tbuckley/cabot-search huggingface dataset:
Enzalutamide plus exemestane: A pilot study to assess safety, pharmacokinetics, and effects on circulating estrogens in women with advanced hormone-positive breast cancer.
Authors: Lee Steven Schwartzberg, Denise A. Yardley, Anthony D. Elias, Manish R. Patel, Ayca Gucalp, Howard A. Burris, Amy C. Peterson, Alison L. Hannah, Martha Elizabeth Blaney, Jackie Gibbons, Iulia Cristina Tudor, Joyce L. Steinberg, Patricia LoRusso, Jeffrey R. Infante, Clifford A. Hudis, Tiffany A. Traina
Journal: Journal of Clinical Oncology (2014)

545 Background: Exemestane (EXE) is a commonly used aromatase inhibitor (AI) in patients (pts) with advanced ER/PgR+ breast cancer (BC). The androgen receptor (AR), expressed in the majority of ER/PgR+ BC, is believed to play a role in resistance to AI therapy. Enzalutamide (ENZA), a potent inhibitor of AR signaling, induces CYP3A4, an enzyme involved in the metabolism of EXE. We previously reported that the addition of ENZA (160 mg/day) to EXE 25 mg/day resulted in ~40% reduction in EXE exposure. The US product label recommends doubling the dose of EXE when administered in combination with a potent CYP3A4 inducer. This trial investigates daily ENZA 160 mg + EXE 50 mg. Methods: Postmenopausal pts with ER/PgR+ advanced BC received ≥14 days of EXE 50 mg/day prior to initiating ENZA 160 mg/day on Day 1 (NCT01597193). Prior EXE and non-measurable disease was allowed. Blood sampling occurred on Day -1 (no ENZA) and on Day 29 (+ ENZA) to assess PK interactions and effects on circulating estrogens (estradiol and estrone). Available tumor tissue was analyzed centrally for AR expression although AR+ disease was not required. Response assessments (RECIST 1.1) were performed approximately every 3 months. Results: As of 11 Dec 2013, data were available for 18 of the 24 pts enrolled. Median age/ECOG was 66/0; median number of prior hormonal therapies was 2.5. Common (>10%) treatment-related adverse events (AEs) included nausea, vomiting and fatigue. No treatment-related serious AEs or AEs ≥ Grade 3 have been reported. Preliminary data indicate that ENZA + EXE 50 mg achieves similar EXE exposure to EXE 25 mg alone (AUC=127±70 vs. 131±64 ng.h/mL) and maintains estrogen suppression for the majority of pts. Full data on PK, tolerability, estrogen levels and anti-tumor activity will be presented. Conclusions: To date, the combination of daily ENZA 160 mg + EXE 50 mg has been well tolerated. Doubling the dose of EXE appears to restore EXE exposure thereby maintaining the suppression of estrogens. An ongoing randomized double-blind, placebo-controlled phase 2 trial in ER/PgR+ advanced BC will determine if the combination of daily ENZA 160 mg + EXE 50 mg is more active than EXE 25 mg alone. Clinical trial information: NCT01597193.
A Gut Commensal Bacterium Promotes Mosquito Permissiveness to Arboviruses
Authors: Pa Wu, Peng Sun, Kaixiao Nie, Yibin Zhu, Mingyu Shi, Changguang Xiao, Han Liu, Qiyong Liu, Tongyan Zhao, Xiaoguang Chen, Hongning Zhou, Penghua Wang, Gong Cheng
Journal: Cell Host & Microbe (2018)
BRCA1 &amp; BRCA2 Germline Variants Are Enriched in MDS/AML and Portend Higher Average Mutational Burden
Authors: Louis Williams, Teodora Kuzmanovic, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Yogenthiran Saunthararajah, Hassan Awada, Vera Adema, Amy C Graham, Tomas Radivoyevitch, Hetty E. Carraway, Aziz Nazha, Mikkael A. Sekeres, Jaroslaw P. Maciejewski
Journal: Blood (2018)
TGF-Beta Signaling in Mesenchymal Stromal Cells Contributes to Myelofibrosis but Not Hematopoietic Phenotypes in Myeloproliferative Neoplasms
Authors: Juo-Chin Yao, Grazia Abou Ezzi, Joseph R. Krambs, Eric J. Duncavage, Daniel C. Link
Journal: Blood (2018)
Mirk/Dyrk1B drives cell survival and proliferation of NSCLC cells interacting with MAPK/ERK pathway
Authors: Jingchun Gao, Arthur Edwards, Eileen Friedman, Eric B. Haura
Journal: Cancer Research (2008)

3482  Minibrain-related kinase (Mirk) is a member of the dual specificity tyrosine-phosphorylation-regulated kinase (Dyrk)/minibrain family of dual-specificity protein kinases and is identical to Dyrk1B. Mirk/Dyrk1B is a serine/threonine kinase that has been found to be up-regulated in many solid tumors and mediates cell survival in colon, pancreatic ductal carcinomas and rhabdomyosarcomas. Mirk/Dyrk1B can be negatively regulated by mitogenic-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase signaling. As part of a phosphoproteomics screen in human non-small cell lung cancer (NSCLC) cells, we identified peptides corresponding to the phosphotyrosine (pY) autophosphorylation site of Mirk/Dyrk1B. Mirk/Dyrk1B immunoprecipitation coupled with anti-pY western blotting confirmed tyrosine phosphorylation of Mirk/Dyrk1B in NSCLC cells. Mirk protein was widely overexpressed in 10 of 15 NSCLC cell lines examined and correlated with the levels of activated ERK by western blot analysis. Knockdown of Mirk by small interfering RNA (siRNA) resulted in reduction of viable cells and cell apoptosis in 11 of 15 NSCLC cell lines (Group 1). Interestingly, knockdown of Mirk in the other four NSCLC cells (Group 2) resulted in increased cell number. To examine this further, knockdown of Mirk in A549 cells (Group 1) led to increase of PARP cleavage but no changes in activated ERK. In H292 cells (Group 2), Mirk knockdown resulted in increased activation of ERK, increased cyclin D1, reduced p27, and no evidence of cleaved PARP. We hypothesized that the increased activation of ERK after Mirk siRNA treatment may block the anti-proliferative effects of Mirk siRNA in some lines or may counterbalance cell loss through apoptosis. In H292 cells, the increase in cell proliferation induced by Mirk siRNA could be blocked by the MEK inhibitor U0126 in a dose-dependent manner. MEK inhibition abrogated the activation of ERK and subsequent changes in cell cycle proteins (cyclin D1, p27) induced by Mirk knockdown. Combined Mirk siRNA and U0126 induced cell apoptosis in H292 cells. Finally, we found increased Mirk protein levels in cells grown in mitogen-poor conditions (serum starvation and MEK inhibition), suggesting Mirk may mediate cell survival of NSCLC cells in low growth factor conditions. In summary, Mirk is a survival factor for NSCLC cells and may be a novel therapeutic target.
Discovery of biomarkers associated with cancer survival using Outcomes Explorer, a web-based translational research tool for the visualization and analysis of cancer outcomes data.
Authors: Michael A. Harris, Varun Singh, Subha Madhavan
Journal: Journal of Clinical Oncology (2014)

e22157 Background: The analysis of cancer outcomes data with the genotype and clinical parameters is a challenging task that often requires complex software and the involvement of statisticians for even the most preliminary analysis. There is a critical need for a tool that facilitates the independent exploration of these data sets by translational researchers. The Outcomes Explorer (OE) is a web-based and mobile device compatible application that allows a clinician researcher to explore clinical outcomes data in in the context of molecular markers and other ‘omics data. Using the OE tool, the researcher is able to dynamically generate Kaplan-Meier (KM) plots for biomarkers or clinical variables of interest. In addition the OE will automatically identify highly significant biomarkers that can be further explored using the tool. Methods: We used data from the dbGap study CALGB80303 that contains both phenotype and genotype data for 351 patients with advanced pancreatic cancer treated with gemcitabine. SNPs significantly associated with overall survival were identified using the OE automatic biomarker identification that is based on high-throughput survival analysis. These SNPs where then further analyzed using the OE data exploration capabilities. Results: The SNPs identified include rs763780 in the IL17 gene (previously reported) as well as rs3743979 a missense mutation in the ACSF3 gene predicted to be damaging by Polyphen and previously associated with pediatric GC-derived B-cell lymphoma. Other SNPs identified include rs2230009 (WRN), rs2403730 (HHLA1), rs3948463 (SP110), rs11879465 (ZNF211), rs3207775 (GTPBP4), rs10157422 (SLC35D1), rs2289741 (RPAP1). Conclusions: We demonstrate an analysis of cancer outcomes in a complex data set containing patient phenotype and genotype information using and easy to use tool developed for translational researchers.
Clinicopathologic characteristics and prognostic impact of MET receptor overexpression in patients with stage I-IIIA squamous cell lung carcinomas (SQCLCs).
Authors: Matthew David Hellmann, Todd A Anderson, Juliana Eng, Camelia S. Sima, Mark G. Kris, Andre L. Moreira, Natasha Rekhtman, Paul K. Paik
Journal: Journal of Clinical Oncology (2014)

7570 Background: MET is an oncogenic driver involved in cellular proliferation, survival, and invasion (Rong et al, PNAS 1994) and has been identified as a therapeutic target in some patients with lung cancers (Dziadziuszko et al, J Thorac Oncol 2012; Spigel et al, J Clin Oncol 2013). The clinicopathologic features and outcomes of patients with stage I-IIIA SQCLCs with MET receptor overexpression have not previously been described. Methods: A cohort of histopathologically-defined completely resected SQCLCs were tested for membranous MET receptor expression using IHC (Ventana, SP44) and assessed by two thoracic pathologists independently (TA, NR). Expression was scored using the METmAb scoring system, in which “MET+” tumors had moderate/strong intensity expression (i.e., ≥2+) in ≥50% of tumor cell membranes. Associations between MET status and clinical features, DFS, and OS were assessed using the Fisher’s exact, unpaired T-, log-rank tests and Kaplan-Meier methods. Multivariate DFS and OS analyses were performed using Cox regression. Results: 17 of 62 stage I-IIIA SQCLCs were MET+ (27%, 95% CI 18-40%). There were no differences in age (p=0.31), gender (p=1.0), or tobacco exposure (p=0.78) between pts with MET+ and MET- SQCLCs. Median DFS and OS were significantly inferior in pts with MET+ vs MET- SQCLCs (15 vs 37 mo, p=0.01; 32 vs 54 mo, p=0.04, respectively). In this cohort, age or KPS were not associated with OS or DFS. In multivariate analyses including stage, gender, and MET status, outcomes of pts with MET+ SQCLC remained significantly inferior (HR for recurrence=4.1, 95% CI 1.6-10; HR for survival=2.2, 95% CI 1.0-4.7). Conclusions: More than a quarter of pts with stage I-IIIA SQCLCs are characterized by MET receptor overexpression. DFS and OS are significantly shorter in pts with MET+ SQCLCs. Pts with MET+ SQCLCs represent an oncogene-defined subgroup and should be considered for enrollment in clinical trials of agents targeting the MET pathway in this illness. MET+ (n=17) MET- (n=45) Median DFS 15 mo 37 mo p-value 0.01 Multivariate HR for recurrence (95% CI) 4.1 (1.6-10) Median OS 32 mo 54 mo p-value 0.04 Multivariate HR for survival (95% CI) 2.2 (1.0-4.7)
The anti-CD19 immunotoxin (HD37-dgRTA) is more effective when combined with chemotherapy
Authors: Cristina L. Stanciu-Herrera, David Morgan, Randall Alfano, Victor Ghetie, Ellen Vitetta, Larry Herrera
Journal: Cancer Research (2005)

685  The anti-CD19 (HD37-dgRTA) immunotoxin (IT) is a murine IgG1 monoclonal antibody conjugated to a deglycosylated ricin A chain (dgRTA). This IT is effective in selectively killing B-lineage leukemia cells obtained from children with leukemia. It is also effective in prolonging the survival and curing severe combined immunodeficient mice (SCID) mice injected with the NALM-6-UM-1 human pre-B acute lymphoblastic leukemia (ALL) cell line. The purpose of this study was to identify effective combinations of HD37-dgRTA with chemotherapy agents. To evaluate the efficacy of this IT in combination with chemotherapy, we performed in vitro and in vivo experiments combining the IT with two chemotherapy agents commonly used in the treatment of childhood ALL. The in vitro cytotoxicity assays demonstrate that the combination of HD37-dgRTA with daunorubicin or with vincristine is synergistic. The in vivo experiments show that mice treated with HD37-dgRTA had improved survival when compared to the chemotherapy agents. The mean survival for mice treated with HD37-dgRTA was 90.7 days vs 91.8 days for those receiving HD37-dgRTA plus daunorubicin. Mice that were treated with HD37-dgRTA plus vincristine survived a mean of 147.1 days. Most strikingly, 80% of the mice treated with combination of HD37-dgRTA and vincristine were long term survivors. The disease burden in each of 8 organs was also determined for the different treatment groups by polymerase chain reaction (PCR) analysis. None of the mice treated with the combination of HD37-dgRTA plus vincristine had evidence of residual disease.
AB0763 Bioelectrical impedance analysisfor the assessment of body composition in patients with systemic sclerosis
Authors: G. Cuomo, G. Guarino, F. Danzo, C. Romano, F. Masini, R. Ferrara, S. Gentile, L.E. Adinolfi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> The aim of the present study was to evaluate the body composition by bioelectrical impedance analysis (BIA) and to assess the nutritional status by BMI and possible correlations with epidemiological and clinical characteristics in patients with SSc <h3>Methods</h3> Malnutrition was defined as BMI &lt;18.5 kg/m 2 or unintentional weight loss &gt;10% in combination with a fat-free mass index (FFMI) &lt;15 kg/m 2 for women or &lt;17 kg/m 2 for men or BMI &lt;20.0 kg/m 2 (age &lt;70 years) or &lt;22 kg/m 2 (age &gt;70 years). Body composition was assessed in 40 patients (female) (age mean ±sd: 45.2±12.2) and 20 healthy controls (age mean ±sd 41.5±5.3) with BIA (Akern, Italy) and BMI. The manufacturer's equation and the Geneva equation were used to estimate fat mass (FFM). In addition, correlations with disease activity, gastrointestinal severity, disease subset, autoantibody profile, skin score were evaluated. <h3>Results</h3> Malnutrition was found in 10% of patients vs 8% of healty controls; and low FFMI in 30% of patients vs 10 5 of HC. Bioimpedentiometry showed a Fat Free Mass (FFM) (metabolically active component of fat free mass) reduced in patients compared to controls (46.8±7.6 vs 53.6±6.3 respectively; p=0.01). Furthermore, with the same instrument a lower basal metabolic rate was found in patients compared to controls: 1462±145 vs 1720±169 calories (p=0.001). The correlations between FFM and basal metabolism with the clinical features of the patients were not statistically significant <h3>Conclusions</h3> This study confrim the study of Spanjer MJ et al<sup>1</sup> and shows a relatively low prevalence of malnutrition in comparison with other studies, but a high prevalence of low FFMI, underlining the necessity of measuring body composition in SSc patients with a standardised and validated method. Furthermore, Caporali et al,<sup>2</sup> have shown an alteration of the nutritional status of patients of SSc probably related to a gastro-intestinal commitment. In our patients despite the presence of an apparent good nutritional status the use of bioimpedanceometry revealed a different body composition, a lower share of muscle mass, in patients compared to controls, related, in part, to musculoskeletal involvement by systemic sclerosis (increase in muscle catabolism and/or poor nutrient supply due to malabsorption phenomena). The early detection of such alterations could be useful to insert subjects at risk in physical rehabilitation programs. <h3>References</h3> [1] Spanjer MJet al, Rheumatology2017 [2] Caporaliet al; Clin Nutr2012 <h3>Disclosure of Interest</h3> None declared
Gene profiling and circulating tumor cells in patients with locoregional breast cancer.
Authors: Renata Kelly Kuniyoshi, Flavia de Sousa Gehrke, Beatriz da Costa Aguiar Alves, Viviane Vilas Boas, Anna Estela Luiza Colo, Naiara Souza, Joao Soares Nunes, Fernando Luiz Affonso Fonseca, Auro Del Giglio
Journal: Journal of Clinical Oncology (2014)

e22182 Background: The gene profile of primary tumors, as well as the identification of circulating tumor cells (CTCs), can provide important prognostic and predictive information. In this study, our objective was to perform tumor gene profiling (TGP) in combination with CTC characterization in women with non-metastatic breast cancer Methods: Biological samples (from peripheral blood and tumors) from 167 patients diagnosed with stage I, II and III mammary carcinoma, who were also referred for adjuvant/neoadjuvant chemotherapy, were assessed for the following parameters: a) the presence of CTCs identified by the expression of CK-19 and c-erbB-2 in the peripheral blood mononuclear cell (PBMC) fraction by quantitative RT-PCR and b) the TGP, which was determined by analyzing the expression of 21 genes in paraffin-embedded tissue samples by quantitative multiplex RT-PCR with the Plexor system. Results: We observed a statistically significant correlation between the progression-free interval (PFI) and the clinical stage (p = 0.000701), the TGP score (p = 0.006538) and the presence of hormone receptors in the tumor (p = 0.0432). We observed no correlation between the PFI and the presence or absence of CK-19 or HER2 expression in the PBMC fraction prior to the start of treatment or in the 2 following readouts. Multivariate analysis revealed that only the TGP score significantly correlated with the PFI (p = 0.029247). Conclusions: The TGP is an important prognostic variable for patients with locoregional breast cancer. The presence of CTCs adds no prognostic value to the information already provided by the TGP. Clinical trial information: 011/2009.
Type I Protein Arginine Methyltransferases Overexpression Promotes Transformation and Potentiates Her2/Neu–Driven Tumorigenesis
Authors: Zachary L. Watson, Benjamin G. Bitler
Journal: Cancer Research (2019)

Abstract Bao and colleagues demonstrate that type I protein arginine methyltransferases (PRMT) are directly involved in mammary gland transformation and tumor progression. Notably, several distinct phenotypes require further investigation such as PRMT1/CARM1–induced transformation, CARM1-mediated delay in tumorigenesis, and PRMTs potentiation of Her2-dependent tumors. The PRMT overexpression transgenic mouse models should encourage and facilitate further mechanistic interrogation and the development of PRMT-directed therapies. See related article by Bao et al., p. 21
Relationship between RECIST response and variation of circulating tumor cells (CTC) for patients enrolled in phase I trials.
Authors: Christophe Massard, Françoise Farace, Isabelle Borget, Christophe Le Tourneau, Jean-Yves Pierga, Francois Clement Bidard, Jean-Philippe Spano, Charles Ferte, Jean-Charles Soria, Ludovic Lacroix
Journal: Journal of Clinical Oncology (2014)

11023 Background: Because CTC counting has been shown to be a marker independent of tumor type or treatment, it could represent a new parameter to improve evaluation of tumor response to drugs in phase I clinical trials. We hypothesized that early change of CTC counts could occur before detectable variation in tumor size evaluated by imaging using RECIST criteria. Methods: Consenting patients with advanced and metastatic cancer referred three phase I units (Gustave Roussy, Institiut Curie, Pitie Salpétrière) were enrolled prospectively in this study. CTCs from 7.5 mL of whole blood drawn before treatment initiation (baseline) and 4 weeks after starting experimental therapy were enumerated using the CellSearch system, and tumor response was assessed using RECIST Criteria at baseline and 2 months after treatment initiation. Results: Between March 2010 and May 2013, a total of 326 patients were enrolled in phase I trials across 3 centres, among which 215 were evaluable (48% were male, median age=57; main tumor types: lung (25), colon (54), bladder (14), breast (28)). At baseline we detected ³ 1CTC/7.5 ml in 114/215 (53% ; median CTC count=4 (1-3,264)), and at week 4, we observed ³ 1CTC/7.5 ml in 103/215 (48% ; median CTC count=3 (1-100)). Sensitivity and specificity of CTC variation to detect progressive disease were 41% (32-51%) and 80% (72-87%) respectively. At the first follow-up imaging visit, 10 (5%) of the 215 patients were classified as having partial response, with 9 of these patients having no CTC or a decrease in CTC count after therapy. In contrast of the 102 patients (47%) classified as having progressive disease, 22 patients (21%) had an increase of CTC. The remaining 103 patients (48%) were classified as having stable disease, 35 of them (33%) had a decrease in CTC count, possibly suggesting a therapeutic benefit despite the lack of criteria for objective response. Conclusions: Early CTC change following therapy does not correlate with RECIST response in patients with advanced cancer enrolled in phase I trials. However, our results suggest that this biomarker may still have some interest to identify stable diseases with a certain anti-tumor effect.
Safety/efficacy of MK-8669 (ridaforolimus) plus MK-2206 (AKT inhibitor) in patients with advanced breast cancer with low RAS signature and PTEN deficient prostate cancer.
Authors: Shilpa Gupta, Pamela N. Munster, Antoine Hollebecque, Guillem Argiles, Olav Dajani, Jonathan D. Cheng, Ann M. Swift, Alessandra Tosolini, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2014)

2509 Background: The PI3K/AKT/mTOR signaling pathway is aberrantly activated in a variety of cancers. The combination of ridaforolimus (mTOR inhibitor) and MK-2206 may lead to blockade of the PI3K pathway. Methods: We conducted a phase 1 study with ridaforolimus + MK-2206 in advanced solid tumors (n=35). Part A defined the maximum-tolerated dose (MTD); part B evaluated preliminary clinical efficacy in enriched breast cancer (BCa) and prostate cancer (PCa) patients. BCa patients had low RAS gene signature; ER+ BCa patients required a high Ki67 index. PCa patients had evidence of PTEN deficiency. Results: Eleven patients were in part A and 24 patients were in part B (16 BCa/8 PCa patients). In addition, 1 BCa patient from part A was found to be biomarker-eligible when tested after a clinical response. Total of 124 BCa patients were prescreened: 98 tissues were evaluable; 51were biomarker-eligible. Sixty-eight PCa patients were prescreened: 40 tissues were evaluable; 24 had loss of PTEN. The MTD was 10 mg qd ridaforolimus 5 days/wk + 90 mg weekly MK-2206; 1/17 patients had a dose limiting toxicity of G3 rash. For BCa patients, investigator-assessed objective responses were seen in 2/16 (2 partial responses [PR], 12.5%), centrally read objective responses were seen in 2/14 (2 complete responses [CR], 14.3%), and objective responses using volumetric 3-D assessment were seen in 4/14 (2 PR + 2 CR, 28.6%). In addition, stable disease (SD) ≥6 months was seen in 1 patient by the investigator assessment and 1 patient by central read. For PCa patients, 1/8 patient had SD for > 6 months. No responses were seen in other non-biomarker-tested tumors in part A (although one subject with colorectal cancer had SD for 7 months). At the MTD, the following drug-related AEs were seen: rash (44.4%); stomatitis (38.9%); diarrhea and decreased appetite (27.8%); asthenia, nausea and fatigue (22.2%). Conclusions: The combination of ridaforolimus and MK-2206 shows promising activity in BCa patients with low RAS. This combination was overall well tolerated with rash, stomatitis, diarrhea and asthenia being among the most common drug-related AEs. Clinical trial information: NCT01295632.
Characteristics and Outcome of Early T Cell Precursor ALL (ETP-ALL) Patients Treated with High-Risk Spanish Pethema Protocols
Authors: Eulalia Genesca, Mireia Morgades, Pau Montesinos, Pere Barba, Cristina Gil, Ramon Guàrdia, Maria Jose Moreno, Daniel Martínez-Carballeira, Irene García-Cadenas, Susana Vives, Jordi Ribera, José González-Campos, Marina Diaz-Beyá, Santiago Mercadal, Maria Teresa Artola, Antonia Cladera, Mar Tormo, Arancha Bermudez, Ferran Vall-Llovera, Pilar Martinez, María-Luz Amigo, Juan-Miguel Bergua, María Calbacho, Jesús-María Hernández-Rivas, Silvia Monsalvo, Andrés Novo, Marta Cervera, Antonio Garcia-Guiñon, Jordi Junca, Juana Ciudad, Alberto Orfao, Josep-Maria Ribera
Journal: Blood (2018)