tbuckley/cabot-search huggingface dataset:
Abstract LB-062: Evaluation of drug conjugation sites in an anti-EGFR Centyrin
Authors: Rosa Cardoso, Shalom Goldberg, Tricia Lin, Tracy Spinka-Doms, Donna Klein, Steven Jacobs, Gary Gilliland, Karyn O’Neil
Journal: Cancer Research (2016)

Abstract Centyrins are engineered alternative scaffold proteins that combine the affinity and specificity of antibodies with increased tissue penetration and simplified manufacturing. To identify optimal positions for chemical conjugation within the Centyrin scaffold, the crystal structure of an anti-EGFR Centyrin was solved and a library consisting of all possible single-cysteine variants was constructed and assessed for expression level in E. coli, efficiency of conjugation to maleimide derivatives, protein aggregation, thermostability, and EGFR binding. The best variants were conjugated to cytotoxic drugs and compared in a cell-killing assay. Three optimal positions were identified at which the Centyrin conjugated efficiently to maleimides; retained high expression, antigen binding, and biophysical properties; and showed increased cell-killing potency relative to the parent molecule. Citation Format: Rosa Cardoso, Shalom Goldberg, Tricia Lin, Tracy Spinka-Doms, Donna Klein, Steven Jacobs, Gary Gilliland, Karyn O’Neil. Evaluation of drug conjugation sites in an anti-EGFR Centyrin. [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-062.
Abstract 3390: CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors
Authors: Seongyea Jo, Jaemin Lee, jinhoi song.
Journal: Cancer Research (2016)

Abstract CTHRC1 (collagen triple helix repeat-containing 1), a protein secreted during the tissue repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 plays an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here, we demonstrate a novel role of CTHRC1 as a potent endothelial activator, promoting angiogenesis by recruiting bone marrow-derived cells into the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, consistent with observed increases in neovascularization in vivo. Moreover, rCTHRC1 induced upregulation of angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody abrogated Ang-2 expression in ECs in vitro. Moreover, CTHRC1-neutralizing antibody treatment in a xenograft mouse model reduced tumor burden and infiltration of TEMs in tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the conclusion that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers. Citation Format: Seongyea Jo, Jaemin Lee, jinhoi song. CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors. [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 3390.
Effect of therapeutic targeting of EMP2 on breast and endometrial cancer stem cells.
Authors: Madhuri Wadehra, Meagan Kiyohara, Negin Ashki, Ann Chan
Journal: Journal of Clinical Oncology (2013)

3080 Background: There is increasing evidence that tumor-initiating cancer stem cells (CSCs) contribute to tumor metastasis and therapeutic resistance. In breast and endometrial cancers, metastatic CSCs are defined as CD44+/CD24- and ALDH+, and in this study, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple-negative breast, ovarian, and endometrial tumors. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels alter the number and expression of CSC markers. To translate this work, EMP2 and ALDH expression were correlated in primary human endometrial and breast cancers. To determine the therapeutic efficacy of our fully-human EMP2 IgG1 antibody, xenografts from breast or uterine cancer were treated, removed, and then reinjected into secondary mice. Results: In this study, we show new evidence that EMP2 is highly expressed in CSCs. High levels of EMP2 increase the tumor forming potential of both endometrial and breast cancer lines. In tumors created from these cells, high levels of ALDH+ expression were also observed. In contrast, reduction in EMP2 decreased CD44 expression and ALDH activity both in vitro and in vivo, with the net consequence of poorly vascularized and slow growing tumors. We have recently developed a novel monoclonal antibody to EMP2 and have started testing its therapeutic efficacy. In vitro treatment with EMP2 IgG1 reduced HIF-1a, CD44, and ALDH levels, ultimately leading to caspase mediated apoptosis. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load in both subcutaneous and metastatic models of breast and endometrial cancer resulting in a significant improvement in survival. Reinjection of these cells post treatment into secondary mice failed to efficiently form, and histological examination of the tumors revealed significant necrosis and elimination of ALDH+ CSCs. Conclusions: These results suggest that targeting EMP2 may reduce CSCs and represent an attractive target for further therapeutic development.
Abstract 4255: EpCAM positive lung cells are involved in organoid formation
Authors: Takashi Semba, Ryo Sato, Makoto Suzuki, Hideyuki Saya, Yoshimi Arima
Journal: Cancer Research (2016)

Abstract A combination of fluorescence activated cell sorting (FACS) and 3D culture techniques enable us to isolate specific lung cells and to form organoids, which recapitulate organ architectures in vitro. To clarify the cells of origin in the formation of lung organoids and to apply for oncogene-mediated transformation, we conducted spheroid culture and 3D culture experiments using mice lung cells. We isolated the CD31-/CD45- cells from the lungs of wild-type (wt) or Ink4a/Arf-knockout (Ink4a/Arf-/-) C57BL/6 mice. The single cells were then cultured in serum-free medium in a low-attachment dish for 7 days to form spheres. The spheres were dissociated into single cells again, and were then infected with retroviruses expressing KRASG12V, EML4-ALK, EZR-ROS1 (Arai et al., PLoS ONE 2013), or KIF5B-RET (Saito et al., Carcinogenesis 2014) genes, which were identified as oncogenes in human lung adenocarcinomas. Those oncogene-expressing sphere-derived cells from wt and Ink4a/Arf-/- lung cells neither expressed EpCAM (the epithelial marker) nor TTF-1 (the lung lineage marker). We found that those cells formed undifferentiated invasive lethal tumors in lung lobes when the cells were inoculated into the lungs of mice via the trachea, after bleomycin treatment. We then isolated the EpCAM+/CD45-/CD31- lung cells from wt or the Ink4a/Arf-/- C57BL/6 mice and these cells were subjected to a 3D culture. Those cells were suspended in a serum-free medium with keratinocyte growth factor, and the 1×104 cells were seeded on a 24 well 0.4μm insert pre-coated with growth factor-reduced Matrigel. After 2 weeks, the cells formed morphologically distinct phenotypes of colonies, such as cystic colonies, dense sphere colonies, and branched colonies. A histopathological study revealed that the EpCAM-positive colonies were composed of TTF-1-positive cells, and included differentiated lung cell markers, SP-C, Aquaporin 5, and CC-10. Interestingly, the EpCAM-/CD45-/CD31- cells from the lungs of the Ink4a/Arf-/- mice did not form organoids under 3D culture conditions. Our data indicates that the EpCAM-positive normal mice lung cells, but not the EpCAM-negative cells, formed lung organoids including TTF-1-positive cells in a 3D culture. Inoculation of EpCAM+/CD45-/CD31- lung cells expressed oncogenes into the lungs of mice might allow us to develop a well-differentiated lung adenocarcinoma model. Citation Format: Takashi Semba, Ryo Sato, Makoto Suzuki, Hideyuki Saya, Yoshimi Arima. EpCAM positive lung cells are involved in organoid formation. [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 4255.
Surgery in Severe Rheumatic Mitral Valve Disease : Recognition of Severity and Risk Factors : Medical and Surgical Aspects of Treatment of "High Risk" Cardiovascular Diseases
Authors: Sanae Takahashi, Masatoshi Kawana, Koshichiro Hirosawa
Journal: Circulation (1983)

The postoperative course of 294 patients with rheumatic mitral valve disease, who underwent mitral valve surgery during a period form July, 1978 to June, 1981, was studied by comparing the influences of the following clinical parameters: a low left ventricular ejection fraction (LVEF), a high pulmonary arterial systolic pressure (PASP), a high pulmonary vascular resistance (PVR), tricuspid regurgitation (TR), a high right ventricular end-diastolic pressure (RVEDP) and a giant left atrium (GLA). The patients with a functional capacity of class II or IV according to the New York Heart Association were classified into 3 groups (improved, unimproved and died), and from this data we calculated the improvement ratio and the mortality rate. The improvement ratios were 73% in patients with a low LVEF, 70% with a high RASP, 78% with a high PVR, 66% with TR, 11% with a high RVEDP and 77% with a GLA; the mortality rates were 19, 14, 17, 24, 78 and 19%, respectively. As compared with the case of deteriorated left ventricular performance and pulmonary hypertension, deteriorated right ventricular performance, especially high RVEDP, was accompanied by a comparatively poorer surgical prognosis. It is concluded that mitral valve surgery should be performed during the period in which the right ventricular function is still preserved.
Abstract 3389: Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts
Authors: Kwanghee Kim, Philip A. Watson, Sylvia Jebiwott, Alexander J. Somma, Stephen P. La Rosa, Dipti Mehta, Katie S. Murray, Hans Lilja, David Ulmert, Avigdor Scherz, Jonathan Coleman
Journal: Cancer Research (2016)

Abstract Focal therapies for prostate cancer offer the possibility of less side effects than more aggressive interventions for organ-confined tumors. Vascular targeted photodynamic therapy (VTP) is being investigated in phase II and phase III clinical trials, and relies upon rapid, free radical-mediated destruction of tumor vasculature following photoactivation of a systemic prodrug. In a phase II trial, &amp;gt;80% of patients did not have detectable cancer in prostate biopsies taken 6 months after VTP treatment. Although these early results are encouraging, VTP efficacy could potentially be improved upon by combining with other therapies. Using the LNCaP-AR prostate cancer model system, we employed microarrays and Gene Set Enrichment Analysis (GSEA) to identify potential druggable pathways active in tumors exposed to VTP. Three to six hours post-VTP, androgen responsive gene sets were enriched, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using the AR pathway inhibitors degarelix (to achieve pharmacological castration) or enzalutamide (AR antagonist), alone or in combination with VTP. Degarelix was administered as a single 0.5-1 mg dose 3 days prior to initiation of VTP, while enzalutamide was given daily for two weeks total both before and after VTP. Serum measurements of prostate specific antigen (PSA) were used as a readout of AR activity. Compared to either AR pathway inhibitor or VTP used alone, degarelix or enzalutamide in combination with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition. Combined degarelix plus VTP treated tumors displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. In prostate cancer treated with VTP, compensatory acute upregulation of pro-survival AR signaling may occur. These findings may warrant investigation of combination with androgen deprivation therapy in future clinical trials utilizing VTP for prostate cancer. Citation Format: Kwanghee Kim, Philip A. Watson, Sylvia Jebiwott, Alexander J. Somma, Stephen P. La Rosa, Dipti Mehta, Katie S. Murray, Hans Lilja, David Ulmert, Avigdor Scherz, Jonathan Coleman. Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts. [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 3389.
Nilotinib Following Molecular Suboptimal Response (SoR) To Imatinib In Japanese Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): 12 Month Follow-Up From The SENSOR Study
Authors: Koichi Miyamura, Toshihiro Miyamoto, Mineo Kurokawa, Mitsune Tanimoto, Kazuhito Yamamoto, Masafumi Taniwaki, Shinya Kimura, Kazuma Ohyashiki, Tatsuya Kawaguchi, Itaru Matsumura, Tomoko Hata, Hisashi Tsurumi, Shigeki Saito, Masayuki Hino, Seiji Tadokoro, Kuniaki Meguro, Hideo Hyodo, Masahide Yamamoto, Kohmei Kubo, Junichi Tsukada, Midori Kondo, Taro Amagasaki, Eiji Kawahara, Masamitsu Yanada
Journal: Blood (2013)
Metabolomics analysis of non-muscle invasive and muscle-invasive bladder cancer.
Authors: Divya Sahu, Yair Lotan, Bryan Wittman, Bruce Neri, Donna E. Hansel
Journal: Journal of Clinical Oncology (2016)

362 Background: Bladder cancer accounts for greater than 70,000 new cancer cases in the United States annually and an annual global incidence of more than 400,000 patients. Despite its high incidence, therapeutic options are limited both in early and late stage cancers and there is need for alternative, rational therapies in this population. Methods: We extensively analyzed benign urothelium, high-grade non-muscle invasive bladder cancer and advanced, muscle-invasive bladder cancer using global metabolomics profiling, coupled with publicly available data on transcriptomics of key enzymes, to determine pathways that may be suitable for future therapeutics development. Results: Categorical pathways globally dysregulated in cancer relative to benign urothelium included glucose, TCA cycle, lipid, amino acid and nucleotide pathways. Bladder cancers demonstrated Warburg metabolism, with elevated glucose utilization to drive glycolysis and sorbitol pathway intermediates. Elevated late TCA cycle intermediates, coupled with higher levels of amino acids and dipeptides, suggest the possibility of anaplerotic activity in bladder cancer as a mechanism to sustain energy production. Medium and long chain fatty acids were produced at the expense of dicarboxylic fatty acids. Muscle-invasive bladder cancers showed enhanced use of COX and LOX metabolomics pathways and a possible role for inflammation in regulating NAD+ synthesis in muscle-invasive bladder cancer. Transcriptomic profiling validated that the majority of metabolomics pathway alterations corresponded to gene expression changes of enzymes responsible for metabolite production. Conclusions: This study identifies multiple parallel metabolomics changes unique to non-muscle invasive and muscle-invasive bladder cancer that can be used to justify testing novel therapeutics targeting metabolomics pathways in bladder cancer.
A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma
Authors: Karen L. Reckamp, Vladislava O. Melnikova, Chris Karlovich, Lecia V. Sequist, D. Ross Camidge, Heather Wakelee, Maurice Perol, Geoffrey R. Oxnard, Karena Kosco, Peter Croucher, Errin Samuelsz, Cecile Rose Vibat, Shiloh Guerrero, Jennifer Geis, David Berz, Elaina Mann, Shannon Matheny, Lindsey Rolfe, Mitch Raponi, Mark G. Erlander, Shirish Gadgeel
Journal: Journal of Thoracic Oncology (2016)

In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible.Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC.Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with rociletinib, a rapid decrease in urine T790M levels was observed by day 21.DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.
A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans
Authors: Devin Sok, Matthias Pauthner, Bryan Briney, Jeong Hyun Lee, Karen L. Saye-Francisco, Jessica Hsueh, Alejandra Ramos, Khoa M. Le, Meaghan Jones, Joseph G. Jardine, Raiza Bastidas, Anita Sarkar, Chi-Hui Liang, Sachin S. Shivatare, Chung-Yi Wu, William R. Schief, Chi-Huey Wong, Ian A. Wilson, Andrew B. Ward, Jiang Zhu, Pascal Poignard, Dennis R. Burton
Journal: Immunity (2016)
Incidence of febrile neutropenia with adjuvant docetaxel and cyclophosphamide in patients with early breast cancer.
Authors: F. D. S. Marinho, M. d. S. d. S. Lopes, M. M. F. Monteiro, M. Gifoni
Journal: Journal of Clinical Oncology (2011)

e11501 Background: Adjuvant therapy is a major reason for the improved survival in patients with early breast cancer. The improvement in disease-free survival and overall survival with adjuvant chemotherapy protocol docetaxel and cyclophosphamide (TC) over doxorubicin and cyclophosphamide (AC) was recently reported, with acceptable toxicity profile.This regime has become quite popular, particularly in patients with lymph node negative breast cancer, older and/or with increased risk for cardiotoxicity. Methods: We performed a retrospective cohort of all patients who received adjuvant TC in the Cancer Institute of Ceará, between June 2007 and July 2010. A control group of 46 patients using AC with a similar population was evaluated in an attempt to rule out possible factors in the population for the increased incidence of febrile neutropenia. The primary objective was to compare the rate of febrile neutropenia. We did univariate and multivariate analysis to assess the possible risk factors for the development of this adverse event, using the chi-square and logistic regression. Results: Forty-five patients were treated with TC. The median age was 54 years. Clinical stages I and II comprised the majority of patients (95.5%) and average size of tumors was 1.7 cm. Only 6.7% of patients had positive lymph node. Comorbidities were present in 28.8% of patients. Febrile neutropenia was observed in 28.9% among the patients evaluated. Seven patients were on primary prophylaxis and when these were excluded from the analysis of adverse event, the rate of febrile neutropenia was 31.6%. Among patients over 65 years and with a comorbidity that rate was 40%. There were no deaths related to neutropenia. Among the patients who received AC as adjuvant treatment 10.8% required hospitalization for febrile neutropenia. There was a statistically significant difference in rates of febrile neutropenia, when the two treatment protocols were compared (p = 0.03). Conclusions: The rate of febrile neutropenia was different, contrasting with the toxicity profile reported in the current literature. It is necessary the use of primary preventive measures such as the G-CSF to prevent hospitalization and dose reductions.
Abstract 145: Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma
Authors: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Yutaka Takazawa, Tetsuo Noda
Journal: Cancer Research (2016)

Abstract Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits poor prognosis (5-year survival rates: uterus and ovary; 31 and 7.5%, respectively). Treatment regimen for CS follows to that for endometrioid adenocarcinoma (EC) since CS has been considered as an aggressive form of high-grade EC. However, CS has a significantly worse prognosis than EC. Identification of a molecular target and/or a molecular mechanism in tumorigenesis from a large cohort study may improve unfavorable outcomes. Toward this aim, we perform targeted resequencing analysis with a panel of 596 genes, which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics. Through analyses of 84 cases of uterine and ovarian CS, consensus clustering with deregulated pattern of CS genome identified four genomic subtypes that correlate with genetic or epigenetic alterations, histopathology and patient outcomes. Moreover, potentially actionable alterations were found in a substantial number of genes (including PIK3CA, MTOR, KRAS and CCNE1). This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients. Citation Format: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Yutaka Takazawa, Tetsuo Noda. Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma. [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 145.