57 research outputs found
DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial.
Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2- patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2- patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the 'predicted sensitive' group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2- patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care
Prospective Molecular Profiling of Canine Cancers Provides a Clinically Relevant Comparative Model for Evaluating Personalized Medicine (PMed) Trials.
Background
Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting. Methodology
A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type. Conclusions
Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (\u3c1 \u3eweek). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer into the preclinical modeling of personalized medicine. Future comparative oncology studies optimizing the delivery of PMed strategies may aid cancer drug development
Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFΞ± to Cancer Vasculature
Background: Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings: Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to Ξ±V integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5 x 1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance: The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies
ΠΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΡΠΉ ΠΌΡΠ·ΡΠΊΠ°Π»ΡΠ½ΡΠΉ ΠΊΠΎΠ½ΠΊΡΡΡ Π² ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠΈ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ (Π½Π° ΠΏΡΠΈΠΌΠ΅ΡΠ΅ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ 2017)
ΠΠ½Π½ΠΎΡΠ°ΡΠΈΡ Π²ΡΠΏΡΡΠΊΠ½ΠΎΠΉ ΠΊΠ²Π°Π»ΠΈΡΠΈΠΊΠ°ΡΠΈΠΎΠ½Π½ΠΎΠΉ ΡΠ°Π±ΠΎΡΡ ΠΡΠ»ΠΎΠ² ΠΠΈΠΊΠΈΡΠ° Π‘Π΅ΡΠ³Π΅Π΅Π²ΠΈΡ Β«ΠΠΠΠΠ£ΠΠΠ ΠΠΠΠ«Π ΠΠ£ΠΠ«ΠΠΠΠ¬ΠΠ«Π ΠΠΠΠΠ£Π Π‘ Π Π€ΠΠ ΠΠΠ ΠΠΠΠΠΠ ΠΠΠΠΠΠ Π‘Π’Π ΠΠΠ« ΠΠ ΠΠΠΠΠΠΠΠ― (ΠΠ ΠΠ ΠΠΠΠ Π ΠΠΠ ΠΠΠΠΠΠΠΠ―-2017)Β» Π. ΡΡΠΊ. - ΠΡΠΊΠΎΠ²Π° ΠΠ»Π΅Π½Π° ΠΠ»Π°Π΄ΠΈΠΌΠΈΡΠΎΠ²Π½Π°, Π΄ΠΎΠΊΡΠΎΡ ΡΠΈΠ»ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
Π½Π°ΡΠΊ, Π΄ΠΎΡΠ΅Π½Ρ ΠΠ°ΡΠ΅Π΄ΡΠ° ΡΠ²ΡΠ·Π΅ΠΉ Ρ ΠΎΠ±ΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΡΡΡΡ ΠΡΠ½Π°Ρ ΡΠΎΡΠΌΠ° ΠΎΠ±ΡΡΠ΅Π½ΠΈΡ ΠΠΊΡΡΠ°Π»ΡΠ½ΠΎΡΡΡ: ΠΌΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΡΠΉ ΠΌΡΠ·ΡΠΊΠ°Π»ΡΠ½ΡΠΉ ΠΊΠΎΠ½ΠΊΡΡΡ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΠ΅ ΠΊΠ°ΠΊ ΡΠ°ΠΌΠΎΠ΅ ΠΌΠ°ΡΡΡΠ°Π±Π½ΠΎΠ΅ ΡΠ΅Π³ΡΠ»ΡΡΠ½ΠΎΠ΅ Π²ΡΡΠΎΠΊΠΎΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΡΠ½ΠΎΠ΅ ΡΠ΅Π»Π΅Π²ΠΈΠ·ΠΈΠΎΠ½Π½ΠΎΠ΅ ΠΈ ΠΌΠ΅Π΄ΠΈΠ°-ΡΠΎΠ±ΡΡΠΈΠ΅, ΠΊΠΎΡΠΎΡΠΎΠ΅ . Π Π΅ΠΆΠ΅Π³ΠΎΠ΄Π½ΠΎ Π°ΠΊΡΠ΅Π½ΡΠΈΡΡΠ΅Ρ Π²Π½ΠΈΠΌΠ°Π½ΠΈΠ΅ Π°ΡΠ΄ΠΈΡΠΎΡΠΈΠΈ Π½Π° Π½Π°ΡΠΈΠΎΠ½Π°Π»ΡΠ½ΠΎ-ΠΊΡΠ»ΡΡΡΡΠ½ΡΡ
ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΡΡ
ΡΡΡΠ°Π½Ρ-ΠΎΡΠ³Π°Π½ΠΈΠ·Π°ΡΠΎΡΠ° ΠΊΠΎΠ½ΠΊΡΡΡΠ°, ΡΠΎΡΠΌΠΈΡΡΠ΅Ρ Π·Π½Π°ΡΠΈΡΠ΅Π»ΡΠ½ΡΠ΅ ΡΡΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΏΠΎΡΠΎΠΊΠΈ ΠΈ ΡΠ΅ΠΌ ΡΠ°ΠΌΡΠΌ ΡΠΏΠΎΡΠΎΠ±ΡΡΠ²ΡΠ΅Ρ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΠ΅ΡΡΠΈΡΠΎΡΠΈΠΈ. ΠΠΎΠ»Π΅Π΅ ΡΠΎΠ³ΠΎ, ΠΏΠΎΠ±Π΅Π΄Π° ΡΡΡΠ°Π½Ρ-ΡΡΠ°ΡΡΠ½ΠΈΡΡ ΠΊΠΎΠ½ΠΊΡΡΡΠ° ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ Π·Π°ΡΠ°ΡΡΡΡ ΠΎΡΡΠ°ΠΆΠ°Π΅Ρ ΠΈΠ΄Π΅ΠΎΠ»ΠΎΠ³ΠΎ-ΠΏΠΎΠ»ΠΈΡΠΈΡΠ΅ΡΠΊΠΈΠΉ Π²Π΅ΠΊΡΠΎΡ ΠΠ²ΡΠΎΠΏΡ ΠΈ ΠΏΠΎ ΡΡΡΠΈ Π΄Π΅Π»Π° Π²ΡΠΏΠΎΠ»Π½ΡΠ΅Ρ ΡΡΠ½ΠΊΡΠΈΡ ΠΏΠΎΠ»ΠΈΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ PR ΡΡΡΠ°Π½Ρ-ΠΏΠΎΠ±Π΅Π΄ΠΈΡΠ΅Π»Ρ ΠΈ ΡΡΡΠ°Π½Ρ-Ρ
ΠΎΠ·ΡΠΉΠΊΠΈ ΠΌΠ΅ΡΠΎΠΏΡΠΈΡΡΠΈΡ. Π‘Π»Π΅Π΄ΠΎΠ²Π°ΡΠ΅Π»ΡΠ½ΠΎ Π°Π½Π°Π»ΠΈΠ· ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΠ΅ΠΌΡΡ
Π½Π° ΠΌΠ΅ΡΠΎΠΏΡΠΈΡΡΠΈΠΈ ΠΊΠΎΠΌΠΌΡΠ½ΠΈΠΊΠ°ΡΠΈΠ²Π½ΡΡ
ΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΠΉ ΡΠ²Π»ΡΠ΅ΡΡΡ Π°ΠΊΡΡΠ°Π»ΡΠ½ΡΠΌ ΠΈ Π²ΠΎΡΡΡΠ΅Π±ΠΎΠ²Π°Π½Π½ΡΠΌ Π΄Π»Ρ ΡΠΎΠ±ΡΡΠΈΠΉΠ½ΠΎΠ³ΠΎ ΠΈ ΡΡΡΡΠΎΠΈΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ PR ΠΠ±ΡΠ΅ΠΊΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ: ΠΊΠΎΠΌΠΌΡΠ½ΠΈΠΊΠ°ΡΠΈΠΎΠ½Π½ΡΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΌΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΌΡΠ·ΡΠΊΠ°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΊΠΎΠ½ΠΊΡΡΡΠ° (Π½Π° ΠΏΡΠΈΠΌΠ΅ΡΠ΅ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ Π² ΠΠΈΠ΅Π²Π΅ Π² 2017 Π³.). ΠΡΠ΅Π΄ΠΌΠ΅Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ: ΡΡΠ½ΠΊΡΠΈΡ ΡΡΠ°ΡΡΡΠ½ΠΎΠ³ΠΎ PR-ΠΌΠ΅ΡΠΎΠΏΡΠΈΡΡΠΈΡ Π² ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠΈ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ. Π¦Π΅Π»Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ: Π΄ΠΎΠΊΠ°Π·Π°ΡΡ, ΡΡΠΎ ΠΌΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΡΠΉ ΠΌΡΠ·ΡΠΊΠ°Π»ΡΠ½ΡΠΉ ΠΊΠΎΠ½ΠΊΡΡΡ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΠ΅ ΡΠΏΠΎΡΠΎΠ±ΡΡΠ²ΡΠ΅Ρ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ. ΠΠ°Π΄Π°ΡΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ: ΡΠ°Π·ΡΠ°Π±ΠΎΡΠ°ΡΡ ΡΠ΅ΡΠΌΠΈΠ½ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠΉ Π°ΠΏΠΏΠ°ΡΠ°Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π½Π° ΠΎΡΠ½ΠΎΠ²Π΅ Π½Π°ΡΡΠ½ΠΎΠΉ Π»ΠΈΡΠ΅ΡΠ°ΡΡΡΡ ΠΏΠΎ ΠΈΠΌΠΈΠ΄ΠΆΠΌΠ΅ΠΉΠΊΠΈΠ½Π³Ρ, Π±ΡΠ΅Π½Π΄ΠΈΠ½Π³Ρ ΠΈ ΠΈΠ²Π΅Π½Ρ-ΠΌΠ΅Π½Π΅Π΄ΠΆΠΌΠ΅Π½ΡΡ; ΠΎΠΏΡΠ΅Π΄Π΅Π»ΠΈΡΡ Π°ΠΊΡΡΠ°Π»ΡΠ½ΡΠ΅ ΠΊΠΎΠΌΠΌΡΠ½ΠΈΠΊΠ°ΡΠΈΠΎΠ½Π½ΡΠ΅ ΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΠΈ, ΠΏΡΠΈΠΌΠ΅Π½ΡΠ΅ΠΌΡΠ΅ Π² ΡΠ°ΠΌΠΊΠ°Ρ
ΡΠΏΠ΅ΡΠΈΠ°Π»ΡΠ½ΡΡ
ΡΠΎΠ±ΡΡΠΈΠΉ Π΄Π»Ρ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ; ΠΎΠΏΠΈΡΠ°ΡΡ ΡΠΎΠ»Ρ ΠΠ²ΡΠΎΠΏΠ΅ΠΉΡΠΊΠΎΠ³ΠΎ ΠΠ΅ΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ Π‘ΠΎΡΠ·Π° ΠΊΠ°ΠΊ ΠΎΡΠ³Π°Π½ΠΈΠ·Π°ΡΠΎΡΠ° ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ Π² ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠΈ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ ΠΊΠΎΠ½ΠΊΡΡΡΠ°; ΠΎΡΠ΅Π½ΠΈΡΡ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ΅Π°Π»ΠΈΠ·ΠΎΠ²Π°Π½Π½ΡΡ
ΠΊΠΎΠΌΠΌΡΠ½ΠΈΠΊΠ°ΡΠΈΠ²Π½ΡΡ
ΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΠΉ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ Π² ΡΠ°ΠΌΠΊΠ°Ρ
ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ; Π΄Π°ΡΡ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄Π°ΡΠΈΠΈ ΠΏΠΎ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ Ρ ΠΏΠΎΠΌΠΎΡΡΡ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ. Π’Π΅ΠΎΡΠ΅ΡΠΈΡΠ΅ΡΠΊΠ°Ρ Π±Π°Π·Π°: Π½Π°ΡΡΠ½ΡΠ΅ ΡΡΡΠ΄Ρ Π. ΠΡΠΊΠΎΠ²ΠΎΠΉ, Π. ΠΠ°Π²ΡΡ, Π. ΠΠ°Π½ΠΊΡΡΡ
ΠΈΠ½Π°, Π. ΠΠΆΠ΅Π½Π΅ΡΠ°, Π. ΠΠ°Π²Π΅ΡΠΈΠ½ΠΎΠΉ, Π£. Π₯Π°Π»ΡΡΠ±Π°ΡΡΠ°, ΠΠΆ. ΠΠΎΠ»Π΄Π±Π»Π°ΡΡΠ° Π° ΡΠ°ΠΊΠΆΠ΅ ΡΡΡΠ΄Ρ Π. ΠΠ°ΡΡΠΌΠ°Π½Π° ΠΎ ΠΌΡΠ·ΡΠΊΠ°Π»ΡΠ½ΠΎΠΌ Π±ΠΈΠ·Π½Π΅ΡΠ΅, Π. ΠΠΆΠΎΡΠ΄Π°Π½Π° ΠΎ ΠΏΡΠΎΠ΄Π²ΠΈΠΆΠ΅Π½ΠΈΠΈ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½ Ρ ΠΏΠΎΠΌΠΎΡΡΡ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ ΠΈ Π΄Ρ. ΠΠΌΠΏΠΈΡΠΈΡΠ΅ΡΠΊΠ°Ρ Π±Π°Π·Π°: PR-Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΡ, ΡΠ°Π·ΠΌΠ΅ΡΠ΅Π½Π½ΡΠ΅ Π½Π° ΡΠ°ΠΉΡΠ΅ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ ΠΈ ΠΠ²ΡΠΎΠΏΠ΅ΠΉΡΠΊΠΎΠ³ΠΎ ΠΠ΅ΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ Π‘ΠΎΡΠ·Π°; Π±ΠΎΠ»Π΅Π΅ ΠΏΠΎΠ»ΡΡΠΎΡΠ° ΠΌΠΈΠ»Π»ΠΈΠΎΠ½Π° ΡΡΠ°ΡΠ΅ΠΉ ΠΎΠ± Π£ΠΊΡΠ°ΠΈΠ½Π΅ Π² Π΅Π²ΡΠΎΠΏΠ΅ΠΉΡΠΊΠΈΡ
Π‘ΠΠ, ΡΠ°Π·ΠΌΠ΅ΡΠ΅Π½Π½ΡΠ΅ Π² Π±Π°Π·Π΅ ΠΏΡΠΎΠ΅ΠΊΡΠ° ΠΌΠΎΠ½ΠΈΡΠΎΡΠΈΠ½Π³Π° ΠΌΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΈΠΌΠΈΠ΄ΠΆΠ° Π£ΠΊΡΠ°ΠΈΠ½Ρ Β«OkoΒ»; Π΄Π°Π½Π½ΡΠ΅ Π±Π°Π·Ρ ΠΌΠ°ΡΠ΅ΡΠΈΠ°Π»ΠΎΠ² Π‘ΠΠ ΠΈ ΡΠΎΡΠΈΠ°Π»ΡΠ½ΡΡ
ΠΌΠ΅Π΄ΠΈΠ° Factiva; Π΄Π°Π½Π½ΡΠ΅ Google.Analytics. ΠΡΠ°ΠΊΡΠΈΡΠ΅ΡΠΊΠ°Ρ Π·Π½Π°ΡΠΈΠΌΠΎΡΡΡ: ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ Π΄ΠΎΠΊΠ°Π·ΡΠ²Π°Π΅Ρ, ΡΡΠΎ ΠΌΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΡΠΉ ΠΌΡΠ·ΡΠΊΠ°Π»ΡΠ½ΡΠΉ ΠΊΠΎΠ½ΠΊΡΡΡ ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΠ΅ ΡΠΎΡΠΌΠΈΡΡΠ΅Ρ ΠΈΠΌΠΈΠ΄ΠΆ ΡΡΡΠ°Π½Ρ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ Π½Π΅Π·Π°Π²ΠΈΡΠΈΠΌΠΎ ΠΎΡ ΡΡΠΏΠ΅ΡΠ½ΠΎΡΡΠΈ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΡ ΠΊΠΎΠ½ΠΊΡΠ΅ΡΠ½ΡΡ
ΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΠΉ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½Ρ. Π’Π΅Π·ΠΈΡΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π±ΡΠ»ΠΈ Π°ΠΏΡΠΎΠ±ΠΈΡΠΎΠ²Π°Π½Ρ Π½Π° ΠΌΠ΅ΠΆΠ΄ΡΠ½Π°ΡΠΎΠ΄Π½ΠΎΠΌ Π½Π°ΡΡΠ½ΠΎΠΌ ΡΠΎΡΡΠΌΠ΅ Β«ΠΠ΅Π΄ΠΈΠ° Π² ΡΠΎΠ²ΡΠ΅ΠΌΠ΅Π½Π½ΠΎΠΌ ΠΌΠΈΡΠ΅. 57-Π΅ ΠΠ΅ΡΠ΅ΡΠ±ΡΡΠ³ΡΠΊΠΈΠ΅ ΡΡΠ΅Π½ΠΈΡΒ», ΠΎΠΏΡΠ±Π»ΠΈΠΊΠΎΠ²Π°Π½Ρ Π² ΡΠ±ΠΎΡΠ½ΠΈΠΊΠ΅ ΠΌΠ°ΡΠ΅ΡΠΈΠ°Π»ΠΎΠ² ΡΡΠ°ΡΠ΅ΠΉ ΡΠΎΡΡΠΌΠ° ΠΈ ΠΈΠΌΠ΅ΡΡ ΡΡΠ°ΡΡΡ Π½Π°ΡΡΠ½ΠΎΠΉ ΡΡΠ°ΡΡΠΈ, ΡΠ°Π·ΠΌΠ΅ΡΠ΅Π½Π½ΠΎΠΉ Π² Π±Π°Π·Π΅ Π ΠΠΠ¦. Π‘ΡΡΡΠΊΡΡΡΠ° ΡΠ°Π±ΠΎΡΡ: Π Π°Π±ΠΎΡΠ° ΡΠΎΡΡΠΎΠΈΡ ΠΈΠ· Π²Π²Π΅Π΄Π΅Π½ΠΈΡ, 3 Π³Π»Π°Π²: Β«ΡΡΠ½ΠΊΡΠΈΡ ΡΠΏΠ΅ΡΠΈΠ°Π»ΡΠ½ΠΎΠ³ΠΎ ΡΠΎΠ±ΡΡΠΈΡ Π² ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠΈ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½ΡΒ», Β«ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΠ΅ ΠΊΠ°ΠΊ ΡΠΏΠ΅ΡΠΈΠ°Π»ΡΠ½ΠΎΠ΅ ΡΠΎΠ±ΡΡΠΈΠ΅ ΠΠ²ΡΠΎΠΏΠ΅ΠΉΡΠΊΠΎΠ³ΠΎ ΠΠ΅ΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ Π‘ΠΎΡΠ·Π°Β» ΠΈ Β«ΠΊΠΎΠΌΠΌΡΠ½ΠΈΠΊΠ°ΡΠΈΠΎΠ½Π½ΡΠΉ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» ΠΠ²ΡΠΎΠ²ΠΈΠ΄Π΅Π½ΠΈΡ ΠΊΠ°ΠΊ ΠΏΠ»ΠΎΡΠ°Π΄ΠΊΠΈ Π΄Π»Ρ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠΌΠΈΠ΄ΠΆΠ° ΡΡΡΠ°Π½ΡΒ», Π·Π°ΠΊΠ»ΡΡΠ΅Π½ΠΈΡ, ΡΠΏΠΈΡΠΊΠ° ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½Π½ΠΎΠΉ Π»ΠΈΡΠ΅ΡΠ°ΡΡΡΡ ΠΈΠ· 67 ΠΏΠΎΠ·ΠΈΡΠΈΠΉ ΠΈ 12 ΠΏΡΠΈΠ»ΠΎΠΆΠ΅Π½ΠΈΠΉ. ΠΠ±ΡΠΈΠΉ ΠΎΠ±ΡΠ΅ΠΌ 76 ΡΡΡΠ°Π½ΠΈΡ.Abstract of graduating qualification thesis Mikita Arlou INTERNATIONAL MUSIC CONTEST IN HOST COUNTRY IMAGE FORMATION (ON THE EXAMPLE OF EUROVISION 2017) Supervisor associate professor Elena Bykova, doctor of philology Department of PR in business full-time study Relevance: the international music contest Eurovision as the most wide scale regular high tech TV and Media event which annually emphasizes audience attention on national cultural features of the host country, forms tourist flows which have huge influence on territorial image formation. Besides the win of a participating in the Eurovision country often shows the ideological and political European vector and in fact serves as political PR of the winning or host country. Consequently the analysis of applied communication technologies is relevant and in-demand for event PR. Research object: communication activities of international music contest (on the example of Eurovision in Kyiv in 2017). Research subject: function of status PR event in country image formation. The aim of research: to prove that international music contest Eurovision contributes host country image formation. The tasks of research: to develop research terminology based on scientific literature on image making, branding and event management; to define actual communication technologies applied in special PR events on country image formation; to describe European Broadcasting Union role in host country image formation; to appreciate effectiveness of applied communication technologies on host country image formation in Eurovision; to give recommendations for host country image formation with the help of Eurovision. Theoretical base: scientific works written by E. Bykova, D. Gavra, A. Pankrukhin, B. Jenes, E. Kaverina, U. Halcbaur, J. Goldblatt and D. PassmanΒ΄s works on music business and P. Jordan on county image building with the help of Eurovision, etc. The empirical base: PR documents from official Eurovision and European Broadcasting Union websites; more than 1.5 million articles on Ukraine in European media stored in the base of international Ukrainian image monitoring project Oko; content of the mass media and social media base Factiva; Google.Analytics data. Practical significance: the research proves that international music contest Eurovision is relevant for the host country image formation independently of the success level of applied country image formation communication technologies. Approbation: General positions of current thesis were aprobated on international scientific forum Media in modern world and were published at the collection of articles of the forum and have the status of a scientific article posted in the RINC database. Thesis structure: Research consists of introduction, 3 chapters: Special event function in country image formation, Eurovision as EBU special event and communication potential of Eurovision as a platform for image formation; conclusion, literature list from 67 positions and 12 attachments. The total volume is 76 pages
An idealized view of the opportunity provided by a comparative and integrated oncology drug development path.
<p>This is a theoretical illustration of 100 preclinical agents that may be evaluated by either a conventional or an integrated and comparative drug development path. Data for transition rates and costs of Phase I, II, and III trials are based on published cost estimates <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi2" target="_blank">[3]</a> and reported clinical phase transition probabilities for investigational oncology compounds from the 20 largest firms (by pharmaceutical sales in 2005) from 1993 to 2002 <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi1" target="_blank">[2]</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Roberts1" target="_blank">[4]</a>. Estimates used to derive a vision of the benefit of an integrated approach to drug development are based, in part, on estimates of transition and approval rates for non-oncology therapeutic areas where informative preclinical models exist <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Adams1" target="_blank">[5]</a>. Relative to the conventional development path, the integrated development path is characterized by improved success early in clinical development and a reduction in drug failures late in clinical development. Conventional oncology drug development results in approximately 40% of eligible agents transitioning from preclinical to Phase I, 75% from Phase I to II, 60% from Phase II to III, and 55% from Phase III to approval <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi1" target="_blank">[2]</a>. Therefore, for every 100 preclinical candidates, only ten new drugs will reach the clinic. Of most significance are failures that occur late in the development path (i.e., after Phase II or Phase III evaluation). With an integrated approach, more toxic and ineffective agents may be eliminated prior to Phase I (estimate 30 agents now entering Phase I trials versus 40 in the conventional pipeline). Attrition in Phase I may be minimized (estimated 87.5% success rate) and an additional 30% of drugs may be removed from development prior to Phase II based on comparative studies that demonstrate poor pharmacokinetics, pharmacodynamics, or activity (estimate 18 agents now entering Phase II trials versus 30 in the conventional pipeline). Deprioritization (from above) of these drugs will improve the Phase II success rate (estimate 90%). Data from comparative studies will result in the removal of 20% of remaining drugs prior to Phase III based on lack of efficacy in the adjuvant setting, thereby improving success in Phase III and leading to 90% of Phase III agents receiving FDA approval (compared to 55% in the conventional pipeline). In this model, 12 new drugs out of every 100 preclinical candidates will reach the clinic. Using estimates for Phase I, II, and III trials of US23.5 million, and US86.3 million per trial respectively [3], the total clinical trial expenditures for developing 100 preclinical agents is US2.87 billion using conventional methods. Using the hypothetical improvements described above that result from the integrated approach the clinical costs for development will be US2.03 billion [3]. Factoring in additional costs for comparative studies with this approach of US150,000 for studies conducted in the preclinical setting, US1 million for studies conducted before Phases IIβIII studies, the total cost of development is estimated at US290 million to US$173 million <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Adams1" target="_blank">[5]</a>.</p
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Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma.
BackgroundInterleukin (IL)-12 is a pro-inflammatory cytokine that mediates T-helper type 1 responses and cytotoxic T-cell activation, contributing to its utility as anti-cancer agent. Systemic administration of IL-12 often results in unacceptable toxicity; therefore, strategies to direct delivery of IL-12 to tumors are under investigation. The objective of this study was to assist the preclinical development of NHS-IL12, an immunocytokine consisting of an antibody, which targets necrotic tumor regions, linked to IL-12. Specifically this study sought to evaluate the safety, serum pharmacokinetics, anti-tumor activity, and immune modulation of NHS-IL12 in dogs with naturally occurring cancers.Methodology/principal findingsA rapid dose-escalation study of NHS-IL12 administered subcutaneously to dogs with melanoma was conducted through the Comparative Oncology Trials Consortium (COTC). Eleven dogs were enrolled in four dose-escalation cohorts; thereafter, an additional seven dogs were treated at the defined tolerable dose of 0.8 mg/m2. The expanded cohort at this fixed dose (ten dogs in total) was accrued for further pharmacokinetics and pharmacodynamics assessment. NHS-IL12 levels, serum cytokine concentrations, and peripheral blood mononuclear cell characterization (post-treatment) and draining lymph node immune profiling, and tumor biopsies (pre- and post-treatment) were collected. Adverse events included thrombocytopenia, liver enzymopathies, fever, and vasculitis. Correlation between interferon (IFN)-Ξ³ induction, adverse events, and NHS-IL12 exposure (maximum concentration and area under the concentration-time curve) were dose-dependent. Serum IL-10 levels and intratumoral CD8+ populations increased after treatment. Partial responses, according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, were observed in two dogs treated with NHS-IL12 0.8 mg/m2 and 1.6 mg/m2.Conclusions/significanceNHS-IL12 was administered safely to dogs with melanoma and both immunologic and clinical activity was observed. This study successfully defined a narrow therapeutic window for systemic delivery of NHS-IL12 via the subcutaneous route. Results will inform the design and implementation of first-in-human clinical trials of NHS-IL12 in cancer patients
Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma
<div><p>Background</p><p>Interleukin (IL)-12 is a pro-inflammatory cytokine that mediates T-helper type 1 responses and cytotoxic T-cell activation, contributing to its utility as anti-cancer agent. Systemic administration of IL-12 often results in unacceptable toxicity; therefore, strategies to direct delivery of IL-12 to tumors are under investigation. The objective of this study was to assist the preclinical development of NHS-IL12, an immunocytokine consisting of an antibody, which targets necrotic tumor regions, linked to IL-12. Specifically this study sought to evaluate the safety, serum pharmacokinetics, anti-tumor activity, and immune modulation of NHS-IL12 in dogs with naturally occurring cancers.</p><p>Methodology/Principal Findings</p><p>A rapid dose-escalation study of NHS-IL12 administered subcutaneously to dogs with melanoma was conducted through the Comparative Oncology Trials Consortium (COTC). Eleven dogs were enrolled in four dose-escalation cohorts; thereafter, an additional seven dogs were treated at the defined tolerable dose of 0.8 mg/m<sup>2</sup>. The expanded cohort at this fixed dose (ten dogs in total) was accrued for further pharmacokinetics and pharmacodynamics assessment. NHS-IL12 levels, serum cytokine concentrations, and peripheral blood mononuclear cell characterization (post-treatment) and draining lymph node immune profiling, and tumor biopsies (pre- and post-treatment) were collected. Adverse events included thrombocytopenia, liver enzymopathies, fever, and vasculitis. Correlation between interferon (IFN)-Ξ³ induction, adverse events, and NHS-IL12 exposure (maximum concentration and area under the concentration-time curve) were dose-dependent. Serum IL-10 levels and intratumoral CD8<sup>+</sup> populations increased after treatment. Partial responses, according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, were observed in two dogs treated with NHS-IL12 0.8 mg/m<sup>2</sup> and 1.6 mg/m<sup>2</sup>.</p><p>Conclusions/Significance</p><p>NHS-IL12 was administered safely to dogs with melanoma and both immunologic and clinical activity was observed. This study successfully defined a narrow therapeutic window for systemic delivery of NHS-IL12 via the subcutaneous route. Results will inform the design and implementation of first-in-human clinical trials of NHS-IL12 in cancer patients.</p></div
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