monitored in adult patients with advanced solid tumors (study NCT02376699). Establishing a clear immune biomarker strategy from pre-clinical research to clinical trials is vital for tracking the activity of our immuno-oncology drugs in patients and for identifying a safe and efficacious regimen. Citation Format: Shyra J. Gardai, Haley Neff-LaFord, Angela Epp, Jing Yang, Thomas Manley, Che-Leung Law. SEA-CD40: from bench to bedside. [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 4994.
Abstract 2618: Oncogenic mutant KRAS modulates CREB activation through MEK-ERK and AKT signaling in pancreatic cancer
Authors: Jason Castellanos, Supriya Srinivasan, Kumar Honnenahally, Chanjuan Shi, Michael VanSaun, David Robbins, Nipun Merchant, Nagaraj Nagathihalli
Journal: Cancer Research (2016)

Abstract Introduction: Cyclic AMP (cAMP) response element binding (CREB) overexpression in pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcome, however, the mechanism(s) driving CREB overexpression in PDAC are not fully understood. We investigated the association of CREB activation with oncogenic KRAS, MEK-ERK and AKT signaling pathways. Experimental procedure: Mouse lines derived from the Ptf1aCre/+; LSL-KrasG12D/+ (K518), Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT), LSL-KrasG12D/+;Pdx1Cre/+ (PanIN) and LSL-KrasG12D/+; Trp53R172H/+;Pdx1Cre/+ (PDA) mouse models of PDAC, human immortalized pancreatic ductal epithelial lines (HPDE6-E6E7 or H6c7, HPNE E6/E7 and HPNE E6/E7/KRAS) were immunoblotted for phospho-CREB (pCREB) and total CREB expression. KRAS mutant PDAC cell lines and CREB shRNA flank xenografts (PKT GEMM and nude mice) were treated with CREB (ICG-001), MEK (AZD6244) and AKT (MK-2206) inhibitors. The effects on downstream signaling targets were interrogated with cell cycle, apoptosis, survival and anchorage-independent growth analysis. Human CREB shRNA cells were treated with AZD6244 and MK-2206 to confirm the molecular mechanism of the CREB inhibition together with MEK and AKT. Results: The expression of pCREB was higher in cells with KRAS mutation. MEK inhibition resulted in activation of AKT, while combined inhibition of CREB and MEK prevented AKT reactivation. Treatment with the combination of MEK and CREB inhibitors significantly decreased tumorigenic potential and increased cell apoptosis. Combined MEK, AKT and CREB inhibition synergistically enhanced these effects further, more so in KRAS mutant cell lines. To explore the relationship of CREB, MEK and AKT signaling in vivo, PKT mice were treated with their respective inhibitors individually and in combination. Either CREB/MEK or CREB/AKT two drug combinations significantly extended the median survival compared with individual agents. Lysates from MEK and AKT inhibited tumors showed decreased phosphorylation of CREB, confirming that CREB is activated through both, MEK and AKT signaling in vivo. Conclusions: Our study demonstrates that oncogenic KRAS activation enhances the expression of CREB through MEK and AKT signaling. CREB inhibition results in increased sensitivity to MEK and AKT targeted therapy in KRAS mutant PDACs. Citation Format: Jason Castellanos, Supriya Srinivasan, Kumar Honnenahally, Chanjuan Shi, Michael VanSaun, David Robbins, Nipun Merchant, Nagaraj Nagathihalli. Oncogenic mutant KRAS modulates CREB activation through MEK-ERK and AKT signaling in pancreatic 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 2618.
P0484 : CD3(+)CD56(+) NK-like T cells show reduced anti-viral activity in acutely HCV/HIV infected patients
Authors: P. Kokordelis, B. Krämer, C. Boesecke, E. Voigt, P. Ingiliz, A. Glässner, F. Wolter, C.P. Strassburg, U. Spengler, J.K. Rockstroh, J. Nattermann
Journal: Journal of Hepatology (2015)
A phase I dose-escalation study of the polo-like kinase 1 inhibitor volasertib (BI 6727) with two different dosing schedules in patients with advanced solid malignancies.
Authors: C. Lin, W. Su, C. Yen, A. Cheng, Y. Lu, C. Hsu, W. Su, D. C. Huang, H. Fritsch, F. Voss, R. Schreck, T. Taube, C. Yang
Journal: Journal of Clinical Oncology (2011)

3046 Background: Polo-like kinase 1 (Plk1) controls several key steps in mitosis. Volasertib is a potent and highly selective Plk1 inhibitor. Plk1 inhibition results in cell cycle arrest in prometaphase with a distinct cellular phenotype (“polo arrest”) eventually leading to apoptosis. This is the first report of the maximum tolerated dose (MTD) of two different dosing schedules of volasertib in Asian patients with solid tumors. Preliminary data on safety, pharmacokinetics and antitumor activity are also reported. Methods: Sequential cohorts of 3-6 patients with advanced or metastatic solid tumors received a 2-hr infusion of volasertib on day 1 every 3 weeks (schedule A) or on days 1 and 8 every 3 weeks (schedule B) in a toxicity guided dose escalation study. There were 4 prespecified doses per schedule (A: 100-300 mg; B: 50-200 mg). Further treatment courses were administered in the absence of progressive disease (PD) or in case of symptom improvement despite PD. Results: 52 Asian patients with advanced solid tumors (9 colorectal, 6 esophageal, 6 skin/melanoma, 5 bladder and 26 others) were treated. To date, reversible thrombocytopenia, neutropenia and febrile neutropenia were dose-limiting toxicities (DLTs). Fatigue, decreased appetite, and nausea were among the most frequent drug-related non-hematologic events. MTD was 300 mg for schedule A and 150 mg for schedule B. The median number of initiated courses was 3 over all dose groups (range 1-21). Volasertib showed multi-compartmental PK behavior with a mean terminal elimination half-life of 107 hours, moderate clearance (807 mL/min) and a large volume of distribution (4,500 L). Two patients with bladder cancer and melanoma, respectively, had partial responses. Conclusions: This is the first study to test two different schedules of volasertib, day 1 and days 1 and 8 every 3 weeks respectively, to investigate MTD, safety and preliminary antitumor activity. The MTD of volasertib was determined for both dosing schedules. Volasertib was well tolerated and had a favorable PK profile. The data support Plk1 as a therapeutic target and further clinical investigation of volasertib is warranted.
Abstract 1737: Reproductive and hormonal factors in relation to lung cancer among Nepali women
Authors: Sanah N. Vohra, Amir Sapkota, Mei-Ling T. Lee, Mia Hashibe, Bhola Siwakoti, Chin B. Pun, Cher M. Dallal
Journal: Cancer Research (2016)

Abstract Of the 1.8 million global incident lung cancer cases estimated in 2012, approximately 58% occurred in less developed regions (LDRs). Studies conducted in more developed regions suggest potential gender differences in lung cancer risk, whereby women may be more susceptible to the carcinogenic effects of tobacco. However, studies of reproductive and hormonal factors and lung cancer among women have been inconsistent and to date, no prior study has assessed these relationships among Nepali women. Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009-2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23-85 years. Lung cancer cases (n = 268) were frequency-matched to controls (n = 226), on the basis of age (±5 years), ethnicity and residential area. Controls were selected from visitors of non-lung cancer patients within the same hospital. Participants completed an interviewer-administered questionnaire and provided detailed information on demographics, medical history, smoking history, and reproductive and hormonal factors. The main exposures in this analysis included menopausal status, age at menarche, age at menopause, menstrual duration, gravidity, and age at first live-birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Final models include adjustment for key confounders including age and smoking status. Among postmenopausal women, those with a younger age at menopause (&amp;lt;45years; 45-49years) had an increased odds of lung cancer compared to those with an older (≥50years, referent) age at menopause (OR = 2.14, 95%CI = 1.09, 4.17; OR = 1.93, 95%CI = 1.07, 3.51, respectively), after adjusting for age and cumulative active smoking (CAS). No statistically significant associations were observed with the other exposures examined. Ongoing analyses include stratification by key factors including CAS years. Further research is needed to corroborate and expand on these findings in order to better understand hormonal risk factors for lung cancer among Nepali women. Citation Format: Sanah N. Vohra, Amir Sapkota, Mei-Ling T. Lee, Mia Hashibe, Bhola Siwakoti, Chin B. Pun, Cher M. Dallal. Reproductive and hormonal factors in relation to lung cancer among Nepali women. [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 1737.
AML1/ETO Expresssion in Myeloid Leukemia Cells Is Associated with Enhanced Growth-Inhibitory and P15/INK4b Demethylating Effects of 5-AZA-2′-Deoxycytidine.
Authors: Tobias Berg, Mahmoud Abdelkarim, Yalin Guo, Manfred Fliegauf, Michael Lübbert
Journal: Blood (2004)
A Randomized Phase 2 Study Comparing the Combination of Ficlatuzumab and Gefitinib with Gefitinib Alone in Asian Patients with Advanced Stage Pulmonary Adenocarcinoma
Authors: Tony Shu Kam Mok, Sarayut Lucien Geater, Wu-Chou Su, Eng-Huat Tan, James Chi-Hsin Yang, Gee-Chen Chang, May Han, Philip Komarnitsky, Francis Payumo, Jennifer E. Garrus, Sandra Close, Keunchil Park
Journal: Journal of Thoracic Oncology (2016)
Abstract 777: The CoGAPS matrix factorization algorithm infers feedback mechanisms from therapeutic inhibition of EGFR that increases expression of growth factor receptors
Authors: Elana J. Fertig, Hiroyuki Ozawa, Manjusha Thakar, Jason Howard, Gabriel Krigsfeld, Alexander V. Favorov, Daria A. Gaykalova, Michael F. Ochs, Christine H. Chung
Journal: Cancer Research (2016)

Abstract Next generation sequencing technologies enable precise personalized medicine. Thus, patients with oncogene driven tumors are currently treated with targeted therapeutics such as EGFR inhibitors. However, drug interactions with other activated signaling pathways in treated tumors often alter predicted therapeutic response. Therefore, bioinformatics algorithms are needed to infer unanticipated molecular interactions from anticipated molecular response to targeted therapeutics in diverse genetic backgrounds. To model heterogeneous genetic backgrounds in HNSCC, we use HaCaT cells with forced overexpression of EGFR, HRAS, and PIK3CA. Previously, the CoGAPS matrix factorization algorithm was shown to infer the specific signaling pathways that were activated in these HaCaT knock-in constructs from gene expression data. In this study, we evaluated whether CoGAPS could also delineate unanticipated signaling changes from anticipated cellular signaling response caused by targeted therapeutic in diverse genetic backgrounds. To delineate these signaling responses, we measured gene expression after treating the modified HaCaT cells with three EGFR targeted agents (gefitinib, cetuximab and afatinib) for 24 hours. The CoGAPS matrix factorization algorithm distinguished a gene expression signature associated with the anticipated silencing of the EGFR network and a signature associated with unanticipated transcriptional feedback in HaCaT constructs that were sensitive to EGFR inhibitors. Notably, the feedback signature showed that EGFR gene expression itself increased in cells that were responsive to EGFR inhibitors. The CoGAPS algorithm further associated such feedback with increased expression of several growth factor receptors by the AP-2 family of transcription factors. Once transcribed, these growth factor receptors may ultimately compensate for EGFR inhibition in these sensitive cells. Our data suggest, that CoGAPS gene expression signatures delineate on target and feedback effects of drugs related to therapeutic sensitivity in diverse genetic backgrounds. Citation Format: Elana J. Fertig, Hiroyuki Ozawa, Manjusha Thakar, Jason Howard, Gabriel Krigsfeld, Alexander V. Favorov, Daria A. Gaykalova, Michael F. Ochs, Christine H. Chung. The CoGAPS matrix factorization algorithm infers feedback mechanisms from therapeutic inhibition of EGFR that increases expression of growth factor receptors. [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 777.
Abstract 2866: Sodium channel γENaC mediates salt induced inflammatory stress in cancer cells
Authors: Suneetha Amara, Venkataswarup Tiriveedhi
Journal: Cancer Research (2016)

Abstract Chronic inflammation is known to play a critical role in the development of cancer. Recent evidence suggests that high salt in the tissue microenvironment induces chronic inflammatory milieu. Further, high salt intake has been correlated with higher incidence of cardiovascular diseases and cancers. In this report, using breast cancer cell lines, MDA-MB-231 (highly invasive), MCF-7 (poorly invasive), and a normalized breast epithelial cell line, MCF10A, we determined the molecular basis of the potential inflammatory effect of high sodium chloride (NaCl) in the extracellular environment. Dose response studies demonstrated a significantly reduced cell viability (&amp;gt;50%) with external NaCl concentration above 0.25 M. Combined treatment of high NaCl (0.15 M) with sub-effective interleukin (IL)-17 (0.1 nM) induced reactive nitrogen (RNS) and oxygen (ROS) species release along with upregulation of the enzymes iNOS, SOCS and SOD1. Similar effect was not observed with equi-molar mannitol. Western-blot and qRT-PCR analysis demonstrated an elevated expression of an inflammation-specific epithelial sodium channel, γENaC, in MDA-MB-231 (7.1±1.4 fold, p&amp;lt;0.05), MCF-7 (3.9±0.8 fold, p&amp;lt;0.05) and MCF10A (2.2±0.4 fold, p&amp;lt;0.05) cell lines following combined treatment of high NaCl with sub-effective IL-17. This was significantly abrogated by lipid raft depletion and ERK-1/2 knock-down. These culture conditions have also induced cellular expression of cytokines, IL-6 (3 fold), TNFα (6.2 fold); chemokines, CCL5 (2.3 fold), CXCL-12 (2 fold), MIP-1δ (2.7 fold); and angiogenic growth factor, VEGF (2.5 fold). Taken together, these data suggest that high NaCl in the cellular microenvironment induces a γENaC mediated chronic inflammatory response with a potential pro-carcinogenic effect. Citation Format: Suneetha Amara, Venkataswarup Tiriveedhi. Sodium channel γENaC mediates salt induced inflammatory stress in cancer cells. [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 2866.
hs-CRP Predicts Improvement in Depression in Patients With Type 1 Diabetes and Major Depression Undergoing Depression Treatment: Results From the Diabetes and Depression (DAD) Study
Authors: Daniela Zahn, Stephan Herpertz, Christian Albus, Norbert Hermanns, Christoph Hiemke, Wolfgang Hiller, Kai Kronfeld, Johannes Kruse, Bernd Kulzer, Matthias J. Müller, Christian Ruckes, Frank Petrak
Journal: Diabetes Care (2016)

hs-CRP is elevated in depression (1), but evidence on decreases of hs-CRP during depression treatment or the role of hs-CRP in the prediction of response to depression treatment is still controversial (2,3). To date, no study has examined this association in patients with diabetes. As elevated hs-CRP increases the risk of diabetes complications in diabetes (4), we aimed to explore hs-CRP in patients with diabetes and major depression undergoing depression treatment based on the data of the Diabetes and Depression (DAD) study (5).

Participants were randomized to 12 weeks (short-term phase) of diabetes-specific group cognitive behavioral therapy or sertraline treatment and followed up for 15 months (long-term phase). hs-CRP was assessed at baseline and at the end of the long-term phase with a latex-enhanced immunoturbidimetric method. Ethics approval and written informed consent were obtained (5). Information on baseline hs-CRP was available in 219 patients (mean age 48.1 ± 12.0 years, 62% female, mean HbA1c 9.25 ± 1.4% [78 ± 16.2 mmol/mol], 51.6% type 2 diabetes, median hs-CRP 0.33 mg/dL [interquartile range 0.10, 0.84]). Depression outcomes included short-term treatment response (≥50% reduction of the Hamilton Depression Rating Scale [HAMD-17] baseline score or HAMD-17 posttreatment score ≤7), remission of depression at the end of the long-term phase (HAMD-17 scores ≤7 and no …
Abstract 3278: Dopamine inhibits growth of multiple myeloma
Authors: Chandrani Sarkar, Debanjan Chakroborty, Sujit Basu
Journal: Cancer Research (2016)

Abstract Introduction: Multiple myeloma (MM), progressive plasma cell tumor leading to overproduction of monoclonal immunoglobulins, osteolytic bone lesions, renal disease and immunodeficiency, is the second most prevalent hematologic malignancy in the United States. Vascular endothelial growth factor-A (VEGF-A) is a critical cytokine responsible for the induction of angiogenesis in several solid and hematological malignancies like MM. It is likely that VEGF-A induced bone marrow (BM) angiogenesis promotes the survival, growth and proliferation of MM .Therefore targeting BM angiogenesis in MM may be effective for the treatment of MM patients Objective/Hypothesis: Bone marrow stromal cells (BMSC) are believed to play a central role in progression of MM pathogenesis. Along with other factors, these cells overproduce IL-6 that in turn stimulates growth, survival and progression of MM cells. Since it has been shown that VEGF-A can stimulate IL-6 secretion by these cells and because we have demonstrated that neurotransmitter dopamine (DA) can inhibit VEGF-A functions by acting through its D2 receptors (D2R) and BMSC express DAD2R, we therefore hypothesize that DA or D2R agonists have a role in inhibiting VEGF-A mediated IL-6 secretion by BMSC and thereby, MM progression. Results: Our results indicate that VEGF-A can significantly increase the secretion of IL6 by isolated BMSC cells in vitro. Addition of DA or D2R agonist, quinpirole, to VEGF-A treated BM cells results in suppression of IL-6 production. However treatment with D2R antagonist, eticlopride, prior to treatment with DA results in abrogation of the effect of DA. Similar effects of DA on VEGF-A induced IL-6 secretion was also observed in HS-5 human BM stromal cells. Our results further indicate that VEGF-A induced VEGFR1 phosphorylation is suppressed in HS-5 cells on treatment with D2R agonist. Furthermore, DA also inhibits the proliferation of MM1.S human MM cells in vitro. Conclusion: DA may be a new and an effective approach to retard the progression of MM. Since anti-angiogenic monotherapy cannot eradicate the disease completely, strategies using DA with more traditional modalities to eradicate the disease at the time of initial treatment might be beneficial. Finally, DA or its D2R agonists are being used in the clinics for several years for the treatment of other disorders, therefore these inexpensive drugs (in comparison to presently available drugs for the treatment of MM) with known and manageable side effects can be used in the clinics in near future for the treatment of both early and late stage MM. Citation Format: Chandrani Sarkar, Debanjan Chakroborty, Sujit Basu. Dopamine inhibits growth of multiple myeloma. [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 3278.