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      A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors

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          Abstract

          Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients.

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          Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

          Priscilla K. Brastianos, Peleg Horowitz, Sandro Santagata … (2013)
          Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas 1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
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            Signal transduction by focal adhesion kinase in cancer.

            Jihe Zhao, Jun-Lin Guan (2009)
            Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.
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              Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.

              M.J Byrne, A.K. Nowak (2004)
              The growth pattern of malignant pleural mesothelioma makes the use of RECIST (response evaluation criteria in solid tumours) response criteria difficult. We have developed and validated Modified RECIST criteria adapted to the growth pattern of malignant pleural mesothelioma. We evaluated 73 patients from two clinical trials of cisplatin/gemcitabine chemotherapy in malignant pleural mesothelioma. Tumour thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on thoracic CT scans. The sum of the six measurements defined a pleural unidimensional measure. Bidimensionally measureable lesions were measured unidimensionally as for RECIST. All measurements were added to obtain the total tumour measurement. A reduction of at least 30% on two occasions 4 weeks apart defined a partial response; an increase of 20% over the nadir measurement, progressive disease. The validity of the modified criteria was gauged by evaluating survival and pulmonary function. Response according to these criteria predicted for superior survival (15.1 versus 8.9 months; P = 0.03) and forced vital capacity (FVC) increase during treatment (P <0.0001). A significant correlation between change in linear tumour measurement and FVC was seen (R = 0.63; P = 0.0001). These Modified RECIST criteria for tumour response correlate with survival and lung function and can be used to measure outcome in pleural mesothelioma.
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                Author and article information

                Journal
                Title: Annals of Oncology
                Abbreviated Title: Ann Oncol
                Publisher: Oxford University Press (OUP)
                ISSN (Print): 0923-7534
                ISSN (Electronic): 1569-8041
                Publication date Created: December 22 2016
                Publication date (Print): December 2016
                Publication date (Electronic): October 11 2016
                Volume: 27
                Issue: 12
                Pages: 2268-2274
                Article
                DOI: 10.1093/annonc/mdw427
                PubMed ID: 27733373
                SO-VID: 475ed799-0d24-415d-afc0-543ab6d3f446
                Copyright © © 2016
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