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Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition.

Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or &quot;slow&quot; substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors.

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Celator® Pharmaceuticals Announces New Data for VYXEOS™ in FLT3-ITD Mutated AML Cells Derived from Patients with Newly Diagnosed AML to be Presented at the American Association for Cancer Research Annual Meeting

On March 31, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that data for VYXEOS (cytarabine:daunorubicin) Liposome for Injection (also known as CPX-351), its lead product candidate, will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, April 16-20, 2016 (Press release, Celator Pharmaceuticals, MAR 31, 2016, View Source [SID:1234510229]).

The research was conducted in the laboratory of Dr. Jeffrey Tyner at Oregon Health & Science University. The objective of the research was to examine the ex vivo sensitivity of acute myeloid leukemia (AML) cells derived from newly diagnosed patients to VYXEOS. This work supports the observed clinical benefit of VYXEOS in high-risk AML patients and may provide a means of identifying patient genotypes/phenotypes most sensitive to VYXEOS.

"We continue to learn more about the unique activity of VYXEOS in AML and enhance our ability to match this performance with specific patient characteristics that could be predictive of improved outcomes," said Lawrence Mayer, Ph.D., President and Chief Scientific Officer at Celator. "The research being undertaken by Dr. Tyner reflects Celator’s goal to elucidate the clinical benefits of VYXEOS by expanding our scientific understanding of its mechanism of action, particularly in AML cells with important molecular phenotypes."

Details on the AACR (Free AACR Whitepaper) poster presentation:

Presentation Title:
CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes
Date/Time:
Sunday, April 17, 2016 – 1:00pm-5:00pm
Session Category:
Poster Presentation
Session Title:
ET01-03, Combination Chemotherapy
Location:
New Orleans Convention Center, Halls G-J Poster Section 15
Abstract Number:
287

The poster will be available on Celator’s website (www.celatorpharma.com) at the conclusion of the AACR (Free AACR Whitepaper) meeting.

A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.
VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.
Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).
VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

Subsecond and Submillimeter Resolution Positional Verification for Stereotactic Irradiation of Spinal Lesions.

Spine stereotactic body radiation therapy (SBRT) requires highly accurate positioning. We report our experience with markerless template matching and triangulation of kilovoltage images routinely acquired during spine SBRT, to determine spine position.
Kilovoltage images, continuously acquired at 7, 11 or 15 frames/s during volumetric modulated spine SBRT of 18 patients, consisting of 93 fluoroscopy datasets (1 dataset/arc), were analyzed off-line. Four patients were immobilized in a head/neck mask, 14 had no immobilization. Two-dimensional (2D) templates were created for each gantry angle from planning computed tomography data and registered to prefiltered kilovoltage images to determine 2D shifts between actual and planned spine position. Registrations were considered valid if the normalized cross correlation score was ≥0.15. Multiple registrations were triangulated to determine 3D position. For each spine position dataset, average positional offset and standard deviation were calculated. To verify the accuracy and precision of the technique, mean positional offset and standard deviation for twenty stationary phantom datasets with different baseline shifts were measured.
For the phantom, average standard deviations were 0.18 mm for left-right (LR), 0.17 mm for superior-inferior (SI), and 0.23 mm for the anterior-posterior (AP) direction. Maximum difference in average detected and applied shift was 0.09 mm. For the 93 clinical datasets, the percentage of valid matched frames was, on average, 90.7% (range: 49.9-96.1%) per dataset. Average standard deviations for all datasets were 0.28, 0.19, and 0.28 mm for LR, SI, and AP, respectively. Spine position offsets were, on average, -0.05 (range: -1.58 to 2.18), -0.04 (range: -3.56 to 0.82), and -0.03 mm (range: -1.16 to 1.51), respectively. Average positional deviation was &lt;1 mm in all directions in 92% of the arcs.
Template matching and triangulation using kilovoltage images acquired during irradiation allows spine position detection with submillimeter accuracy at subsecond intervals. Although the majority of patients were not immobilized, most vertebrae were stable at the sub-mm level during spine SBRT delivery.
Copyright © 2016 Elsevier Inc. All rights reserved.

DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising anti-tumor efficacy with differentiation from T-DM1.

An anti-HER2 antibody drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new anti-tumor drug candidate, and its preclinical pharmacological profile was assessed.
In vitro and in vivo pharmacological activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.
DS-8201a exhibited a HER2 expression-dependent cell growth inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable to unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a’s being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated anti-tumor efficacy against several breast cancer PDX models with low HER2 expression.
DS-8201a exhibited a potent anti-tumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1 insensitive HER2 positive cancers and low HER2-expressing cancers.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).