tbuckley/cabot-search huggingface dataset:
Abstract LB-007: Interaction between integrin α4β1 and IGF1 and its role in IGF signaling in hematologic malignancies
Authors: Dora M. Cedano Prieto, Jessica Yu, Yoko Takada, Yoshikazu Takada
Journal: Cancer Research (2016)

Abstract Integrins are transmembrane αβ heterodimers that function as cell adhesion receptors. Integrins are aberrantly overexpressed in cancer cells and also in tumor-associated cells. They are involved in cancer cell proliferation, invasion and survival. It has been proposed that the interaction between integrin α4β1, a major integrin in hematologic cancer, and VCAM-1 and fibronectin is responsible for drug resistance in these malignances, since antagonists to this integrin reduce drug resistance. However these results are based on the assumption that VCAM-1 and fibronectin are the only ligands for α4β1. Insulin-like growth factor 1 (IGF1) signaling plays a critical role in drug resistance and radio resistance hematologic cancer. IGF1 is a polypeptide hormone that binds to tyrosine kinase receptor IGF1R and activates the PI3K/Akt signaling pathway. This pathway is involved in cell proliferation, survival, and inhibition of apoptosis. In various types of cancer IGF1 is over expressed and the PI3K/Akt pathway is activated at a much higher rate than in normal cells. This results in the growth of cancer cells and resistance to chemotherapy. IGF1 signaling is implicated in drug resistance, and is a good therapeutic target in hematologic cancers. It is unclear if α4β1 and IGF signaling work independently in drug resistance. Recently we established that IGF1 binds to integrins αvβ3 and α6β4, and subsequent integrin-IGF1-IGF1R ternary complex formation is a critical step in IGF signaling in non-hematologic cancer. We developed the R36E/R37E IGF1 mutant that is defective in integrin binding and a dominant-negative antagonist of IGF signaling. Here we show that IGF1 is a ligand for integrin α4β1 and induces a ternary complex with IGF1R and α4β1. Antagonists to integrin α4β1 and the R36E/R37E IGF1 mutant reduced intracellular signaling in Chinese hamster ovary cells expressing human integrin α4 (α4-CHO cells) and also in different hematologic cancer cells such as Reh, Molt-4, U937 and JY cells. These results suggest that integrin α4β1 is involved in IGF signaling through direct binding to IGF1 in hematologic cancer. The α4β1-IGF1 interaction is a novel therapeutic target for drug resistance in hematologic cancer. Citation Format: Dora M. Cedano Prieto, Jessica Yu, Yoko Takada, Yoshikazu Takada. Interaction between integrin α4β1 and IGF1 and its role in IGF signaling in hematologic malignancies. [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-007.
Satire
Authors: Raymond G Bunge
Journal: JAMA (2016)

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A retrospective evaluation of antiangiogenic therapy induced hypertension in metastatic renal cell carcinoma.
Authors: K. L. Wilhelm, B. J. Atkinson, A. Y. Khakoo, N. M. Tannir, E. Jonasch
Journal: Journal of Clinical Oncology (2010)

e15047 Background: Treatment of metastatic renal cell carcinoma (mRCC) includes antiangiogenic (AAG) therapy such as; sorafenib, sunitinib, and bevacizumab. Though better tolerated than historical therapies, hypertension (HTN) is a common and potentially serious complication. In phase III studies, HTN occurred in 21-32% of patients (pts). The true incidence of HTN is unknown due to differing definitions in these trials. We sought to identify 1) the incidence of HTN in pts treated with sunitinib, sorafenib, or bevacizumab; 2) most common antihypertensive interventions; 3) cardiovascular events (CVEs) within 1 year of treatment initiation; and 4) all cause mortality. Methods: Single center, retrospective review from 1/1/06 to 12/31/07. Pts > 18 years of age with mRCC of clear cell histology and who received AAG therapy were included. Pts who received prior AAG treatment or inadequate follow up were excluded. HTN was defined as: 1) SBP > 140 or DBP > 90 for normotensive pts, 2) exacerbation of pre-existing HTN by SBP >20 or DBP >10, or 3) initiation or escalation of an antihypertensive agent. CVEs included MI, stroke, angina, coronary revascularization, and CHF. Analysis of outcomes were completed by two-tailed, Fischer's exact test. Results: 131 pts were reviewed of which 63% (n=83) developed HTN during therapy. At 6 mo, 65% of pts who developed HTN continued on AAG therapy compared to 38% who did not (p<0.05; 95% CI 1.140 - 2.043). This trend continued at 12 mo, 37% vs. 19% respectively (p<0.05; 95% CI 1.063 - 1.731). Progressive disease occurred in 37% of pts with HTN vs. 56% without HTN (p<0.05; 95% CI 1.006 – 1.765). In the HTN group, outcomes were similar for pts who had de novo HTN (n=34) vs exacerbation (n=49) at 6 and 12 mo (p>0.05). Median interventions were one with ACEI/ARB initiation or dose escalation the most common. CVEs were only in pts who developed HTN (10%; n=3 HTN urgencies, 2 CVA, 2 MI). At 12 mo, the mortality rate was 27% for the non-HTN group vs. 8% for the HTN group (p<0.05; 95% CI 0.2776 - 0.9414). Conclusions: The incidence of HTN was higher than previously reported and may be associated with positive treatment outcomes. Prospective investigations of HTN as a potential biomarker for AAG therapies are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Genentech, Pfizer Genentech, Pfizer
Abstract 4796: BTK inhibitor BGB-3111 synergizes with lenalidomide in MCL models
Authors: Nan Hu, Shuo Zhang, Min He, Jiye Zhang, Bin Jiang, Zhijian Sun, Lusong Luo, Lai Wang
Journal: Cancer Research (2016)

Abstract Background BGB-3111 is a novel, irreversible, second generation BTK inhibitor with better selectivity profile and DMPK property compared to ibrutinib. It has demonstrated promising anti-tumor activities in patients with advanced B cell malignancies, including mantle cell lymphoma (MCL). Lenalidomide is an immunomodulatory agent with single-agent activity in several histologic subtypes of B-cell non-Hodgkin lymphoma (NHL). It was approved for the treatment of patients with MCL whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. In this study, we sought to investigate the combination activities of BGB-3111 and lenalidomide in MCL models. Methods In vitro drug efficacy was determined using MCL cell lines including REC-1, MINO and JEKO-1. Cell viability was assessed with Cell Titer Glo® assay and half maximal inhibitory concentrations (IC50) were estimated upon exposure to single agents or drug combinations. In vivo activity was assessed in REC-1 and MINO subcutaneous mouse xenograft models. Treatments were administered by oral gavage when tumors were palpable and individual body weight and tumor volume was recorded twice weekly. Results The in vitro combination activity of BGB-3111 and lenalidomide was tested in MCL cell lines. Strong synergy was observed in REC-1 and MINO cells, but not in JEKO-1 cells. When tested in vivo, both BGB-3111 (7.5 mg/kg, BID) and lenalidomide (30 mg/kg, QD) significantly inhibited the REC-1 xenograft tumor growth with TGI of 86% and 56%, respectively. The combination treatment resulted in 100% TGI. In MINO xenograft model, combination treatment of BGB-3111 (30 mg/kg, BID) and lenalidomide (30 mg/kg, QD) was also more efficacious than either single agent. Conclusions In summary, BGB-3111 and lenlidomide showed interesting in vitro and in vivo combination activity in MCL models, providing rationale for testing this combination in clinic. Citation Format: Nan Hu, Shuo Zhang, Min He, Jiye Zhang, Bin Jiang, Zhijian Sun, Lusong Luo, Lai Wang. BTK inhibitor BGB-3111 synergizes with lenalidomide in MCL models. [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 4796.
ROR1 Can Interact With TCL1 and Enhance Leukemogenesis In Eµ-TCL1 Transgenic Mice
Authors: George F. Widhopf, Bing Cui, Emanuela M. Ghia, Liguang Chen, Karen Messer, Zhouxin Shen, Steven P. Briggs, Carlo M. Croce, Thomas J. Kipps
Journal: Blood (2013)
Abstract 804: Gene-environment interactions and the risk of Barrett's esophagus in three US cohorts
Authors: Marta Crous-Bou, Diane Feskanich, Meir J. Stampfer, Charles S. Fuchs, Immaculata De Vivo, Brian C. Jacobson
Journal: Cancer Research (2016)

Abstract Background: Several single nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. Additionally, environmental factors including smoking, alcohol consumption and heartburn have been shown to increase BE risk. However, no studies have evaluated whether interactions between these genetic and environmental factors influence BE risk. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE. Objectives: To examine the main effects and the potential effect-modification between known genetic loci (SNPS) and established environmental risk factors for BE. Patients and Methods: We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. We genotyped SNPs identified in previous BE GWAS as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed. Results and Conclusions: We found a borderline association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of Barrett's esophagus by a factor of 1.20 (95%CI = 1.00-1.44; p = 0.057). We observed a significant interaction between smoking and BE genotypes (p-interaction = 0.016). However, while alcohol consumption and heartburn duration were strongly associated with BE, we did not observe any significant gene-environment interactions. Citation Format: Marta Crous-Bou, Diane Feskanich, Meir J. Stampfer, Charles S. Fuchs, Immaculata De Vivo, Brian C. Jacobson. Gene-environment interactions and the risk of Barrett's esophagus in three US cohorts. [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 804.
Direct 3D bioprinting of perfusable vascular constructs using a blend bioink
Authors: Weitao Jia, P. Selcan Gungor-Ozkerim, Yu Shrike Zhang, Kan Yue, Kai Zhu, Wanjun Liu, Qingment Pi, Batzaya Byambaa, Mehmet Remzi Dokmeci, Su Ryon Shin, Ali Khademhosseini
Journal: Biomaterials (2016)
RESPONSE: Re: Continuing Outcomes Relevant to Evista: Breast Cancer Incidence in Postmenopausal Osteoporotic Women in a Randomized Trial of Raloxifene
Authors: S. Martino, J. A. Cauley, E. Barrett-Connor, T. J. Powles, J. Mershon, D. Disch, R. J. Secrest, S. R. Cummings
Journal: JNCI Journal of the National Cancer Institute (2005)
A phase 2 study of a nivolumab (nivo)-containing regimen in patients (pts) with newly diagnosed classical Hodgkin lymphoma (cHL): Study 205 Cohort D.
Authors: Philippe Armand, Margaret Ann Shipp, John Kuruvilla, Graham P Collins, Rod Ramchandren, John Timmerman, Anne Sumbul, Mary M. Ruisi, Kazunobu Kato, Stephen Maxted Ansell
Journal: Journal of Clinical Oncology (2016)

TPS7573 Background: Nivo is a human IgG4 monoclonal antibody immune checkpoint inhibitor that targets programmed death receptor-1 (PD-1) on activated immune cells and disrupts engagement of the receptor by its ligands PD-L1 and PD-L2. cHL tumors very frequently harbor amplifications at 9p24.1, causing overexpression of PD-L1 and PD-L2, which suggests a unique dependence on the PD-1 pathway for survival. This tumor may therefore be particularly sensitive to PD-1 blockade. In a phase 1 study (NCT01592370) of 23 heavily pretreated pts with cHL, nivo showed an acceptable safety profile and promising anti-tumor activity, with an investigator-assessed ORR of 87% and median duration of response not reached after a median follow-up of 23 months. Moreover, 60% of responders had a response within 8 wks (Ansell SM et al, NEJM 2015;372:311–9; Ansell SM et al, ASH 2015 [583]). Immune-modulating therapy, which requires pts to mount an immune response, may be more effective before exposure to many prior chemotherapy regimens. We hypothesized that nivo could lead to deep responses in pts never exposed to chemotherapy, and could synergize with chemotherapy to provide curative treatment. We are therefore testing nivo in combination with chemotherapy in pts with newly diagnosed cHL, with a window period to assess response to single-agent immunotherapy. Methods: This study involves Cohort D of the broader phase 2 study of nivo in cHL (NCT02181738). To be eligible for Cohort D, pts must be ≥ 18 years with newly diagnosed cHL (stage III, IV, or IIB with B symptoms, extranodal or bulky disease) and ECOG performance status < 2. Nivo 240 mg IV is administered every 2 wks for 4 doses, then every 2 wks with AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) for 6 cycles (22 wks). Safety and tolerability of the regimen is being assessed. Primary endpoint is the proportion of pts with ≥ 1 treatment-related grade 3–5 AEs ≤ 30 days after the last study dose. Other selected endpoints include treatment discontinuation rate and incidence of treatment-related grade 3–5 AEs during nivo monotherapy and nivo-AVD combination, objective response rates, and biomarker studies. Planned enrollment in Cohort D is 50 pts. Clinical trial information: NCT02181738.
Bevacizumab and risk of hand-foot syndrome associated with chemotherapy.
Authors: Ronald A. Flores, Mario E. Lacouture, Shenhong Wu
Journal: Journal of Clinical Oncology (2012)

e13591 Background: Hand-foot syndrome (HFS) is a dose-limiting cutaneous side effect of many chemotherapeutic agents. Its pathogenesis and risk factors have not been well understood. In this study, we propose that the inhibition of angiogenesis may contribute to the development of HFS. We investigated the risk of chemotherapy-induced HFS in patients treated with bevacizumab, an angiogenesis inhibitor that is widely used for the treatment of various cancers with a systematic review and a meta-analysis of published randomized-controlled clinical trials (RCTs). Methods: Databases from PUBMED, Cochrane Database, and abstracts presented at the American Society of Clinical Oncology until December, 2011 were searched for the identification of relevant studies. Eligible studies included prospective RCTs in which the addition of bevacizumab to chemotherapy was compared directly to chemotherapy alone in cancer patients. Relative risk (RR), and 95% confidence interval (CI) were calculated using a fixed-or random-effects model based on the heterogeneity of the included studies. Results: A total of six RCTs including 5,043 patients (bevacizumab 2665, control 2378) with a variety of tumors were analyzed. The addition of bevacizumab to chemotherapy significantly increased the risk of developing HFS with an RR of 1.68 (95% CI: 1.17-2.40, p=0.005) in comparison to chemotherapy alone. The risk of HFS significantly increased in patients receiving bevacizumab at 2.5 mg/kg/week (RR of 1.88, 95% CI: 1.39-2.54, p&lt;0.001) and at 5 mg/kg/week (RR of 1.19, 95% CI: 1.03-1.36, p=0.016); however, the increased risk of HFS did not vary significantly with bevacizumab dosage (p=0.72) and with tumor types (p=0.92). The increased risk of HFS varied with concurrent chemotherapeutic agents with a significant difference (p=0.034) between docetaxel (RR 6.94, 95% CI: 1.67-28.81) and 5-FU based agents, including capecitabine (RR 1.25, 95% CI: 1.10-1.42). Conclusions: The risk of HFS associated with chemotherapeutic agents significantly increased with the use of bevacizumab, suggesting an important role of angiogenesis in the development of HFS. Moreover, combination with docetaxel appears to confer a higher risk than 5-FU based agents.
P0383 : Combined sequential use of HAP and ART scores to predict transarterial chemoembolization failure in hepatocellular carcinoma: A multi-center comparative study
Authors: D.J. Pinato, T. Arizumi, J.W. Jang, E. Allara, P. Suppiah, C. Smirne, G. Grossi, M. Pirisi, M. Kudo, R. Sharma
Journal: Journal of Hepatology (2015)
Early closure of clinical trials: The experience of the National Cancer Institute of Canada Clinical Trials Group
Authors: W. Parulekar, J. L. Pater
Journal: Journal of Clinical Oncology (2006)

6053 Background: Phase III studies require a significant commitment on behalf of researchers and patients. Closure of a study before the originally planned number of patients have been enrolled may be due to a number of reasons such as poor accrual, information within the study that precludes continuation such as excess toxicity, an interim futility or extreme efficacy analysis or data from outside sources that render the study question obsolete. Methods: We reviewed the phase III activity of our group since inception. Reasons for early closure were classified in the following manner: accrual failure (AF), external information (EI), internal information (II). Studies were grouped by site and time period of study activation to demonstrate any trends over time. Results: 94 phase III studies led by our group were identified from our roster. Reasons for early closure are presented below. Other sites include brain with an early closure due to AF, head/neck where 1 of 3 studies closed due to AF, melanoma where 1 of 3 studies closed due to EI and sarcoma where 2 studies were successfully completed. Several of the studies that closed for accrual failure were nevertheless published either singly or as part of a meta-analysis. Conclusions: Slightly over one third of studies closed prior to achievement of the targeted sample size. Accrual failure continues to be the main cause of early study closure (27/34 or 80%) with a trend towards decreasing frequency of occurrence over time. Emerging data within or external to a study leading to study closure are important but relatively rare reasons for early closure. [Table: see text] No significant financial relationships to disclose.
Abstract 4800: Covalent Flt3-Cys828 inhibition represents a novel therapeutic approach for the treatment of Flt3-ITD and Flt3-D835 mutant acute myeloid leukemia
Authors: Matthias Versele, Burkhard Haefner, Berthold Wroblowski, Ian Stansfield, Laurence Mevellec, Ron Gilissen, Lars Neumann, Martin Augustin, Kris Jacobs, Jan Cools, S Barluenga, M Röthlingshöfer, G Karthikeyan, Ricardo Attar, Lieven Meerpoel, Nicolas Winssinger
Journal: Cancer Research (2016)

Abstract Inhibition of Flt3 kinase activity is a promising strategy for the treatment of Flt3 mutant acute myeloid leukemia (AML). However, clinical studies with Flt3 kinase inhibitors have shown that mutations of the gate keeper or an activation loop residue in the Flt3 catalytic domain limits the duration of response. Such mutations generally reduce kinase domain binding affinity and residence time of the kinase inhibitor, and consequently its efficacy. We therefore investigated whether covalent, irreversible binding to Flt3 could overcome some of the limitations of classic non-covalent Flt3 inhibitors. Here, we report for the first time on the high-affinity Cys828-covalent binding mode of a resorcylic acid lactone to the isolated Flt3 kinase domain using X-ray crystallography and kinetic binding assays. In a cellular context (Ba/F3-Flt3-ITD), mutation of Cys828 to Ala reduces potency (IC50) from low nM to microM, demonstrating all relevant Flt3 inhibition in cells critically depends on Cys828. Consistently, the molecule is a low nM inhibitor of both Flt3-ITD and Flt3D835Y in vitro and in BaF3 cells, translating to potent nM inhibition of Flt3-ITD driven AML cell line proliferation, with only microM antiproliferative activity in non-Flt3 driven AML and unrelated leukemia cell lines. Finally, in spite of its fast clearance when dosed to MV4-11 (Flt3-ITD AML) xenograft bearing mice, robust anti-tumor activity was observed using a once-daily treatment schedule. These data demonstrate the feasibility of covalent Flt3 inhibition, and suggest it represents an attractive novel therapeutic approach for the treatment of Flt3-driven AML. Citation Format: Matthias Versele, Burkhard Haefner, Berthold Wroblowski, Ian Stansfield, Laurence Mevellec, Ron Gilissen, Lars Neumann, Martin Augustin, Kris Jacobs, Jan Cools, S Barluenga, M Röthlingshöfer, G Karthikeyan, Ricardo Attar, Lieven Meerpoel, Nicolas Winssinger. Covalent Flt3-Cys828 inhibition represents a novel therapeutic approach for the treatment of Flt3-ITD and Flt3-D835 mutant acute myeloid leukemia. [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 4800.