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Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.

Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the impact of genetic changes on the activation state and drug responses is needed to better link the genomic data and treatment options. We here apply a direct comparative and comprehensive analysis of FGFR3 kinase domain variants representing the diversity of point-mutations reported in this domain. We reinforce the importance of N540K and K650E and establish that not all highly activating mutations (for example R669G) occur at high-frequency and conversely, that some &quot;hotspots&quot; may not be linked to activation. Further structural characterization consolidates a mechanistic view of FGFR kinase activation and extends insights into drug binding. Importantly, using several inhibitors of particular clinical interest (AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534), we find that some activating mutations (including different replacements of the same residue) result in distinct changes in their efficacy. Considering that there is no approved inhibitor for anticancer treatments based on FGFR-targeting, this information will be immediately translatable to ongoing clinical trials.

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Analysis of HER2 status in gastroesophageal tumor specimens using a new automated HER2 IQFISH pharmDx™ (Dako Omnis) assay.

The human epidermal growth factor receptor 2 (HER2) is an important target for treatment of gastroesophageal cancer. Different slide-based assays are available for assessment of HER2 status. Overexpression of the HER2 protein is assessed by immunohistochemistry (IHC) whereas amplification of the HER2 gene is assessed by fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods. Here we report a summary of the validation data on HER2 IQFISH pharmDx (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. This assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of less than 4 hours from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary cover method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay, with high precision and at least comparable to the manual HER2 IQFISH pharmDx assay. The HER2 IQFISH pharmDx (Dako Omnis) assay is currently not commercially available outside the Europe Union.

Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay.

This study aimed to identify providers involved in diagnosing ankylosing spondylitis (AS) following back pain diagnosis in the USA and to identify factors leading to the delay in rheumatology referrals. The Truven Health MarketScan US Commercial Database was searched for patients aged 18-64 years with back pain diagnosis in a non-rheumatology setting followed by AS diagnosis in any setting during January 2000-December 2012. Patients with a rheumatologist visit on or before AS diagnosis were considered referred. Cox regression was used to determine factors associated with referral time after adjusting for age, sex, comorbidities, physician specialty, drug therapy, and imaging procedures. Of 3336 patients included, 1244 (37 %) were referred to and diagnosed by rheumatologists; the others were diagnosed in primary care (25.7 %), chiropractic/physical therapy (7 %), orthopedic surgery (3.8 %), pain clinic (3.6 %), acute care (3.4 %), and other (19.2 %) settings. Median time from back pain diagnosis to rheumatology referral was 307 days and from first rheumatologist visit to AS diagnosis was 28 days. Referred patients were more likely to be younger (hazard ratio [HR] = 0.986; p &lt; 0.0001), male (HR = 1.15; p = 0.0163), diagnosed with uveitis (HR = 1.49; p = 0.0050), referred by primary care physicians (HR = 1.96; p &lt; 0.0001), prescribed non-steroidal anti-inflammatory drugs (HR = 1.55; p &lt; 0.0001), disease-modifying antirheumatic drugs (HR = 1.33; p &lt; 0.0001), and tumor necrosis factor inhibitors (HR = 1.40; p = 0.0036), and to have had spinal/pelvic X-ray prior to referral (HR = 1.28; p = 0.0003). During 2000-2012, most patients with AS were diagnosed outside of rheumatology practices. The delay before referral to rheumatology was 10 months; AS diagnosis generally followed within a month. Earlier referral of patients with AS signs and symptoms may lead to more timely diagnosis and appropriate treatment.

20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)]

(Filing, Annual, GlaxoSmithKline, 2015, MAR 18, 2016, View Source [SID:1234509645])

Puma Biotechnology Announces Publication of Abstracts on Neratinib for the AACR Annual Meeting 2016

On March 18, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported publication of abstracts on neratinib for the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Puma Biotechnology, MAR 18, 2016, View Source [SID:1234510445]). The AACR (Free AACR Whitepaper) Annual Meeting will be held at the Ernest N. Morial Convention Center in New Orleans from April 16 to April 20.

Sun, Apr 17, 1:00 – 5:00 p.m. CDT – Abstract 298, Section 16, Poster Board 9: Amplification of mutant ERBB2 drives resistance to the irreversible kinase inhibitor neratinib in ERBB2-mutated breast cancer patients.
FJ Carmona, D Hyman, G Ulaner, J Erinjeri, N Bouvier, H Won, R Cutler, A Alani, M Berger, J Baselga, M Scaltriti.

Tue, Apr 19, 8:00 a.m. – 12:00 p.m. CDT – Abstract 3140, Section 22, Poster Board 7: Differential clonal selection in tumor tissue and cell-free DNA from a neratinib-treated refractory breast cancer patient harboring an activating ERBB2 (HER2) mutation.
L Joenson, CW Yde, O Østrup, M Mau-Sørensen, FC Nielsen, U Lassen

Wed, Apr 20, 8:00 a.m. – 12:00 p.m. CDT – Abstract 4760, Poster Board 11: Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations.
MJ Wick, M Farley, T Vaught, J Meade, M Glassman, A Moriarty, AW Tolcher, D Rasco, A Patnaik, KP Papadopoulos

The abstracts are available online at: View Source;DetailItemID=363#.Vusrr-IrKUk.

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Author: [email protected]

Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.

Analysis of HER2 status in gastroesophageal tumor specimens using a new automated HER2 IQFISH pharmDx™ (Dako Omnis) assay.

Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay.

20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)]

Puma Biotechnology Announces Publication of Abstracts on Neratinib for the AACR Annual Meeting 2016