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  • 1
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A249-A249
    Abstract: PTK2/FAK is a widely expressed non-receptor tyrosine kinase located mainly at focal adhesions. Sensing upstream signals from growth factor receptors as well as integrins, the enzyme contributes to activation of multiple downstream signaling pathways involved in the regulation of cell survival, proliferation and motility. PTK2 protein expression is elevated in many human cancers, and dysregulated PTK2 is known to mediate anchorage-independent growth of malignant cells. Inhibition of PTK2 activity thus may interfere with tumor growth and metastasis formation. BI 853520 inhibited the enzymatic activity of PTK2 at low nanomolar concentrations. In a selectivity screen of 264 tyrosine and serine/threonine kinases, BI 853520 inhibited only 4 enzymes at a concentration of 1,000 nM by more than 50%. In contrast to PTK2 inhibitors described previously, the compound showed more than 1,000-fold selectivity against closely related kinases such as PYK2/PTK2B. In human PC-3 prostate carcinoma cells, PTK2 is highly expressed and phosphorylated on Tyr397. Treatment of PC-3 cells with BI 853520 inhibited autophosphorylation with an EC50 of 1 nM. Colony formation of PC-3 cells in a soft agar matrix was inhibited with an EC50 of 3 nM. In contrast, the same cell line growing in conventional monolayer culture showed growth inhibition only at 1,000-fold higher concentration. Similar results were obtained for other carcinoma cell lines. BI 853520 administered to immunodeficient nude mice showed good oral bioavailability (F = 90%) and a half-life of 5 hours. Daily oral treatment at dose levels up to 100 mg/kg over a period of several weeks was well tolerated by the animals. Treatment with BI 853520 resulted in suppression of PTK2 autophosphorylation in tissue samples from both human tumor xenografts and mouse skin. BI 853520 was tested for efficacy in a panel of 18 human tumor xenograft models representing multiple indications, including carcinomas of the lung, ovary, pancreas and prostate as well as sarcomas. At daily oral doses of 50 mg/kg the compound was highly active in a subset of models, including the PC-3 prostate carcinoma, resulting in strong suppression of tumor growth (TGI & gt; 90% compared to controls) or tumor regression in individual animals. Significant inhibition of tumor growth was observed at doses as low as 6 mg/kg, indicating a substantial therapeutic window and opportunities for combination therapy. Another subset of models showed intermediate drug sensitivity (TGI 40 − 80%), whereas several models were resistant to treatment (non-significant TGI). This database is currently being explored to identify biomarkers predicting sensitivity to BI 853520 based on genetic aberrations, gene expression signatures and phosphoproteome analysis of xenograft tumors. In conclusion, BI 853520 is a novel, highly selective PTK2 kinase inhibitor that demonstrates anti-tumor activity in vitro and in vivo. Clinical development of BI 853520 has recently been initiated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A249.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    SSG: 12
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  • 2
    In: Oncogene, Springer Science and Business Media LLC, Vol. 14, No. 22 ( 1997-06-05), p. 2619-2631
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1997
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  • 3
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 7, No. 2 ( 2018-02-23)
    Abstract: Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as a target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, a novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation in PC-3 prostate carcinoma cells with an IC 50 of 1 nmol/L and blocks anchorage-independent proliferation of PC-3 cells with an EC 50 of 3 nmol/L, whereas cells grown in conventional surface culture are 1000-fold less sensitive. In mice, the compound shows long half-life, high volume of distribution and high oral bioavailability; oral dosing of immunodeficient mice bearing subcutaneous PC-3 prostate adenocarcinoma xenografts resulted in rapid, long-lasting repression of FAK autophosphorylation in tumor tissue. Daily oral administration of BI 853520 to nude mice at doses of 50 mg/kg was well tolerated for prolonged periods of time. In a diverse panel of 16 subcutaneous adenocarcinoma xenograft models in nude mice, drug treatment resulted in a broad spectrum of outcomes, ranging from group median tumor growth inhibition values 〉 100% and tumor regression in subsets of animals to complete lack of sensitivity. Biomarker analysis indicated that high sensitivity is linked to a mesenchymal tumor phenotype, initially defined by loss of E-cadherin expression and subsequently substantiated by gene set enrichment analysis. Further, we obtained microRNA expression profiles for 13 models and observed that hsa-miR-200c-3p expression is strongly correlated with efficacy ( R 2  = 0.889). BI 853520 is undergoing evaluation in early clinical trials.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 4
    In: Cancers, MDPI AG, Vol. 12, No. 6 ( 2020-05-31), p. 1425-
    Abstract: This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3610-3610
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3610-3610
    Abstract: The IMI-funded CANCER-ID consortium (https://www.cancer-id.eu/) was created in order to facilitate the use of Circulating Tumor Cells (CTCs) and other liquid biopsies (ctDNA, miRNA, exosomes) in the monitoring and treatment of cancer, via establishing and validating protocols for their detection and characterization. CTCs are tumor cells that have passively or actively migrated from the bulk of the primary or metastatic tumor(s) into the peripheral blood stream. While some of these cells may establish new metastases and mediate outgrowth of the disease, they can also serve as diagnostic, prognostic or potentially predictive biomarkers, providing non-invasive access to tumor material and information on tumor evolution. However, a major challenge remains in the identification of these very rare cells (1:106-8 WBCs). In the past years, a plethora of methods have been developed to isolate CTCs, via antibody enrichment/depletion strategies, size exclusion and/or based on density and dielectric properties. Yet despite this progress, the detection rate of CTCs in NSCLC (non-small cell lung cancer) is still very low (only ca. 20-30% of metastatic NSCLC patients have detectable CTCs). In stark contrast, SCLC (small cell lung cancer) patients have usually hundreds of detectable CTCs. A potential reason for the lack of detection of NSCLC CTCs may be the choice of surface markers used to detect the CTCs. Using NSCLC cell lines spiked into healthy donor blood, novel antibody cocktails, including positive and negative selection markers, and also markers for cells undergoing epithelial-mesenchymal transition were tested for their sensitivity and specificity to detect tumor cells in blood. Blood samples from NSCLC and SCLC patients are currently being analyzed using the Cell Search system (an EpCAM-based, FDA approved device - the current ‘gold standard' for CTC detection and enumeration), in parallel with the Parsortix device (a micro-fluidic platform that isolates CTCs according to size and deformability). This direct comparison permits an understanding of whether the combination of the Parsortix device with downstream novel antibody cocktails for CTC identification improves sensitivity, over Cell Search, while still retaining good selectivity. Results from this ongoing study will be presented. The goal of this project is to generate and clinically validate a protocol that would enable the use of CTCs as a liquid biopsy for NSCLC patients. Such an approach would be of particular benefit to these patients, since tumor biopsies cannot always being readily attained and the use of invasive intervention carries some risk of bleeding and infection. This work is supported by IMI JU & EFPIA (grand no. 115749). Citation Format: Linda Scarrott, Hanny Musa, Harriet Wikman, Sonja Loges, Juergen Braunger, Klaus Pantel, Ralph Graeser. CANCER ID and the identification of circulating tumor cells (CTCs) in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3610.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 410466-3
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  • 6
    In: Clinical Colorectal Cancer, Elsevier BV, Vol. 20, No. 1 ( 2021-03), p. 84-95.e8
    Type of Medium: Online Resource
    ISSN: 1533-0028
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2572502-6
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