tbuckley/cabot-search huggingface dataset:
Abstract 1878: Inhibition of the Transforming Growth Factor beta pathway in human glioblastoma cell lines induces apoptosis and inhibits anoikis escape
Authors: Gabriel Gallo-Oller, Javier Dotor, Xing Fan, Javier S. Castresana
Journal: Cancer Research (2016)

Abstract Glioblastoma Multiforme (GBM) is the most prevalent malignant brain tumor accounting for 60-70% of all gliomas. Current achieved median patient survival ranges only 12-15 months, and improvements in survival over the last century can be measured only in weeks. A hallmark of this malignancy is the intrinsic resistance to current therapies. The Transforming Growth Factor beta (TGF-beta) signaling pathway plays a key role in GBM. Several inhibitors of different elements and regulators of the TGF-beta pathway have entered to clinical trials. Here, we analyzed the potential effect of P144, a TGF-beta pathway inhibitor peptide, over cell proliferation and apoptosis in commercial GBM cell lines (A172 and U-87 MG). We found that treatment with P144 significantly decreased cell proliferation of both cell lines analyzed. In addition, different apoptosis determinations such as ELISA and Acridine Orange/Ethidium Bromide (AO/EB) staining, confirmed a significant increase in apoptosis in both cell lines. Quantification of SMAD2 phosphorylation status and its nuclear translocation, by western blot, confirmed the inhibition of TGF-beta signaling by P144. These data support the correlation between TGF-beta pathway inhibition and the apoptotic process induction. Anoikis escape sustains invasiveness and metastatic potential in GBM, and has been established as a clear target against tumor progression. Due to P144 clear effect on apoptosis, we analyzed its influence on anoikis escape. The inhibition of anoikis escape by P144 was confirmed in A172 and U-87 MG cell lines under in vitro anchorage-independent culture conditions. The significant upregulation of BAX, Lamin A and Lamin C produced by P144 confirmed the induction of this apoptotic subtype process in the analyzed cell lines. We can conclude that P144 increases apoptosis and induces anoikis through inhibition of the TGF-beta signaling pathway. Our results highlight the therapeutic potential of P144 for the treatment against GBM. However, previous to further clinical development, additional studies are required in order to confirm the effect of P144 over GBM in the brain environment, as well as to explore the therapeutic potential of P144 in combination with current and emerging molecular based therapies. Citation Format: Gabriel Gallo-Oller, Javier Dotor, Xing Fan, Javier S. Castresana. Inhibition of the Transforming Growth Factor beta pathway in human glioblastoma cell lines induces apoptosis and inhibits anoikis escape. [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 1878.
First-in-human dose escalation study of oral ONC201 in advanced solid tumors.
Authors: Mark N. Stein, Tina M. Mayer, Rebecca Anne Moss, Ann W. Silk, Nancy Chan, Bruce George Haffty, Robert S. DiPaola, Yasmeen Beckett, Edward Bentlyewski, Ling Zheng, Bruno Fang, Joshua Allen, Janice M. Mehnert
Journal: Journal of Clinical Oncology (2015)

TPS2623 Background: ONC201 is an orally active first-in-class small molecule with strong antitumor activity in preclinical models of advanced cancers. In cancer cell lines and patient samples ONC201 induces an integrated stress response (Ishizawa et al, 2014), late-stage inactivation of Akt and ERK, and downstream activation of the apoptotic TRAIL pathway as part of innate immune surveillance (Allen J et al, Sci Trans Med, 2013). Activity is independent of p53 status. ONC201 is well tolerated at efficacious doses in animal models, crosses the blood brain barrier, is particularly effective in refractory tumors, depletes cancer stem cells (Ishizawa et al, ASH 2014; Prabhu et al, Blood 2014; Zhao et al, ASCO 2014), and is effective with infrequent dosing preclinically. Based on the compelling efficacy and safety profile of ONC201 as well as the engagement of signaling pathways critical for many cancers, the clinical introduction ONC201 in advanced cancer patients is warranted. Methods: The first-in-human study of ONC201 (NCT02250781) began in January 2015 as an open-label single-site phase I trial enrolling adult patients with refractory advanced solid tumors and glioblastoma (GBM). Patients with symptomatic brain metastases or prior bevacizumab for treatment of GBM are excluded. The primary endpoint is determination of the recommended phase II dose (RP2D) of single agent ONC201 given orally once every 3 weeks (1 cycle). Secondary endpoints include assessment of pharmacodynamics using select biomarkers for ONC201 (Allen et al, 2015), pharmacokinetics, toxicity, and efficacy. The study employs an accelerated, single patient per cohort, dose escalation design with expansion to a standard 3+3 design if a subject has grade > / = grade 2 toxicity or dose limiting toxicity within cycle 1. The maximum tolerated dose is the highest dose level in which 6 patients have been treated with < / = 1 instance of DLT. A subject in Cohort 1 (125mg) has completed the first cycle of treatment without any > / = grade 2 toxicity. Cohort 2 (250mg) is currently enrolling. This phase I study will identify the RP2D to enable evaluation of the antitumor efficacy of ONC201 in select advanced cancer indications. Clinical trial information: NCT02250781.
Case 12-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Edward H. Ahrens, Benjamin Castleman
Journal: New England Journal of Medicine (1973)

Presentation of CaseA 50-year-old man was admitted to the hospital because of abdominal pain.He was well until 21 years previously, when multiple small xanthomas developed on the elbows and coalesced into larger lesions; the masses were excised and did not recur. One year later he began to experience intermittent claudication and episodes of blindness that lasted from two to five minutes and disappeared completely. A physician informed him that his "blood fat level was very high," and he gradually reduced his weight by 20 kg or more. For at least 20 years he had recurrent abdominal pain that . . .
Abstract LB-042: Xenopatients help in redefining medical therapeutic algorithms in high risk ovarian cancer
Authors: Jessica Erriquez, Martina Olivero, Gloria Mittica, Maria Stella Scalzo, Marco Vaira, Michele De Simone, Riccardo Ponzone, Dionyssios Katsaros, Massimo Aglietta, Raffaele Calogero, Maria Flavia Di Renzo, Giorgio Valabrega
Journal: Cancer Research (2016)

Abstract Platinum-based chemotherapy is the recommended first-line treatment for high-grade serous (HGS) epithelial ovarian cancer (EOC). However, most patients relapse because of platinum refractory/resistant disease. We aimed at assessing whether other drugs, commonly used to treat relapsed HGS-EOC and poorly active in this clinical setting, might be more effective against chemotherapy-naïve cancers. We collected samples of advanced HGS-EOC from the same patients before and after neo-adjuvant platinum-based chemotherapy. Samples were propagated as Patient Derived Xenografts (PDXs) in immunocompromised mice (“xenopatients”). Xenopatients were treated with carboplatin, gemcitabine, pegylated liposomal doxorubicin (PLD) and trabectedin. One patient was studied who experienced clinically platinum-sensitivity first and then discordant responses of different tumor sites to platinum re-challenge. PDXs derived from this patient before chemotherapy showed responsiveness to carboplatin, trabectedin and gemcitabine. The PDXs from the same patient after chemotherapy did no longer respond to trabectedin and gemcitabine and showed a heterogeneous response to carboplatin. Expression profiling showed that loss of responsiveness to drugs of the post-chemotherapy PDXs was associated with the up-regulation of NR2F2 gene expression. A second patient with platinum refractory HGS-EOC responded poorly to PLD as second-line treatment. PDXs obtained from this patient's tumor before chemotherapy showed a complete response to PLD, which was lost in the post-chemotherapy PDXs. Response to PLD was associated with the over-expression of the TOP2A protein, which was lost in the post-chemotherapy PDXs. Thus, PDXs demonstrated that chemotherapy-naïve HGS-EOC might display susceptibility to agents not used commonly as first line treatment. These data suggest the importance of tailoring chemotherapy. Citation Format: Jessica Erriquez, Martina Olivero, Gloria Mittica, Maria Stella Scalzo, Marco Vaira, Michele De Simone, Riccardo Ponzone, Dionyssios Katsaros, Massimo Aglietta, Raffaele Calogero, Maria Flavia Di Renzo, Giorgio Valabrega. Xenopatients help in redefining medical therapeutic algorithms in high risk ovarian 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 LB-042.
Abstract 971: A novel long noncoding RNA, onco-lncRNA 230, induces apoptosis and invasion in lung squamous cell carcinoma
Authors: Cynthia Y. Tang, Jessica M. Silva-Fisher, Ha X. Dang, Nicole M. White, Christopher A. Maher
Journal: Cancer Research (2016)

Abstract Long non-coding RNAs (lncRNAs) are RNAs that are longer than 200 base pairs and do not translate into proteins but have been shown to play roles in all aspects of biological regulation. LncRNAs have also been shown to regulate gene expression including chromatin organization, transcriptional regulation, and post-transcriptional control. In addition, they are now emerging to be important players in our understanding of cancer and have been shown to promote tumorigenesis. However, the mechanisms driving the advancement of tumor progression to metastasis is poorly understood. To identify lncRNAs critical to tumorigenesis, our lab conducted a pan-cancer analysis of normal and primary tumor tissues from The Cancer Genome Atlas to discover lncRNAs that are commonly altered across cancer types, which we termed ‘onco-lncRNAs’. During our analysis, we discovered a novel unannotated onco-lncRNA, onco-lncRNA-230, that was significantly up regulated in head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC) tumors relative to matched adjacent normal tissues, when available. We chose to focus on onco-lncRNA-230 as it displayed more than seven fold increase in LUAD and more than thirty seven fold change in LUSC tumors relative to adjacent normal. First, we validated this finding by quantitative PCR which revealed greater than a two fold enrichment of onco-lncRNA-230 expression in two out of seven LUAD and all six LUSC cells lines compared to a normal lung cell line. Because we observed the greatest increase in expression in HCC95 LUSC cells, we next sought to determine if modulating the expression of onco-lncRNA-230 promotes oncogenic phenotypes. Silencing of onco-lncRNA-230 in HCC95 cells did not change cellular proliferation but significantly increased apoptosis. Furthermore, silencing onco-lncRNA-230 resulted in a decrease in cellular invasion by transwell assay. Taken together, this represents the first study reporting that onco-lncRNA-230 is dysregulated in multiple cancer types, significantly up-regulated in lung cancer patient samples and lung cancer cell lines, and confers oncogenic phenotypes. Moving forward, we intend to explore how onco-lncRNA-230 mechanistically promotes lung cancer with the objective of utilizing onco-lncRNA-230 as a novel cancer diagnostic and therapy. Citation Format: Cynthia Y. Tang, Jessica M. Silva-Fisher, Ha X. Dang, Nicole M. White, Christopher A. Maher. A novel long noncoding RNA, onco-lncRNA 230, induces apoptosis and invasion in lung squamous cell 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 971.
Nonclinical safety assessment of a humanized IgG4 anti-SEMA4D antibody to support clinical development.
Authors: C. A. Cornelius, T. Fisher, L. A. Winter, J. Seils, C. A. Reilly, A. S. Jonason, E. S. Smith, R. Watkins, M. Zauderer, J. E. Leonard
Journal: Journal of Clinical Oncology (2011)

e13071 Background: VX15/2503 is a humanized IgG4 monoclonal antibody binding with approximately 3 nM affinity to Semaphorin 4D (SEMA4D, CD100); an important mediator of axonal growth cone guidance, vascular development, angiogenesis, and T/ B cell activation. The pharmacology and toxicology of single and repeat doses of VX15/2503 was evaluated in rodents and primates. Methods: Toxicology and pharmacology studies of VX15/2503 were performed using Sprague-Dawley rats and cynomolgus macaques administered single or five weekly intravenous injections. Single dose studies employed doses of between 0.01 and 100 mg/kg; repeat dose studies evaluated 10, 30 and 100 mg/kg. Appetite, body weights, safety pharmacology, clinical pathology, anatomic pathology, and immunotoxicology data were collected in each study. Pharmacokinetics (PK), pharmacodynamics (T cell associated SEMA4D saturation; PD), and immunogenicity were also assessed. Results: Toxicology profiles were similar for both species in both studies; NOAEL = 100 mg/kg. No adverse effects were noted in any toxicology or safety pharmacology endpoint. Single dose VX15/2503 half-life values increased with dose and ranged from 27 to 246 hours in rats; similar results were obtained from the primate single dose study. Repeat dose Cmax and AUC (exposure) values were higher in both species than those from the single dose studies and steady-state was achieved after the fourth dose. PD was dose dependent for animals in both studies. Single dose animals that reached a VX15/2503 serum concentration of ≥2 µg/mL exhibited transient complete T cell SEMA4D saturation. Antigen saturation lasting longer than 130 days occurred in both species at the 100 mg/kg dose level. Anti-VX15/2503 responses were detected in the sera of most animals in both studies; however, anti-VX15/2503 antibodies showed modest effects on PK only at low MAb doses. Conclusions: VX15/2503 was well tolerated and safe over the course of five weekly injections in rats and cynomolgus macaques at doses up to 100 mg/kg. A phase 1 repeat dose, dose escalation study has been initiated to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of VX15/2503 in adult patients with advanced solid tumors.
Comparing Single-Agent Ibrutinib, Bendamustine Plus Rituximab (BR) and Ibrutinib Plus BR in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): An Indirect Comparison of the RESONATE and HELIOS Trials
Authors: Peter Hillmen, Graeme Fraser, Jeffrey Jones, Simon Rule, Susan O'Brien, Marie Sarah Dilhuydy, Ulrich Jaeger, Sebastian Grosicki, Florence Cymbalista, Steven Sun, Joi Ninomoto, Michelle Mahler, Mei Cheng, Joris Diels, Fong Clow, Mariya Salman, Danelle F. James, Angela Howes, Asher Chanan-Khan
Journal: Blood (2015)
A novel live cell platform diagnostic utilizing phenotypic biomarkers for assessing prostate cancer aggressiveness.
Authors: Kevin B. Knopf, Kimberly M. Rieger-Christ, Travis B. Sullivan, Naveen Kella, Hani H. Rashid, Vladimir Mouraviev, Michael S. Manak, Brad J. Hogan, Gauri Dixit, Wendell R. Su, Delaney Berger, Matthew J. Whitfield, Jonathan S. Varsanik, Mani Foroohar, Stephen M Zappala, David Albala, Ashok C. Chander, Grannum R. Sant
Journal: Journal of Clinical Oncology (2016)

e16567 Background: A novel tissue based biomarker panel is developed to objectively assess disease aggressiveness and invasive potential of Prostate Cancer (CaP). The biomarker diagnostic platform incorporates matrix biology, phenotypic biomarkers, microfluidics, image analysis, and predictive statistical algorithms that may allow an improved understanding of disease progression and metastatic spread. This technology presents the opportunity to culture samples, and both determine and automate biomarker measurements via image analysis algorithms to generate predictive metrics. Data are presented towards clinical validation, the ability to risk stratify, and prediction of local aggressiveness and metastasis. Methods: Conditions were optimized for reliably imaging primary cancer cells in vitro by simulating in vivo conditions on an extracellular matrix formulation. A microfluidics device was used to culture live tumor samples ex vivo enabling automated imaging of the phenotypic biomarkers. Results: The validation study was IRB approved and performed in 250 consecutive CaP radical prostatectomy derived specimens collected between 03/2014 and 01/2016. Data was analyzed with receiver operating characteristics (ROC) generated Area-under-the-Curve (AUC) and specifically included capsular penetration, seminal vesicle invasion, as well as margin-positive disease. The study further demonstrated that a normal set of phenotypic biomarkers can be synthesized into predictive scores termed Local Adverse Pathology Potential (LAPP) and Metastatic Adverse Pathology Potential (MAPP). Concordance analysis supports that LAPP and MAPP are integral for distinguishing between benign histology and malignancy, predicting both stage and adverse pathology such as extra-prostatic extension (EPE) and lympho-vascular invasion (LVI). The study results demonstrate AUCs greater than 0.80 in predicting EPE and LVI. Conclusions: Results support the clinical validation of a novel live- cell phenotypic in vitro tumor diagnostic test. This test has the potential to predict adverse pathologies for CaP and may have extended clinical applications to optimize staging and risk stratification.
Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy.
Authors: Nasser H. Hanna, Rolf Kaiser, Richard N. Sullivan, Osvaldo Rudy Aren, Myung-Ju Ahn, Beatrice Tiangco, Zanete Zvirbule, Carlos H. Barrios, Ahmet Demirkazik, Birgit Gaschler-Markefski, Isabelle Voccia, Jose Barrueco, Joo-Hang Kim
Journal: Journal of Clinical Oncology (2013)

8034 Background: Nintedanib (N) is an oral inhibitor of VEGFR, FGFR, and PDGFR. This global phase 3 study investigated the safety and efficacy of N + pemetrexed (PEM) vs placebo (P) + PEM in patients (pts) with advanced, non-squamous NSCLC previously treated with chemotherapy. Methods: Pts were randomized 1:1 to N 200 mg po bid + PEM 500 mg/m 2 iv q21d (n=353, Arm A) or P + PEM (n=360, Arm B). Continuation until PD or unacceptable toxicity with N, P, PEM, or a combination was permitted. 1° endpoint was centrally reviewed PFS. The null hypothesis was tested on the ITT population after 394 events had occurred (two sided α=5%). 2° endpoints included OS, investigator-assessed PFS, response rate (RR), safety, and QoL. Results: Baseline pt characteristics were balanced between Arm A vs B (median age 59 y, female 45–42%, ECOG PS 1 62-61%, adenocarcinoma 95–93%, prior bevacizumab 8%). Based on a planned DMC futility analysis of investigator-assessed PFS, enrolment was halted after randomizing 713/1300 planned pts (no safety issues identified). Ongoing pts were unblinded and follow-up continued per protocol. Subsequent ITT analysis of the 1° endpoint (centrally reviewed PFS) favored Arm A vs B (median 4.4 vs 3.6 mo, HR 0.83 [95% CI: 0.7–0.99], p=0.04). Disease control was also significantly improved in N-treated pts (61 vs 53%, odds ratio 1.37, p=0.039). No difference in OS (HR 1.03) or RR (9%) was found. Exploratory analyses identified time since start of 1 st -line therapy as a predictive marker of improved outcome with N + PEM (ASCO 2013). There was no increase in SAEs or G5 AEs with N + PEM. Addition of N to PEM resulted in a higher incidence of ≥G3 elevated ALT (23 vs 7%), elevated AST (12 vs 2%), and diarrhea (3 vs 1%), but no difference in ≥G3 hypertension, bleeding, thrombosis, mucositis, or neuropathy. Conclusions: The 1° endpoint was met even though the study was stopped prematurely. Treatment with N + PEM significantly improved centrally reviewed PFS vs P + PEM in pts with advanced non-squamous NSCLC previously treated with chemotherapy, and had a manageable safety profile. Clinical trial information: NCT00806819.
Abstract 4784: FGFR-selective inhibitor Debio 1347 induces tumor regressions in FGFR2-altered gastric cancer PDX models
Authors: Brichory Franck, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin
Journal: Cancer Research (2016)

Abstract Dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway due to receptor overexpression, gene amplification, point mutations or fusions/chromosomal translocations is associated with cancer development and progression. In gastric cancer, alterations of FGFR2 are observed in a subset of patients, overexpression being more frequently observed as compared to FGFR2 amplifications. In addition, FGFR2 amplification and ERBB2, EGFR, MET and KRAS amplifications are mutually exclusive suggesting that FGFR targeted therapy would be most effective in the FGFR2-amplified subgroup of patients. Debio 1347 (CH5183284) is an oral selective FGFR inhibitor currently in clinical development. The aim of the study was to investigate the preclinical activity of Debio 1347 in patient derived xenograft (PDX) mouse models harboring diverse FGFR alterations in multiple indications, including gastric cancer. The mouse trial was conducted in 39 different PDX models selected according to FGFR1, 2 and 3 alterations status. Debio 1347 was administered orally once daily and tumor volume was monitored for 14 consecutive days. PDX tumors were extensively characterized using FISH, RNAseq, nCounter Gene Expression and immunohistochemistry (IHC), and FGFR molecular alterations were correlated with Debio 1347 efficacy. The level of tumor heterogeneity for FGFR2 amplification and expression and its impact on drug response were also assessed. In gastric cancer, Debio 1347 induced tumor regression in models harboring the commonly found FGFR2 amplification. Interestingly, Debio 1347 was also highly effective in models with high FGFR2 expression but without FGFR2 amplification, indicating that not only gene amplification drives the activity of Debio 1347 in this indication, but also the expression level of FGFR2. Altogether, these data demonstrate that Debio 1347 could be highly effective in gastric cancer patients harboring FGFR2 amplification and/or high FGFR2 expression. Debio 1347 is currently investigated in a Phase I trial in selected patients harboring FGFR alterations (NCT01948297). Citation Format: Brichory Franck, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin. FGFR-selective inhibitor Debio 1347 induces tumor regressions in FGFR2-altered gastric cancer PDX 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 4784.
Reply to Thorsten Derlin, Matthias Eiber, Markus Schwaiger, and Frank M. Bengel's Letter to the Editor re: Lars Budäus, Sami-Ramzi Leyh-Bannurah, Georg Salomon, et al. Initial Experience of 68Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur Urol 2016;69:393–6
Authors: Lars Budäus, Sami-Ramzi Leyh-Bannurah, Thomas Steuber
Journal: European Urology (2015)