tbuckley/cabot-search huggingface dataset:
Abstract 2875: Genes associated with neuronal development, including splicing regulatory factors, increase in expression across epithelial-mesenchymal transition
Authors: Yevgenia L. Khodor, Daisy Riquelme, Frank Gertler, Christopher B. Burge
Journal: Cancer Research (2016)

Abstract The program by which epithelial cells lose their polarity and close contacts with neighboring cells and acquire migratory and invasive properties is known as epithelial-mesenchymal transition (EMT). Initially identified as a critical developmental process, EMT is now understood to occur during cancer, where it has been shown to confer resistance to senescence and apoptosis. Previous work indicates that cancer cells that escape the site of the primary tumor hijack at least a portion of the EMT program to increase their invasive properties and metastasize. Earlier work in the field has focused on cell signaling and transcriptional regulation changes that lead to EMT, but changes in the gene expression and post-transcriptional regulation of the cell have only recently become the focus of study. We characterized gene expression and splicing across EMT in the luminal epithelial MCF7ras SLUG+SOX9 breast cancer cell line by collecting samples at 2-day intervals across its 6-day transition and profiling the RNA by RNA-seq. We found over 4,000 significantly changing genes, and that the majority of gene expression and splicing changes occurred in the first two days of the transition, with few changes noted between days 4 and 6. Genes that changed could be broadly categorized into those whose expression decreased, increased, or peaked in the middle of the transition before decreasing. Intriguingly, genes whose expression increased during EMT were enriched for gene ontology terms related to cell signaling and neuronal development. We specifically observed increased expression of mRNAs encoding splicing factors and other RNA-binding proteins (RBPs) associated with neuronal development, in contrast to the majority of RBPs whose expression decreases in EMT. We are currently exploring various aspects of this program, including effects of increased expression of the neuronal-associated splicing regulatory factor quaking (QKI). These may include downregulation of the Notch pathway via effects on splicing of NUMB, a Notch inhibitor. We are currently validating the role of QKI on this and other RNA processing changes and will report our findings. Citation Format: Yevgenia L. Khodor, Daisy Riquelme, Frank Gertler, Christopher B. Burge. Genes associated with neuronal development, including splicing regulatory factors, increase in expression across epithelial-mesenchymal transition. [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 2875.
Additive therapeutic effect of a non-lytic retroviral replicating vector (Toca 511) and 5-fluorocytosine in combination with lomustine in experimental glioma models.
Authors: Joan M. Robbins, Tiffany T. Huang, Kader Yagiz, Fernando Lopez Espinoza, Bryan Martin, Maria Rodriguez-Aguirre, Carlos E. Ibanez, Harry E. Gruber, Douglas J. Jolly
Journal: Journal of Clinical Oncology (2015)

e13033 Background: We are conducting ascending dose trials in subjects with High Grade Glioma (HGG, NCT01156584, NCT01470794, NCT01985256), using an investigational retroviral replicating vector (Toca 511, vocimagene amiretrorepvec) in combination with Toca-FC (oral extended release 5-fluorocytosine). Toca 511 encodes an optimized yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil in infected tumors. Preclinical models provide support for a dual mechanism of action of Toca 511&5-FC that includes both direct killing of tumor by locally produced 5-fluorouracil, and induction of a local and systemic immunotherapeutic response resulting in long term survival after cessation of 5-FC treatment, and resistance to tumor re-challenge. Lomustine, an alkylating agent, is currently approved for the treatment of malignant brain tumors. To assess the safety and therapeutic potential of Toca 511&5-FC with lomustine, studies were performed in syngeneic, orthotopic glioma models. Methods: Fischer rats with F98 glioma and B6C3F1 mice with Tu2449 glioma were used to evaluate the effect of addition of lomustine on the efficacy of Toca 511&5-FC treatment and its immunological impact. Results: There were no safety related findings in animals treated with Toca 511&5-FC. Animals treated with lomustine alone or in combination with Toca 511&5-FC had transient weight loss and transient hematologic effects. In both models, animals that received Toca 511&5-FC or Toca 511&5-FC with lomustine had statistically prolonged survival compared to controls (Toca 511&PBS or 5-FC&lomustine, p < 0.05). 80% of mice that received Toca 511&5-FC with lomustine were alive > 70 days after tumor implantation compared to 60% that received Toca 511&5-FC alone (median survival not defined, not statistically significant). Rats that received Toca 511&5-FC with lomustine had statistically prolonged survival compared to Toca 511&5-FC alone (median survival 70 and 48 days respectively, p = 0.02). Conclusions: These results provide support for the investigation of Toca 511 & 5-FC in combination with lomustine in patients with HGG.
Abstract 1219: Sym015, a novel antibody mixture targeting non-overlapping epitopes of MET, effectively inhibits growth of MET dependent tumors and overcomes resistance to a single monoclonal antibody
Authors: Thomas T. Poulsen, Michael M. Grandal, Helle J. Jacobsen, Dorte S. Hansen, Trine Lindsted, Mikkel W. Pedersen, Ivan D. Horak, Michael Kragh, Johan Lantto
Journal: Cancer Research (2016)

Abstract The tyrosine kinase receptor MET is involved in progression of a variety of human cancers and constitutes a promising therapeutic target. Particularly, subsets of tumors originating from lung or gastric tissues appear to be truly MET dependent. MET dependency is driven by alterations, such as MET-gene amplification, MET-exon 14 deletion, kinase activating mutations, or autocrine HGF production. Furthermore, MET-amplification has been reported as a key mechanism of de novo resistance to EGFR targeting agents in lung and colorectal cancers. Sym015, a novel antibody mixture comprising two monoclonal antibodies targeting non-overlapping epitopes on the SEMA domain of MET, was shown to effectively inhibit cell growth in vitro through effective MET degradation. In the present study, we screened a large panel of highly annotated human cancer cell lines for sensitivity to Sym015 in order to identify potential markers of response. Sym015 effectively inhibited growth of cell lines with MET-amplification, MET-exon 14 deletion, and autocrine HGF production, including MET-amplified cell lines with acquired resistance to EGFR targeting agents. To validate the in vitro findings, a range of cell line- and patient-derived xenograft models with MET amplification or Exon 14 deletion were tested for sensitivity to Sym015 and an analogue of the clinical stage anti-MET monoclonal antibody emibetuzumab (LY2875358). Sym015 effectively inhibited growth of tumors with autocrine HGF production, MET-amplification, and/or Exon 14 deletion, and had superior activity compared to the emibetuzumab analogue in many of the models. Importantly, tumors with a partial response to the emibetuzumab analogue were strongly inhibited by subsequent treatment with Sym015 in two MET-amplified models, one of which also harbors a MET-exon 14 deletion. In summary, our findings demonstrate a potent antitumor effect of Sym015 in MET-dependent models. The data thus strongly support initiation of clinical trials for patients with MET-amplification and Exon 14 deletions. Citation Format: Thomas T. Poulsen, Michael M. Grandal, Helle J. Jacobsen, Dorte S. Hansen, Trine Lindsted, Mikkel W. Pedersen, Ivan D. Horak, Michael Kragh, Johan Lantto. Sym015, a novel antibody mixture targeting non-overlapping epitopes of MET, effectively inhibits growth of MET dependent tumors and overcomes resistance to a single monoclonal antibody. [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 1219.
Chromosomal imbalances as biomarkers for recurrence and antiangiogenic resistance in clear cell renal cell carcinoma.
Authors: F. A. Monzon, K. Alvarez, R. J. Amato, L. Peterson, S. S. Shen, J. Hernandez-McClain, K. Sircar, P. Tamboli, N. M. Tannir, E. Jonasch
Journal: Journal of Clinical Oncology (2010)

e15012 Background: A key dilemma in the management of clear cell renal cell carcinoma (ccRCC) is the lack of reliable biomarkers for recurrence, prognosis, and prediction of resistance to anti-angiogenic therapy. Chromosome copy number alterations (CCNAs) by conventional cytogenetics have been shown to be associated with outcomes. In this study, the goal was to determine whether CCNAs identified with SNP arrays could be used as prognostic biomarkers for recurrence and predictors of antiangiogenic therapy response in ccRCC. Methods: We obtained archival formalin fixed paraffin embedded (FFPE) tumor samples from 32 patients with organ confined ccRCC, and 56 patients with metastatic ccRCC treated with sorafenib (after tumor removal, n=23) or bevacizumab (neoadjuvant treatment, n=33). DNA from the FFPE tissue sections was analyzed with Affymetrix 250K Nsp SNP microarrays to identify genomic CCNAs. Marker associations with tumor recurrence were evaluated using the Fisher's exact test. Logistic regression was used to evaluate the association between markers and response. Results: In the organ confined cohort, 14q loss showed a significant association with tumor recurrence (log rank P= 0.017), and a 3-locus model (gains of 1q or 12p or loss of 14q) showed a stronger association with recurrence (P= 0.0014). Gain of 5q was strongly associated with longer progression free survival (PFS) in both sorafenib and bevacizumab treated cohorts (HR = 0.25, 95% CI 0.08 to 0.81, P = 0.021 and HR = 0.82 95% CI 0.65- 1, P < 0.0001 respectively). In the bevacizumab cohort, 14q loss showed a significant association with worse response to treatment (CR or PR vs SD or PD, Fisher exact test, P = 0.0473). There was a nonsignificant trend toward a higher hazard of progression among patients who had loss of 9p or loss of 14q in the sorafenib cohort. Conclusions: Our results show that whole genome analysis with virtual karyotyping identifies genetic alterations associated with outcomes in ccRCC. These data suggest that genomic analysis of renal tumors with SNP arrays provides important prognostic information and may lead to a mechanistic understanding of progression and resistance to antiangiogenic therapy of ccRCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer/Onyx, Genentech, iKaryos Diagnostics iKaryos Diagnostics Bayer/Onyx Genentech
Correlation between Oncotype Dx score with histologic grade, tumor size and Ki67 in patients with early stage breast cancer: A single academic institution experience.
Authors: Kate Ida Lathrop, Marcela Mazo- Canola, Jonathan Gelfond, Barbara Hinojosa, Jay C Shiao, Katherine A Terracina
Journal: Journal of Clinical Oncology (2015)

146 Background: Oncotype DX is an RT-PCR based assay that calculates a recurrence score (RS) to predict chemotherapy benefit in patients with breast cancer. Some authors have proposed using Ki-67, receptor status, Nottingham grade, and tumor size as histo-pathologic variables that could potentially substitute for the RS. Comprehensive and larger reviews are still lacking in this filed. To our knowledge this is the largest retrospective review of cases in a single academic institution. Methods: We retrospectively reviewed and reported baseline patient demographic characteristics (including age, race and gender) and routine pathological features such as histologic grade, Ki-67, tumor size, and histologic type. All patients included in this study had an Oncotype Dx ordered between 2007 and 2014. Results: Our analysis included 252 patients of which 248 were females and 4 were males, median age was 56, median tumor size of 2.1 cm. The majority of cases were grade 2 with 49.4%, followed by grade 3 with 28.1% and grade one represented 22.5% of the sample. Ki-67 ranged from 2-98 %. Three variables correlated significantly with Oncotype Dx: tumor size (p = 0.0115), Ki-67 (p = 1.509e-09) and grade (p = 0.0307). Using these three variables together, the percentage of variance on the Oncotype Dx score was 0.35 (R2- coefficient of determination). Conclusions: While tumor size, grade and Ki-67 individually correlate significantly with Oncotype Dx score, taken together, they cannot reliably predict the RS. Also, the capability of these three factors to predict the RS decreases for tumors with high RS. Therefore, we conclude the RS can provide additional valuable information and should not be replaced by analysis of routine histologic variables alone.
Quantitative Bioluminescent Method Appropriate for Bimodality Analysis To Improve and Follow a Syngenic Murine Model of B-Cell Lymphoma Expressing Human CD20.
Authors: David Daydé, Florence Dommange, Stéphanie Lerondel, Josée Golay, Alain Le Pape, Gilles Paintaud, Pierre Bardos, Hervé Watier, Guillaume Cartron
Journal: Blood (2007)
Decreased in-vitro cellular drug resistance by addition of vascular endothelial growth factor receptor (VEGFR) inhibitor, PTK787/ZK 222584, to conventional chemotherapy in pediatric AML.
Authors: Esjm De Bont, T Meeuwsen-de Boer, F Scherpen, E Streefland, WA Kamps
Journal: Leukemia (2003)
Cellulitis
Authors: Adam B. Raff, Daniela Kroshinsky
Journal: JAMA (2016)

Cellulitis is an infection of the deep dermis and subcutaneous tissue, presenting with expanding erythema, warmth, tenderness, and swelling. Cellulitis is a common global health burden, with more than 650,000 admissions per year in the United States alone.In the United States, an estimated 14.5 million cases annually of cellulitis account for $3.7 billion in ambulatory care costs alone. The majority of cases of cellulitis are nonculturable and therefore the causative bacteria are unknown. In the 15% of cellulitis cases in which organisms are identified, most are due to β-hemolytic Streptococcus and Staphylococcus aureus. There are no effective diagnostic modalities, and many clinical conditions appear similar. Treatment of primary and recurrent cellulitis should initially cover Streptococcus and methicillin-sensitive S. aureus, with expansion for methicillin-resistant S. aureus (MRSA) in cases of cellulitis associated with specific risk factors, such as athletes, children, men who have sex with men, prisoners, military recruits, residents of long-term care facilities, those with prior MRSA exposure, and intravenous drug users. Five days of treatment is sufficient with extension if symptoms are not improved. Addressing predisposing factors can minimize risk of recurrence.The diagnosis of cellulitis is based primarily on history and physical examination. Treatment of uncomplicated cellulitis should be directed against Streptococcus and methicillin-sensitive S. aureus. Failure to improve with appropriate first-line antibiotics should prompt consideration for resistant organisms, secondary conditions that mimic cellulitis, or underlying complicating conditions such as immunosuppression, chronic liver disease, or chronic kidney disease.
Abstract 509: HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer
Authors: NAOKI TAKEGAWA.
Journal: Cancer Research (2016)

Abstract Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. We previously found that HER2 amplification was one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target (Yonesaka et al, STM 2011). The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. We aimed to obtain at least 100 droplets for HER2 and EFTUD2 to accurately assess the ratio. Digital PCR data were analyzed using the QuantaSoft analytical software package (Bio-Rad). The copy number concentration of each gene (HER2 and EFTUD2) was estimated from the Poisson distribution. HER2 amplification with digital PCR was defined as a HER2 ratio (HER2/EFTUD2 copy number ratio) of 1.25 accordingly (Gevensleven H et al, CCR 2013). HER2 gene copy number was analyzed using fluorescence in situ hybridization also in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Results: Our data showed various HER2 copy number in plasma ctDNA from CRC patients (median: 1.09; range: 0.94-5.18). 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy (pre: 1.14, post: 2.78). Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy. We are now conducting another, large-scale study for evaluating HER2 amplification by ctDNA in CRC patients using digital PCR. Citation Format: NAOKI TAKEGAWA. HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal 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 509.
Phase 1/1b Pharmacokinetic (PK) and Safety Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) with Severe Renal Impairment or End-Stage Renal Disease (ESRD) Requiring Hemodialysis
Authors: Neeraj Gupta, Michael J Hanley, R. Donald Harvey, Ashraf Z Badros, Brea C. Lipe, Vishal Kukreti, Jesus G. Berdeja, Huyuan Yang, Ai-Min Hui, Xiaoquan Zhang, Karthik Venkatakrishnan, Ajai Chari
Journal: Blood (2015)
Abstract 4944: Detection of functional P-selectin ligands expressed on colon cancer tissue using a novel flow-based assay
Authors: Eric W. Martin, Ramiro Malgor, Vicente A. Resto, Douglas J. Goetz, Monica M. Burdick
Journal: Cancer Research (2016)

Abstract The presence of functional P-selectin ligands is well-documented for human colon cancer cell lines, but not in situ on human colon carcinoma tissue. Presently, immunostaining with antibodies is used to detect critical components of selectin ligands, e.g., sialofucosylated moieties. However, this static biochemical tissue analysis (SBTA) cannot ascertain if a potential selectin ligand is able to mediate (rolling) adhesion. Due to the immense difficulty in detecting functional selectin ligands using traditional methods, we have developed a flow-based assay known as dynamic biochemical tissue analysis (DBTA) for detecting functional selectin ligands expressed on human tissue. DBTA using P-selectin microspheres was performed on colon cancer tissue sections from multiple cases, in conjunction with SBTA using P-selectin, antibodies against purported selectin ligand carbohydrate moieties sLeX and sLeA (HECA-452, CSLEX-1, and KM-231), and antibodies against peptide structures of putative P-selectin ligands (CD24, CD44, and PSGL-1). Examination of serial sections, in the same regions of tissue displaying DBTA probe adhesion, revealed significant detection inconsistencies with SBTA. Subsequently, due to the well-documented force-dependency of selectin ligands, DBTA was conducted with microspheres coated with either HECA-452, CSLEX-1, or KM-231 to determine the effect of applied force on the detection capabilities of these antibodies. Analysis of signet ring cell colon carcinoma tissue revealed microspheres coated with HECA-452, CSLEX-1, or KM-231 antibodies all displayed significantly lower amounts of adhesion than the DBTA P-selectin microspheres. Interestingly, although microspheres coated with these antibodies adhered to signet ring cell carcinoma tissue, these DBTA probes did not interact with all regions of tissue that displayed adhesion with P-selectin microspheres. Specificity of interaction was validated using corresponding isotype control coated microspheres. Taken together, these results show DBTA with P-selectin coated microspheres is able to unequivocally detect functional P-selectin ligands, in contrast to SBTA (immunostaining) and DBTA using microspheres coated with antibodies. In summary, DBTA using P-selectin coated microspheres is able to detect functional P-selectin ligands expressed on colon cancer tissue, data that may provide valuable diagnostic and prognostic information for malignant tumors. Citation Format: Eric W. Martin, Ramiro Malgor, Vicente A. Resto, Douglas J. Goetz, Monica M. Burdick. Detection of functional P-selectin ligands expressed on colon cancer tissue using a novel flow-based assay. [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 4944.
Assessment of treatment response using Computed Tomography (CT) tumor volume measurements and lesion number in metastatic urothelial carcinoma (mUC) patients (pts) receiving cabozantinib.
Authors: Kimaada Allette, Puskar Pattanayak, Seth M Steinberg, Howard Parnes, Gloria Jackson, Deneise Francis, Elizabeth Lamping, Les Folio, Andrea Borghese Apolo
Journal: Journal of Clinical Oncology (2015)

e15503 Background: Assessment of tumor burden change is crucial in clinical trials and patient care. We compared cabozantinib-induced volume changes of all metastatic tumor lesions, total tumor lesion number and unidimensional Response Evaluation Criteria In Solid Tumors (RECIST), and their association with progression free survival (PFS) and overall survival (OS) in mUC pts receiving cabozantinib therapy. Methods: Three tumor response assessment methods (CT tumor volumes of all metastatic lesions, total lesion number and RECISTv1) were captured at baseline and on follow-up (C3D1) CT scans. CT tumor volume measurements were evaluated using a semi-automated Computed Tomography (CT) PACS Lesion Management Algorithm. Total metastatic lesion number and standard RECIST measurements of target lesions were recorded. Results: In total, 26 mUC pts (median age 61.5 (42–76); 69% male) had both baseline and follow-up CT scans with measurable disease. Change in lesion number correlated with PFS (p = 0.0002) and OS (0.049); follow-up RECIST values correlated with PFS (p = 0.026) and OS (p = 0.056); and total CT volume measurements on follow-up scans correlated with PFS (p = 0.017) and OS (p = 0.039). Conclusions: Of the 3 methods tested in this cohort of mUC pts receiving cabozantinib, change in lesion number was most strongly associated with patient outcomes. Tumor burden, measured by total tumor volume on follow-up CT scans, was also associated with PFS and survival. Lesion number and CT tumor volume assessment constitute feasible and clinically useful methods to evaluate response and predict patient benefit.