April 2016 – Page 119 – 1stOncology™: Cancer Intelligence Service

Endocyte Announces Presentations at American Association for Cancer Research (AACR) Annual Meeting 2016

On April 11, 2016 Endocyte, Inc. (NASDAQ:ECYT), a leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy, reported that four posters will be presented by Endocyte scientists at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 to be held in New Orleans, April 16-20, 2016 (Press release, Endocyte, APR 11, 2016, View Source [SID:1234510659]).

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The presentation materials will be available on Endocyte’s website following presentation at the conference.

Presentations are as follows:

Abstract #: 262
Title: Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models
When: Sunday, April 17, 1 p.m. – 5 p.m. EDT
Session Title: Combination Chemotherapy
Location: Halls G-J, Poster Section 15

Abstract #: 3035
Title: Development and characterization of CCK2R-targeted SMDCs and identification of GIST as a potential therapeutic indication
When: Tuesday, April 19, 8 a.m. – 12 p.m. EDT
Session Title: Novel Targets and Pathways
Location: Halls G-J, Poster Section 17

Abstract #: 3754
Title: Pre-clinical studies of a highly potent Folate receptor targeted DNA crosslinking agent
When: Tuesday, April 19, 1 p.m. – 5p.m. EDT
Session Title: Novel Antitumor DNA-Reactive Agents
Location: Halls G-J, Poster Section 16

Abstract #: 4735
Title: Designing Novel Warheads for Targeted Therapies: SAR and Efficient Strategies for Synthesis of Analogs of Tubulysin
When: Wednesday, April 20, 8 a.m. – 12 p.m. EDT
Session Title: HDAC, Methyltransferase Inhibitors, and Novel Anticancer Agents

Computer-aided identification of new histone deacetylase 6 selective inhibitor with anti-sepsis activity.

Histone deacetylase (HDAC) inhibitors have been recognized as promising approaches to the treatment of various human diseases including cancer, inflammation, neurodegenerative diseases, and metabolic disorders. Several pan-HDAC inhibitors are currently approved only as anticancer drugs. Interestingly, SAHA (vorinostat), one of clinically available pan-HDAC inhibitors, shows an anti-inflammatory effect at concentrations lower than those required for inhibition of tumor cell growth. It was also reported that HDAC6 selective inhibitor tubastatin A has anti-inflammatory and anti-rheumatic effect. In our efforts to develop novel HDAC inhibitors, we rationally designed various HDAC inhibitors based on the structures of two hit compounds identified by virtual screening of chemical database. Among them, 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) was identified as a HDAC6 selective inhibitor (IC50 values of 0.199 μM for HDAC6 versus 13.8 μM for HDAC1), and it did not show significant cytotoxicity against HeLa cells. In vivo biological evaluation of 9a was conducted on a lipopolysaccharide (LPS)-induced mouse model of sepsis. The compound 9a significantly improved 40% survival rate (P = 0.0483), and suppressed the LPS-induced increase of TNF-α and IL-6 mRNA expression in the liver of mice. Our study identified novel HDAC6 selective inhibitor 9a, which may serve as a potential lead for the development of anti-inflammatory or anti-sepsis agents.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.

VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research.

Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile variant caller for both DNA- and RNA-sequencing data. VarDict simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on the fly for more accurate allele frequency estimation. VarDict performance scales linearly to sequencing depth, enabling ultra-deep sequencing used to explore tumor evolution or detect tumor DNA circulating in blood. In addition, VarDict performs amplicon aware variant calling for polymerase chain reaction (PCR)-based targeted sequencing often used in diagnostic settings, and is able to detect PCR artifacts. Finally, VarDict also detects differences in somatic and loss of heterozygosity variants between paired samples. VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls. We believe VarDict will greatly facilitate application of NGS in clinical cancer research.
© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Population-based study of giant cell tumor of bone in Sweden (1983-2011).

Giant-cell tumor of bone (GCTB) is a locally aggressive histologically benign neoplasm with a less common malignant counterpart. Longitudinal data sources on GCTB are sparse, limited to single institution case series or surgical outcomes studies. The Swedish Cancer Registry is one of the few national population-based databases recording GCTB, representing a unique source to study GCTB epidemiology. We estimated incidence rate (IR) and overall mortality rates based on registry data.
We identified patients with a GCTB diagnosis in the Swedish Cancer Registry from 1983 to 2011: benign (ICD-7 196.0-196.9; PAD 741) and malignant (PAD 746). Results were stratified by age at diagnosis, gender, and anatomical lesion location.
The cohort included 337 GCTB cases (IR of 1.3 per million persons per year). The majority (n=310) had primary benign GCTB (IR of 1.2 per million per year). Median age at diagnosis was 34 years (range 10-88) with 54% (n=183) females. Malignant to benign ratio for women was 0.095 (16/167) and for men 0.077 (11/143). Incidence was highest in the 20-39 years age group (IR of 2.1 per million per year). The most common lesion sites were distal femur and proximal tibia. Mortality at 20 years from diagnosis was 14% (n=48) and was slightly higher for axial (17%; n=6) and pelvic (17%; n=4) lesions. Recurrence occurred in 39% of primary benign cases and 75% of primary malignant cases.
In our modern population-based series primary malignant cases were uncommon (8%), peak incidence 20-39 years with slight predominance in women. Recurrence rates remain significant with overall 39% occurring in benign GCTB, and 75% in malignant form. The linkage between databases allowed the first population based estimates of the proportion of patients who received surgery at initial GCTB diagnosis, and those who also received subsequent surgeries.
Copyright © 2016 Elsevier Ltd. All rights reserved.

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice.
A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII(). A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics.
Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively).
Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

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Month: April 2016

Endocyte Announces Presentations at American Association for Cancer Research (AACR) Annual Meeting 2016

Computer-aided identification of new histone deacetylase 6 selective inhibitor with anti-sepsis activity.

VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research.

Population-based study of giant cell tumor of bone in Sweden (1983-2011).

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.