tbuckley/cabot-search huggingface dataset:
Abstract 187: ASN0007, a potent ERK1/2 inhibitor with strong antitumor activity in multiple RAS mutant models
Authors: Sanjeeva P. Reddy, Dhanalakshmi Sivanandhan, Raghava Reddy Kethiri, Sreekala Nair, Purushottam Dewang, Mohd Zainuddin, Krishnakumar Vaithilingam, Roger A. Smith, Sandeep Gupta, Scott K. Thompson
Journal: Cancer Research (2016)

Abstract The extracellular-signal-regulated kinases, ERK1 and ERK2 (ERK1/2), play a critical role in the RAS/RAF/MEK signaling pathway which is quite frequently activated by mutations in upstream targets such as BRAF, RAS and receptor tyrosine kinases. Most of the resistance mechanisms to BRAF and MEK inhibitors ultimately lead to increase in phosphorylation of ERK1/2 suggesting the importance of this node in the RAS/RAF/MEK pathway even in the resistance setting. Therefore, inhibition of ERK1/2 offers a promising strategy to address both innate and acquired resistance to BRAF and MEK inhibitors in various solid tumors. In order to inhibit this critical node of the RAS/RAF/MEK pathway, we discovered and characterized ASN007, a novel compound that shows potent inhibition of ERK1/2 kinases in a biochemical assay with low single-digit IC50 values. In mechanistic cell-based assays, ASN007 inhibited the phosphorylation of ERK1/2 substrates such as pRSK1, FRA1 and Elk1 in various cell lines. As expected, the compound did not have any effect on the phosphorylation of ERK1/2. ASN007 showed strong anti-proliferative activity in both BRAF and RAS mutant cell lines. Importantly, when compared to other ERK1/2 inhibitors such as BVD-523 and GDC-0994, ASN007 showed potent antiproliferative activity in a much broader panel of KRAS, NRAS and HRAS mutant cell lines representing various histological tumor types. The compound also caused cell cycle arrest at the G0-G1 phase and induced apoptosis in both BRAF and RAS mutant cell lines. In a daily oral dosing regimen, ASN007 demonstrated strong inhibition of tumor growth in multiple BRAF and KRAS mutant xenograft models in mice and was well tolerated at efficacious doses. ASN007 has a good pharmacokinetic profile in pre-clinical species and does not exhibit significant inhibition of CYP enzymes or hERG channel. Based on its profile in preclinical studies, ASN007 is expected to show strong efficacy in BRAF and RAS mutant cancers. ASN007 is currently in preclinical development. Citation Format: Sanjeeva P. Reddy, Dhanalakshmi Sivanandhan, Raghava Reddy Kethiri, Sreekala Nair, Purushottam Dewang, Mohd Zainuddin, Krishnakumar Vaithilingam, Roger A. Smith, Sandeep Gupta, Scott K. Thompson. ASN0007, a potent ERK1/2 inhibitor with strong antitumor activity in multiple RAS mutant 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 187.
Abstract 4325: High-fat diet enhances and monocyte chemoattractant protein-1 deficiency reduces bone loss in mice with pulmonary metastases of Lewis lung carcinoma
Authors: Sneha Sundaram, Lin Yan
Journal: Cancer Research (2016)

Abstract Bone is adversely affected by metastasis and metastasis-associated complications. Obesity is a risk factor for both bone and cancer. Adipose tissue is an endocrine organ that produces pro-inflammatory adipokines, such as monocyte chemotactic protein-1 (MCP-1), that contribute to obesity and obesity-related diseases. This study (2×2 factorial design) investigated the effects of a high-fat diet (45% of energy from corn oil) and MCP-1 deficiency on bone micro-structural changes, analyzed by micro-computed tomography, in male C57BL/6 mice bearing lung metastases of Lewis lung carcinoma (LLC). Subcutaneous injection of LLC cells resulted in lung metastasis which was significantly enhanced by the high-fat diet and attenuated by MCP-1 deficiency. Micro-computed tomographic measurement showed significant reductions in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in right femurs and vertebrae of LLC-bearing mice compared to non-tumor-bearing controls. In LLC-bearing mice, compared to the low-fat diet (16% of energy from corn oil), the high-fat diet significantly reduced BV/TV, Tb.N and BMD in femurs but not in vertebrae. Furthermore, compared to wild-type mice, MCP-1 deficiency significantly increased BV/TV and Tb.N in both femurs and vertebrae and BMD in vertebrae in LLC-bearing mice. These results demonstrate that metastasis causes bone loss which is enhanced by the high-fat diet and attenuated by MCP-1 deficiency. Overall, it indicates that the high-fat diet and MCP-1 contribute positively to metastasis-associated bone deterioration. Citation Format: Sneha Sundaram, Lin Yan. High-fat diet enhances and monocyte chemoattractant protein-1 deficiency reduces bone loss in mice with pulmonary metastases of Lewis lung carcinoma. [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 4325.
Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain
Authors: Pouria Moshayedi, Lina R. Nih, Irene L. Llorente, Andrew R. Berg, Jessica Cinkornpumin, William E. Lowry, Tatiana Segura, S. Thomas Carmichael
Journal: Biomaterials (2016)

Stem cell therapies have shown promise in promoting recovery in stroke but have been limited by poor cell survival and differentiation. We have developed a hyaluronic acid (HA)-based self-polymerizing hydrogel that serves as a platform for adhesion of structural motifs and a depot release for growth factors to promote transplant stem cell survival and differentiation. We took an iterative approach in optimizing the complex combination of mechanical, biochemical and biological properties of an HA cell scaffold. First, we optimized stiffness for a minimal reaction of adjacent brain to the transplant. Next hydrogel crosslinkers sensitive to matrix metalloproteinases (MMP) were incorporated as they promoted vascularization. Finally, candidate adhesion motifs and growth factors were systemically changed in vitro using a design of experiment approach to optimize stem cell survival or proliferation. The optimized HA hydrogel, tested in vivo, promoted survival of encapsulated human neural progenitor cells (iPS-NPCs) after transplantation into the stroke core and differentially tuned transplanted cell fate through the promotion of glial, neuronal or immature/progenitor states. This HA hydrogel can be tracked in vivo with MRI. A hydrogel can serve as a therapeutic adjunct in a stem cell therapy through selective control of stem cell survival and differentiation in vivo.
Abstract 500: Prognostic impact of CTC detected using a novel fluidic cell microarray chip CTC detection system in patients with breast cancer
Authors: Takeshi Sawada, Jungo Araki, Toshinari Yamashita, Manami Masubuchi, Tsuneko Chiyoda, Mayu Yunokawa, Kumiko Hoshi, Shoichi Tao, Shohei Yamamura, Shouki Yatsushiro, Kaori Abe, Masatoshi Kataoka, Tatsu Shimoyama, Yoshiharu Maeda, Katsumasa Kuroi, Kenji Tamura, Tsuneo Sawazumi, Hironobu Minami, Yoshihiko Suda, Fumiaki Koizumi
Journal: Cancer Research (2016)

Abstract No current circulating tumor cell (CTC) enumeration system provides better prognostic value than CellSearch. We have developed a novel semi-automated CTC enumeration system (fluidic cell microarray chip system, FCMC) that captures CTC independently of tumor-specific markers or physical properties. This system was validated in preclinical studies and in blood samples from 20 healthy donors and 22 breast cancer patients in this study. Using spike-in samples, a statistically higher detection rate (p = 0.010) of MDA-MB-231 cells and an equivalent detection rate (p = 0.497) of MCF-7 cells were obtained with FCMC in comparison with CellSearch. The number of CTC detected in samples from patients that was above a threshold value as determined from healthy donors was evaluated. The CTC number detected using FCMC was significantly higher than that using CellSearch (p = 0.00037). CTC numbers obtained using either FCMC or CellSearch had prognostic value, as assessed by time-to-treatment-failure. The hazard ratio between CTC+ and CTC- was 4.043 in CellSearch (95% CI, 1.248 to 13.10; p = 0.01985); in contrast, it was 10.97 in FCMC (95% CI, 2.18 to 55.21; p = 0.003662). CTC detected using FCMC have the potential to be a better prognostic factor than CTC detected using CellSearch. Citation Format: Takeshi Sawada, Jungo Araki, Toshinari Yamashita, Manami Masubuchi, Tsuneko Chiyoda, Mayu Yunokawa, Kumiko Hoshi, Shoichi Tao, Shohei Yamamura, Shouki Yatsushiro, Kaori Abe, Masatoshi Kataoka, Tatsu Shimoyama, Yoshiharu Maeda, Katsumasa Kuroi, Kenji Tamura, Tsuneo Sawazumi, Hironobu Minami, Yoshihiko Suda, Fumiaki Koizumi. Prognostic impact of CTC detected using a novel fluidic cell microarray chip CTC detection system in patients with 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 500.
PTU-078 Efficacy of High and low dose Oral Vitamin D Replacement Therapy in Inflammatory Bowel Disease: Single Centre Cohort: Abstract PTU-078 Table 1
Authors: H J Hiew, M Naghibi, J Wu, J Saunders, F Cummings, T R Smith
Journal: Gut (2013)

<h3>Introduction</h3> Inflammatory bowel disease (IBD) patients are at risk of micronutrient deficiencies, including vitamin D. There is increasing evidence that vitamin D deficiency has a negative impact on disease activity. This study aims to determine the vitamin D status of a sub-set of IBD patients at a University Hospital and to evaluate the effectiveness of oral vitamin D treatment in correcting the deficiency. <h3>Methods</h3> All IBD patients with recorded serum vitamin D levels measured in 2011 were identified. Vitamin D deficiency was determined as combined vitamin D2 and D3 plasma levels lower than 52 nmol/L and treatment response was assessed up to 4–6 months after initiation of oral treatment. Oral vitamin D supplementation was classified as ‘low dose’ when patients prescribed daily 800 units of vitamin D2 or D3 and classified as ‘high dose’ when given either 100’000 units once only or 50’000 units per week for 6 weeks. <h3>Results</h3> 205 IBD patients with plasma vitamin D measurements were identified, 95 (46%) were found to be vitamin D deficient. There was no significant difference in the prevalence of vitamin D deficiency between the Crohn’s disease (CD) and ulcerative colitis (UC) patients, 44% vs 50%, (p = 0.449). 50/95 (52.6%) patients received treatment and 32 treatment episodes had follow up vitamin D status measurement within 4–6 months. Those who received ‘high dose’ oral vitamin D demonstrated an increase in vitamin D levels of 150% after treatment compared to an increase of 34% in those put on ‘low dose’ vitamin D supplement (p = 0.001). There was no significant difference in treatment response between CD and UC (p = 0.874) (see table 1). <h3>Conclusion</h3> There were no differences in plasma vitamin D concentrations between patients with CD and UC. Oral vitamin D replacement is an effective treatment for vitamin D deficiency in IBD patients and appears to be dose responsive; irrespective of whether patient have UC or CD (including small bowel disease). The optimal dose of oral vitamin D supplementation is yet to be determined, but higher doses are significantly more effective. <h3>Disclosure of Interest</h3> None Declared
Aortic Calcification and Superior-Mesenteric-Artery Stenosis
Authors: Yoko Ito, Akihiko Nogami
Journal: New England Journal of Medicine (2016)

A 62-year-old man with a history of hemodialysis and continuous ambulatory peritoneal dialysis presented with abdominal pain and refractory ileus. Imaging revealed calcification of the wall of the abdominal aorta, with near-total occlusion and stenosis of the superior mesenteric artery.
Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1
Authors: Raymond D. Hickey, Shennen A. Mao, Jaime Glorioso, Faysal Elgilani, Bruce Amiot, Harvey Chen, Piero Rinaldo, Ronald Marler, Huailei Jiang, Timothy R. DeGrado, Lukkana Suksanpaisan, Michael K. O’Connor, Brittany L. Freeman, Samar H. Ibrahim, Kah Whye Peng, Cary O. Harding, Chak-Sum Ho, Markus Grompe, Yasuhiro Ikeda, Joseph B. Lillegard, Stephen J. Russell, Scott L. Nyberg
Journal: Science Translational Medicine (2016)

Transplantation of gene-corrected autologous hepatocytes can cure metabolic disease in a preclinical pig model of hereditary tyrosinemia type 1.
Simulation of phase III studies of motesanib 125 mg once daily (QD) plus carboplatin/paclitaxel (CPM) or bevacizumab plus carboplatin/paclitaxel (CPB) versus carboplatin/paclitaxel (CP) in first-line non-small cell lung cancer (NSCLC) using a public domain drug–disease modeling framework and phase II data.
Authors: L. Claret, J. Lu, R. Bruno, R. S. Sikorski, Y. Hei, Y. Sun
Journal: Journal of Clinical Oncology (2010)

e18089 Background: Motesanib is an orally administered small-molecule antagonist of VEGF receptors (1, 2, and 3), PDGF, and c-kit receptors with antiangiogenic and direct antitumor activity. A drug-disease model developed by the US Food and Drug Administration (FDA) (Clin Pharmacol Ther. 86:167-174, 2009) was used to simulate survival in phase III studies of CPM or CPB vs CP using data from a phase II study of first-line CPM or CPB in NSCLC (J Thorac Oncol. 4[9 suppl 1]:S354-5, 2009). Methods: Patients were randomized in a 1:1:1 ratio to receive up to six 3-week cycles of CP plus either motesanib 125 mg QD (Arm A), motesanib 75 mg twice daily 5 days on/2 days off (Arm B), or bevacizumab 15 mg/kg by intravenous infusion once every 3 weeks (Arm C). The modeling framework comprised a longitudinal tumor size model and a survival model relating change in tumor size at first visit (week 8) and patient characteristics (baseline tumor size and ECOG performance status) to survival time. The models were used to simulate multiple replicates (n = 5,000) of 700-patient studies of CPM or CPB vs CP with a design similar to an ongoing phase 3 study of CPM vs CP for patients with similar characteristics to patients in the phase 2 study (n = 177). Results: Predicted median survival was 11.0 months (95% CI, 9.8–12.3 months), 10.8 months (95% CI, 9.7–12.1 months) and 9.3 months (95% CI, 7.6–11.1 months) for the CPM, CPB, and CP arms, respectively. Hazard ratios for CPM (0.87; 95% CI, 0.71–1.1) and CPB (0.89; 95% CI, 0.73–1.1) relative to CP were similar. The CPB results were consistent with the hazard ratio determined through similar simulations of the E4599 study (N Engl J Med. 355:2542-2550, 2006) performed by the FDA (0.88; 95% CI, 0.78–1.01). Conclusions: Simulations based on this NSCLC disease model predict that first-line CPM and CPB may have similar survival benefits versus CP alone: an approximately 1.7 month increase in median overall survival. The modeling framework is a useful tool for end-of-phase-II decisions and the design of phase III studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Pharsight Amgen Amgen
Clinical Criteria to Identify Patients With Sepsis
Authors: Martin Gerdin, Tim Baker
Journal: JAMA (2016)

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Abstract 3222: Preclinical development of a humanized blocking antibody targeting the CD39 immune checkpoint for cancer immunotherapy
Authors: Severine Augier, Ivan Perrot, Cecile Dejou, Rachel Joly, Stephane Delahaye, Helene Rispaud Blanc, Caroline Denis, Laurent Gauthier, Armand Bensussan, Jean-francois Eliaou, Yannis Morel, Nathalie Bonnefoy, Jeremy Bastid, Carine Paturel
Journal: Cancer Research (2016)

Abstract CD39 (ENTPD1) is a cell membrane ectonucleotidase that hydrolyzes extracellular immunoactivating ATP and ADP into AMP, which can be further hydrolyzed by ectonucleotidase CD73 into immunosuppressive adenosine. Within the tumor microenvironment, adenosine accumulation causes immune suppression and dysregulation of immune cell infiltrates resulting in tumor spreading. The role of CD39 expression on both Tregs and on tumor cells in promoting immunosuppression has been demonstrated in several reports. Blockade of CD39 may promote anti-tumor immunity by directly accumulating immunostimulating ATP and indirectly by reducing adenosine accumulation. Here, we describe the discovery and preclinical development of an anti-huCD39 blocking antibody for cancer immunotherapy. Parental anti-huCD39 mouse monoclonal antibody was humanized. The humanized mAb specifically binds huCD39 protein, but not CD39-like proteins. Nanomolar affinities for human CD39 were measured in SPR studies on recombinant CD39 protein and in flow cytometry titration studies on CD39 expressing transfectants and tumor cell lines. The humanized mAb blocked human CD39 ATPase activity in vitro in the nanomolar range, as demonstrated using transfected cells, CD39-expressing tumor cell lines, as well as human PBMC and ex-vivo isolated fresh tumor samples. The humanized mAb cross-reacted on cynomolgus CD39 and blocked ATPase activity on cynomolgus PBMC with similar efficacy as on human PBMC. Finally, treatment with blocking anti-CD39 mAb inhibited tumor growth in vivo in mouse tumor models. Taken together, these data support the clinical development of anti-CD39 neutralizing mAb for cancer immunotherapy. Citation Format: Severine Augier, Ivan Perrot, Cecile Dejou, Rachel Joly, Stephane Delahaye, Helene Rispaud Blanc, Caroline Denis, Laurent Gauthier, Armand Bensussan, Jean-francois Eliaou, Yannis Morel, Nathalie Bonnefoy, Jeremy Bastid, Carine Paturel. Preclinical development of a humanized blocking antibody targeting the CD39 immune checkpoint for cancer immunotherapy. [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 3222.
Study in Asia of the combination of transcatheter arterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma (HCC) trial (START): Second interim safety and efficacy analysis.
Authors: Y. Chung, B. Kim, C. Chen, J. Wang, H. CHU, J. Yoon, K. Seetalarom, S. Bae, Y. Chao, C. Li, T. Lee
Journal: Journal of Clinical Oncology (2010)

4026 Background: We report the second interim analysis of START. Methods: START is a phase II, multicenter, open-label, single-arm study being conducted in Asia Pacific. Patients with unresectable, intermediate-stage HCC (BCLC B), and who are candidates for TACE are eligible. Patients receive TACE with lipiodol and doxorubicin (30-60 mg), followed by embolization with absorbable particles. Sorafenib 400mg bid is given continuously, with dose interruptions 4 days before and after TACE, which is performed every 6-8 weeks. Tumor response is assessed every 4 weeks after every TACE. Patients continue sorafenib until disease progression or unacceptable toxicity, even after stopping TACE due to complete response (CR) or inability to continue to receive TACE. The primary endpoint is safety/tolerability. Secondary endpoints include progression-free survival, time to progression, overall survival, and number of TACE cycles. Results: 63 patients were evaluable for safety, and 50 for efficacy. For analysis of efficacy, patients had to have at least 2 CT scans performed. Mean age was 58.7 years (range, 35-78 years). No patients received previous systemic treatment for HCC. Etiologies for HCC included hepatitis B (77.8%), hepatitis C (11.1%), and alcohol-related liver disease (3.2%). Child-Pugh status was A in 94% of patients. Median duration of follow-up was 137 days (range, 15-278 days). Grade 3 adverse events (AEs) occurred in 38 patients (60%), the most common of which were hand-foot skin reaction (15.8%), ALT elevation (12.7%), and leucopenia (12.7%). There was one grade 4 AE (AST elevation). All AEs improved with dose modification of sorafenib. No patients discontinued due to AEs. Of the 50 patients evaluable for efficacy, 20 (40%) did not require > 2 TACE procedures; of these, 18 achieved a CR and 2 had progressive disease. The remaining 30 patients had a partial response or stable disease. Conclusions: Preliminary data show that the combination of TACE and sorafenib is safe and tolerable. This study will continue as planned, as further evaluation of the combination is needed. Expected accrual is 200 patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer, Bayer Schering Pharma