tbuckley/cabot-search huggingface dataset:
Abstract 1317: IT-143: A nanoparticle delivery platform that encapsulates daunorubicin and widens therapeutic window
Authors: Tara Lee Costich, Rick Crouse, Adam Carie, Taylor Buley, Tyler Ellis, Lauren Repp, J.Edward Semple, Tomas Vojkovsky, Suzanne Bakewell, Kevin Sill
Journal: Cancer Research (2016)

Abstract Daunorubicin is an anthracycline family chemotherapeutic with a narrow therapeutic window. Employing our nanoparticle drug delivery platform we encapsulated daunorubicin non-covalently in the hydrophobic core of a polymer micelle (IT-143). IT-143 is a nanoparticle formulation comprised of a hydroxamic acid triblock polymer with ferric crosslinking that increases stability for improved drug circulation and results in a pH dependent release of the encapsulated daunorubicin. Formulation characterization demonstrates a 3.7% weight loading (v/v) of daunorubicin resulting in an average micellar size of 58 nm. In vitro cytotoxicity is comparable to daunorubicin free drug with an IC50 ranging between 60-100 nM, dependent on cell line, compared to 67-114 nM for daunorubicin. In vivo we compared IT-143 plasma pharmacokinetics to daunorubicin administered as free drug and the Cmax was extended from 0.18 μg/mL for daunorubicin to 27.0 μg/mL for IT-143 at the 3 mg/kg dose, and to 49.4 μg/mL at the 6 mg/kg dose. We increased the maximum tolerated dose (MTD) from 7.5 mg/kg to 17.5 mg/kg in mice and improved anti-tumor efficacy. Furthermore, IT-143 eliminated in vivo toxicity compared to equivalent daunorubicin dosed at its MTD. Efficacy studies in 3 xenograft models (HCT116, HT-1080 and HOS-MNNG) compared intravenous bolus administration of IT-143 at equivalent and equitoxic dose to daunorubicin treatment. IT-143 inhibited HCT116 colorectal tumor volume growth by 21% compared to 7% at the equivalent daunorubicin dose, and by 51% at the 17.5 mg/kg dose. In the HT-1080 fibrosarcoma model IT-143 inhibited tumor volume by 38% compared to 37% inhibition at the equivalent daunorubicin dose, and by 94% at the 17.5 mg/kg dose. In the HOS-MNNG osteosarcoma model IT-143 did not inhibit tumor volume compared to 21% inhibition at the equivalent daunorubicin dose, but inhibited tumor volume by 34% at the 17.5 mg/kg dose. The encapsulation of daunorubicin as IT-143 exhibits increased dosage of daunorubicin with decreased toxicities not possible with free daunorubicin. These studies indicate that IT-143 widens the therapeutic window of daunorubicin treatment, providing a safer way to reduce patient toxicity yet increasing antitumor efficacy. Citation Format: Tara Lee Costich, Rick Crouse, Adam Carie, Taylor Buley, Tyler Ellis, Lauren Repp, J.Edward Semple, Tomas Vojkovsky, Suzanne Bakewell, Kevin Sill. IT-143: A nanoparticle delivery platform that encapsulates daunorubicin and widens therapeutic window. [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 1317.
Abstract 1068: The promise of miR-205 in HER2+ breast cancer: predicting response to Trastuzumab and overcoming resistance
Authors: Claudia Piovan, Elvira D’Ippolito, Ilaria Plantamura, Patrizia Casalini, Elda Tagliabue, Marilena V. Iorio
Journal: Cancer Research (2016)

Abstract HER2, member of HER family, is overexpressed in up to 30% of breast cancers and often associated to a more aggressive phenotype, resistance to chemotherapeutic agents and increased risk of metastasis. Anti-HER2 targeted therapies significantly increased the overall survival of HER2 breast cancer patients, however tumor cells frequently develop alternative resistance mechanisms and the molecular bases of this phenomenon are still far to be fully elucidated. A crucial issue is then represented by the urgent need of biomarkers able to predict the response to treatment, and certainly of new therapeutic tools to counteract the resistance mechanisms. The oncosuppressive role of miR-205 in the pathogenesis of breast cancer has been demonstrated, as well as a possible cross-regulation between miR-205 and HER signaling. MiR-205 is in fact negatively regulated by HER2 and is involved in the regulation of HER2-mediated proliferation by directly targeting HER3, preferential partner of HER2. We have investigated miR-205 role on trastuzumab resistance by using human HER2 overexpressing breast cancer cell lines and patient-derived xenograft (PDX) models. Here we show that HER3 silencing, either mediated by miR-205 or by a siRNA specific against HER3, is able to improve the responsiveness to Trastuzumab, reducing tumor cell growth and colony formation capability. This effect is mediated by impairment of Akt-mediated pathway.Combination of Trastuzumab treatment and in vivo delivery of miR-205-conjugated lipid nanoparticles in PDX models is currently on going. Finally, expression analysis of miR-205 in breast cancer patients treated in adjuvant with trastuzumab has provided new insights about its possible role as predictive biomarker of response. In summary, here we show that miR-205 improves the responsiveness to Trastuzumab treatment at least partially though HER3 silencing, and associated to outcome of patients treated in adjuvant setting, thus representing a potential adjuvant tool and predictive biomarker. Citation Format: Claudia Piovan, Elvira D’Ippolito, Ilaria Plantamura, Patrizia Casalini, Elda Tagliabue, Marilena V. Iorio. The promise of miR-205 in HER2+ breast cancer: predicting response to Trastuzumab and overcoming resistance. [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 1068.
Range of generics will be withdrawn across Europe
Authors: Nigel Hawkes
Journal: BMJ (2016)

Many generic medicines sold across Europe will have to be withdrawn from the market, after the European Medicines Agency (EMA) said that studies carried out in India cannot be relied on.1

The ban covers generic medicines approved after studies at Semler Research Centre, Bengaluru (Bangalore), certified that they were biologically equivalent to the original drugs. The EMA is following the lead of the US Food and Drug Administration and the World Health Organization, which inspected Semler’s laboratories at the end …
Nonallergic rhinitis and lower airway disease
Authors: C. Rondón, G. Bogas, E. Barrionuevo, M. Blanca, M. J. Torres, P. Campo
Journal: Allergy (2016)

In the past years, several investigators have demonstrated the existence of local nasal responses in some patients with typical allergic rhinitis symptoms but without atopy and have defined a new phenotype called local allergic rhinitis (LAR) or 'entopy'. In a percentage of LAR subjects, the upper airway disease is also associated with lower airway symptoms. After the description of this phenotype, the differential diagnosis between LAR and nonallergic rhinitis (NAR) has become a challenge for the clinician. To correctly identify LAR patients is of high importance for treatment and management of these patients, and for an appropriate inclusion of patients in clinical trials and genetics studies. The treatment of LAR patients, in contrast with NAR, is oriented to allergen avoidance and specific treatment. Allergen immunotherapy, the aetiological treatment for allergic respiratory diseases, has demonstrated to be an effective and safe treatment in LAR, increasing immunological tolerance, and reducing the clinical symptoms and the use of medication. In this article, the important and novel aspects of LAR in terms of mechanisms, diagnosis and treatment will be discussed. Also, the involvement of the lower airway and the potential role of IgE in the bronchial disease will be also reviewed.
Abstract 17: Metabolic analysis of IDH mutant gliomas in Drosophila
Authors: Michaela Brown, Jenna Buccetti, Marla Tipping
Journal: Cancer Research (2016)

Abstract Metabolic reprogramming is a common hallmark shared by nearly all proliferating cancer cells and has emerged as an exciting new direction in cancer research. Many signaling pathways have been implicated in mechanisms leading to the shift of metabolic programs in tumors, but more recently a small number of metabolic enzymes have also been identified in this process. Genes encoding the metabolic enzymes Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) were found to be mutated in up to 70% of low-grade and medium grade gliomas, and in 15-20% of adult acute leukemia samples. These findings were the first to link the IDH gene to tumorigenesis. IDH1 and IDH2 function to irreversibly catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Although these are important metabolic enzymes, little is known about the metabolic impact harboring mutant IDH protein has on cells. Our goal is to model the IDH mutant phenotype in Drosophila glial cells for further characterization of both metabolic status, and IDH enzymatic activity. To this end, we have generated Drosophila cell lines and transformant flies that express the most commonly identified IDH mutations under control of the UAS-Gal4 system. We have also investigated the metabolic flux of Drosophila cell lines expressing IDH mutant protein, and loss of IDH function, and glycolytic enzyme expression analysis. Currently, we are investigating the metabolic flux analysis (MFA) using labeled metabolites as well as comparing the protein interactions of the wild type to the mutant IDH cells. The results of these investigations will identify potential new targets for the treatment of aggressive gliomas at the level of cellular metabolism. Citation Format: Michaela Brown, Jenna Buccetti, Marla Tipping. Metabolic analysis of IDH mutant gliomas in Drosophila. [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 17.
A novel preoperative inflammatory marker prognostic score in patients with clear cell renal cell carcinoma.
Authors: Rishi Robert Sekar, Dattatraya Patil, Jeff Pearl, Yoram Baum, Omer Kucuk, Wayne B. Harris, Bradley Curtis Carthon, Mehrdad Alemozaffar, Christopher Paul Filson, Kenneth Ogan, Viraj A. Master
Journal: Journal of Clinical Oncology (2016)

566 Background: Several inflammatory markers have been singularly studied as potential biomarkers in clear cell renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate. We hypothesize that a combination of preoperative C-Reactive Protein (CRP), albumin, Erythrocyte Sedimentation Rate (ESR), corrected calcium, and AST/ALT ratio into a RCC Inflammatory Score (RISC) could serve as a rigorous prognostic indicator in patients with clear cell RCC. Methods: Patients that underwent nephrectomy for localized clear cell RCC were queried from our nephrectomy database. The optimal threshold for individual biomarkers was determined using grid search methodology, receiver operating characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. The final score, RISC, was the sum of all points accrued from each biomarker (Table). ROC and chi-square analysis was performed to compare the prognostic ability of RISC to SSIGN and UISS. Impact on overall survival was analyzed with multivariate logistic regression analysis. Results: 280 patients were included in the study. Area under the curve (AUC) for RISC, SSIGN and UISS was 0.77, 0.78, and 0.81, respectively. Chi-square analysis of AUCs revealed no statistically significant difference between RISC, SSIGN, and UISS (p= 0.975 and p =0.299, respectively). On multivariate analysis, after adjusting for confounding variables, each unit increase in RISC was associated with a 31% increase in mortality (HR=1.31, 95%CI 1.13-1.50, p&lt;0.001). Conclusions: RISC is an independent and significant predictor of overall survival in clear cell RCC with accuracy at least as good as other established prognostic tools. Notably, RISC is composed of standardized laboratory markers easily and cost-effectively obtained preoperatively, allowing crucial prognostic information to be integrated into medical decision making prior to surgery. [Table: see text]
Multiple Myeloma (MM) In Older (&gt;70 year) Patients - Similar Benefit From Autologous Hematopoietic Cell Transplantation (AHCT) Compared With Younger Patients
Authors: Manish Sharma, Mei-Jie Zhang, Xiaobo Zhong, Cristina J. Gasparetto, Amrita Y. Krishnan, Sagar Lonial, Parameswaran Hari
Journal: Blood (2013)
Abstract 2529: Expression of ABCF1 with stem cell markers CD133/GEP/beta-catenin in fetal liver and liver cancer cells
Authors: Sze Wai Fung, Phyllis Fung Yi Cheung, Chi Wai Yip, George Sai Wah Tsao, Siu Tim Cheung
Journal: Cancer Research (2016)

Abstract Understanding stem cell biology in relation to cancer is of growing importance with the cancer stem cells (CSCs) notion and recurring deregulated stem cell pathways reported in cancers. ATP-binding cassette (ABC) transporter ABCB1 (also named P-glycoprotein and MDR1) has shown to be CSC marker, mediate multidrug-resistance in model systems though with controversial clinical relevance. We have systemically examined the expression profiles of ABC genes in hepatocellular carcinoma (HCC) clinical samples. ABCF1 was significantly over-expressed in HCCs compared to the adjacent non-tumor liver tissues (P&amp;lt;0.001) and associated with recurrence-free survival after curative partial hepatectomy (log rank, P = 0.010). Recurrences have conventionally been attributed to aggressive cancer features and, recently, CSC features, as CSCs in small load could grow to tumor bulk. We therefore further explored the significance of ABCF1 in both fetal liver and liver cancer cells in respect to stem cell signaling. Expression of ABCF1 in fetal, neonatal and adult mouse livers were examined by immunohistochemistry, western blot and flow cytometry. Consistently, elevated ABCF1 expression was demonstrated in early embryonic stages [embryonic day 13 (E13): 42.4%; E15: 24.6%] but rarely in neonates and adult livers [1.5% and 1.2%, respectively]. Also, ABCF1 co-stained with stem cell-related marker β-catenin and hepatic CSC markers CD133 and GEP in fetal hepatocytes and in HCC cells (Table 1). ABCF1 suppression by siRNA enhanced chemo-sensitivity of the HCC cells Hep3B compared to control cells on cisplatin (cell apoptosis 7.5% vs 1.7%, P&amp;lt;0.001) and 5-Fluorouracil (11.7% vs 4.7%, P&amp;lt;0.001). Subcellular fractionation analysis on HCC cells showed that ABCF1 protein was present in both the cytoplasmic and membrane fractions. The current study highlighted the functional significance of ABCF1 in liver development and liver cancer as stem cell-related molecule regulating chemo-resistance. Table 1.Co-expression of ABCF1 and hepatic stem cell markers in mouse fetal livers and HCC cellsFetal liver cells (E15)Liver cancer cells (Hep3B)ABCF1+24.6%34.5%CD133+16.3%88.8%ABCF1+ CD133+20.9%34.3%GEP+45.7%65.7%ABCF1+ GEP+24.0%29.7%β-catenin+40.6%20.9%ABCF1+ β-catenin+13.5%17.5% Citation Format: Sze Wai Fung, Phyllis Fung Yi Cheung, Chi Wai Yip, George Sai Wah Tsao, Siu Tim Cheung. Expression of ABCF1 with stem cell markers CD133/GEP/beta-catenin in fetal liver and liver cancer cells. [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 2529.
A randomized controlled trial (RCT) of a supportive care package (SurvivorCare, SC) for survivors of colorectal cancer (CRC).
Authors: Michael Jefford, Karla Gough, Allison Drosdowsky, Lahiru Russell, Sanchia Aranda, Phyllis Noemi Butow, Jo Phipps-Nelson, Jane Young, Meinir Krishnasamy, Anna Ugalde, Dorothy King, Andrew Strickland, Michael Edward Franco, Robert helmut Blum, Catherine Johnson, Vinod Ganju, Jeremy Shapiro, Geoffrey Chong, Julie Charlton, Penelope Schofield
Journal: Journal of Clinical Oncology (2016)

79 Background: Colorectal cancer (CRC) and its treatments can cause distressing short and long-term side effects as well as significant functional consequences. Current models of follow-up do not adequately address these issues. We conducted a multi-center RCT of an innovative program (SurvivorCare (SC)); designed to have a beneficial effect on psychological distress, supportive care needs (SCN) and quality of life (QOL). Methods: At the end of active treatment for stage I-III CRC, eligible patients ( =18 years, adequate English) were randomized 1:1 to usual care (UC) or to UC+SC. SC comprised educational materials, needs assessment, an individualized survivorship care plan, nurse-led end-of-treatment session and three follow up (FU) phone calls. Distress (BSI-18), SCN (CaSUN) and QOL (EORTC QLQ-C30, CR29) were assessed at baseline, 2 (FU1) and 6 (FU2) months. Primary hypothesis: SC would have a beneficial effect on distress at FU1. Secondary hypotheses: SC would have a beneficial effect on (1) SCN and QOL at FU1; and (2) distress, SCN and QOL at FU2. 15 items assessed satisfaction with survivorship care. Sample size of 180 (90/arm) was based on 80% power, 2-sided alpha of 0.05, to detect a between groups difference of 3.6 on BSI-18 at FU1. Outcome analysis was ITT. Results: Of 221 patients randomized (111 UC, 110 SC), 4 were ineligible and 1 lost to FU, leaving 110 UC, 106 SC. Groups appeared well balanced. Median age was 64, 52% male, 56% colon, 35% rectal cancer, 10% overlap. Stage I 7%, II 22%, III 71%. Intervention fidelity was acceptable. Baseline distress and QOL were similar to population norms. Between groups differences in distress at FU1 (primary outcome), distress at FU2 and SCN and QOL at FU1 and FU2 were small and non-significant. SC patients were more satisfied with survivorship care than UC patients (significant differences on 10 of 15 items). Conclusions: The addition of SC to UC did not have a beneficial effect on distress, SCN or QOL outcomes but SC patients were more satisfied with survivorship care. Clinical trial information: ACTRN12610000207011.
Abstract 3806: Phosphaplatins are potent inducers of pigment epithelial- derived factor (PEDF)
Authors: Louiza Belkacemi, Armando Rivera, Lu Yang, Rathindra N. Bose, Shaun X. Zhang
Journal: Cancer Research (2016)

Abstract Pigment Epithelial Derived Factor (PEDF) is a secreted glycoprotein that exhibits several biological activities, most notably as a potent anti-angiogenic agent as well as a neurotrophic factor. As such, this molecule has potential application as therapeutics for cancer and a variety of neurological diseases. However, prior art methods directed towards enhancing and stabilizing PEDF expression in vivo have met with little success. Therefore, methods that could lead to the stable expression of PEDF in vivo are still needed. We have recently shown that PEDF protein is overexpressed in tumor cells treated with platinum based drugs; phosphaplatins that are platinum-(II) and platinum-(IV) complexes coordinated to a pyrophosphate moiety. The objective of this study is to extend our previous findings by measuring PEDF expression in both malignant cells and normal neuronal tissues after treating them with these compounds. We also investigated the impact of PEDF upregulation on important biological processes such as apoptosis, proliferation and invasion of tumor cells. Our data showed that there was a significant upregulation (over 4-fold) of PEDF in brain of mice treated with phosphoplatins when compared to the control animals. The compounds were found to stimulate PEDF expression in cultured neuronal cells when assessed in vitro (P&amp;lt;0.05 vs. untreated control groups). In tumor cells, phosphoplatins upregulated PEDF expression in a dose-dependent manner in various tumor cell lines. In one particular mouse breast tumor cell line (4T1), the data showed that phosphaplatin doses in the range of 25 to 100 μM stimulated the expression of PEDF at 12 and 24 hrs, which declined thereafter. Remarkably, a subsequent treatment of the tumor cells with phosphaplatins at 24 hrs prevented the decline of PEDF expression, suggesting a direct correlation between phosphaplatins and PEDF overexpression. The upregulation of PEDF in the tumor cells was paralleled by increased apoptosis and decreased cell proliferation and invasion. In summary, phosphaplatins mediated overexpression of PEDF in vivo suggests a potential neuroprotective effect of these compounds. While in tumors, phosphaplatins may exhibit antitumor activity via multiple effects, including anti-angiogenesis, enhanced apoptosis, and decreased proliferation and invasion, predominately through stimulating overexpression of PEDF. Citation Format: Louiza Belkacemi, Armando Rivera, Lu Yang, Rathindra N. Bose, Shaun X. Zhang. Phosphaplatins are potent inducers of pigment epithelial- derived factor (PEDF). [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 3806.
Abstract 568: FAK/PYK2 inhibition enhances immune checkpoint inhibitor efficacy
Authors: Yan Wang, Jennifer E. Ring, Kam Sprott, David T. Weaver, Jonathan A. Pachter
Journal: Cancer Research (2016)

Abstract Although durable responses to single agent immune checkpoint inhibitors have been reported, additional approaches are needed to improve upon this therapeutic benefit. Combinations of immunotherapy agents with tumor microenvironment modulators have the potential to overcome barriers that tumor cells develop to evade the immune system, and provide benefit to a greater proportion of patients. Focal Adhesion Kinase (FAK) and its family member, PYK2, are potentially valuable targets due to their roles in regulating key cellular populations in the tumor microenvironment. In addition to targeting cancer stem cells, the FAK/PYK2 dual inhibitors, VS-6063 and VS-4718, have been shown to inhibit monocyte-derived macrophages, reduce tumor-associated macrophages in xenograft models, and promote a CD8+ T cell-mediated anti-tumor response in squamous cell carcinoma models. We now report that the combination of VS-4718 with an anti-PD-1 mAb shows improved efficacy over anti-PD-1 mAb alone and extends survival of MC38 syngeneic tumor bearing animals. Analysis of MC38 tumors at day 12 of treatment revealed a significant increase in the CD8+ T cells/Treg ratios in tumors in the VS-4718 + anti-PD-1 combination group, providing a mechanistic understanding for the enhanced efficacy of this combination. To explore additional combination options, we tested the combination of VS-4718 with anti-4-1BB in the MC38 model. Consistent with what was observed with the anti-PD-1 combination, VS-4718 also enhanced the efficacy of an anti-4-1BB mAb. To further delineate direct effect of FAK inhibition on human T cells, in vitro T cell proliferation assays were conducted. VS-6063 and VS-4718 dose-dependently stimulated proliferation of CD8+ cytotoxic T cells isolated from healthy donors. This is in distinct contrast to other protein kinase inhibitors, such as the SRC inhibitor dasatinib which impaired the proliferation of CD8+ cytotoxic T cells. In addition, both VS-4718 and VS-6063 decreased CD8+ T cell exhaustion markers, and increased T cell-mediated tumor cell killing in vitro. These data provide a rationale for clinical trials in cancer patients to test whether a FAK/PYK2 inhibitor in combination with an immune checkpoint inhibitor could increase the breadth of responsive tumor types, increase the number of responders, and confer more durable anti-tumor responses. Citation Format: Yan Wang, Jennifer E. Ring, Kam Sprott, David T. Weaver, Jonathan A. Pachter. FAK/PYK2 inhibition enhances immune checkpoint inhibitor efficacy. [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 568.