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  1. Artikel ; Online: ATR inhibition reverses the resistance of homologous recombination deficient MGMT

    El Touny, Lara H / Hose, Curtis / Connelly, John / Harris, Erik / Monks, Anne / Dull, Angie B / Wilsker, Deborah F / Hollingshead, Melinda G / Gottholm-Ahalt, Michelle / Alcoser, Sergio Y / Mullendore, Michael E / Parchment, Ralph E / Doroshow, James H / Teicher, Beverly A / Rapisarda, Annamaria

    Oncotarget

    2021  Band 12, Heft 21, Seite(n) 2114–2130

    Abstract: The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all ... ...

    Abstract The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMT
    Sprache Englisch
    Erscheinungsdatum 2021-10-12
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.28090
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Atezolizumab for Advanced Alveolar Soft Part Sarcoma.

    Chen, Alice P / Sharon, Elad / O'Sullivan-Coyne, Geraldine / Moore, Nancy / Foster, Jared C / Hu, James S / Van Tine, Brian A / Conley, Anthony P / Read, William L / Riedel, Richard F / Burgess, Melissa A / Glod, John / Davis, Elizabeth J / Merriam, Priscilla / Naqash, Abdul R / Fino, Kristin K / Miller, Brandon L / Wilsker, Deborah F / Begum, Asma /
    Ferry-Galow, Katherine V / Deshpande, Hari A / Schwartz, Gary K / Ladle, Brian H / Okuno, Scott H / Beck, Jill C / Chen, James L / Takebe, Naoko / Fogli, Laura K / Rosenberger, Christina L / Parchment, Ralph E / Doroshow, James H

    The New England journal of medicine

    2023  Band 389, Heft 10, Seite(n) 911–921

    Abstract: Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.: Methods: We conducted an investigator- ... ...

    Abstract Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.
    Methods: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action.
    Results: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1.
    Conclusions: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).
    Mesh-Begriff(e) Adolescent ; Adult ; Child ; Humans ; Infant, Newborn ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use ; B7-H1 Antigen/antagonists & inhibitors ; Body Weight ; Sarcoma, Alveolar Soft Part/drug therapy ; Administration, Intravenous
    Chemische Substanzen Antibodies, Monoclonal, Humanized ; atezolizumab (52CMI0WC3Y) ; B7-H1 Antigen
    Sprache Englisch
    Erscheinungsdatum 2023-09-05
    Erscheinungsland United States
    Dokumenttyp Clinical Trial, Phase II ; Journal Article ; Multicenter Study
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa2303383
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.34: Hefte anzeigen Standort:
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  3. Artikel: Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers.

    Wilsker, Deborah F / Barrett, Allison M / Dull, Angie B / Lawrence, Scott M / Hollingshead, Melinda G / Chen, Alice / Kummar, Shivaani / Parchment, Ralph E / Doroshow, James H / Kinders, Robert J

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2019  Band 25, Heft 10, Seite(n) 3084–3095

    Abstract: Purpose: We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement.: Experimental design: We evaluated the time course and spatial ... ...

    Abstract Purpose: We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement.
    Experimental design: We evaluated the time course and spatial activation of 3 protein biomarkers of DNA damage recognition and repair (γH2AX, pS343-Nbs1, and Rad51) simultaneously in a quantitative multiplex immunofluorescence assay (IFA) to assess DDR pathway activation in tumor tissues following exposure to DNA-damaging agents.
    Results: Because of inherent biological variability, baseline DDR biomarker levels were evaluated in a colorectal cancer microarray to establish clinically relevant thresholds for pharmacodynamic activation. Xenograft-bearing mice and clinical colorectal tumor biopsies obtained from subjects exposed to DNA-damaging therapeutic regimens demonstrated marked intratumor heterogeneity in the timing and extent of DDR biomarker activation due, in part, to the cell-cycle dependency of DNA damage biomarker expression.
    Conclusions: We have demonstrated the clinical utility of this DDR multiplex IFA in preclinical models and clinical specimens following exposure to multiple classes of cytotoxic agents, DNA repair protein inhibitors, and molecularly targeted agents, in both homologous recombination-proficient and -deficient contexts. Levels exceeding 4% nuclear area positive (NAP) γH2AX, 4% NAP pS343-Nbs1, and 5% cells with ≥5 Rad51 nuclear foci indicate a DDR activation response to treatment in human colorectal cancer tissue. Determination of effect-level cutoffs allows for robust interpretation of biomarkers with significant interpatient and intratumor heterogeneity; simultaneous assessment of biomarkers induced at different phases of the DDR guards against the risk of false negatives due to an ill-timed biopsy.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/pharmacology ; Biomarkers, Tumor/metabolism ; Cell Cycle Proteins/metabolism ; Clofarabine/pharmacology ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; DNA Damage ; DNA Repair ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; HCT116 Cells ; HT29 Cells ; Histones/metabolism ; Humans ; Mice ; Mice, Nude ; Nuclear Proteins/metabolism ; Rad51 Recombinase/metabolism ; Topotecan/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemische Substanzen Antineoplastic Agents ; Biomarkers, Tumor ; Cell Cycle Proteins ; H2AX protein, human ; Histones ; NBN protein, human ; Nuclear Proteins ; Deoxycytidine (0W860991D6) ; Clofarabine (762RDY0Y2H) ; Topotecan (7M7YKX2N15) ; gemcitabine (B76N6SBZ8R) ; RAD51 protein, human (EC 2.7.7.-) ; Rad51 Recombinase (EC 2.7.7.-)
    Sprache Englisch
    Erscheinungsdatum 2019-02-21
    Erscheinungsland United States
    Dokumenttyp Evaluation Study ; Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-2523
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 4223: Hefte anzeigen Standort:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  4. Artikel ; Online: Clinical Evolution of Epithelial-Mesenchymal Transition in Human Carcinomas.

    Navas, Tony / Kinders, Robert J / Lawrence, Scott M / Ferry-Galow, Katherine V / Borgel, Suzanne / Hollingshead, Melinda G / Srivastava, Apurva K / Alcoser, Sergio Y / Makhlouf, Hala R / Chuaqui, Rodrigo / Wilsker, Deborah F / Konaté, Mariam M / Miller, Sarah B / Voth, Andrea Regier / Chen, Li / Vilimas, Tomas / Subramanian, Jyothi / Rubinstein, Lawrence / Kummar, Shivaani /
    Chen, Alice P / Bottaro, Donald P / Doroshow, James H / Parchment, Ralph E

    Cancer research

    2019  Band 80, Heft 2, Seite(n) 304–318

    Abstract: The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial-mesenchymal phenotypic characteristics ... ...

    Abstract The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial-mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and colocalized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution ("EMT-IFA"). We report the discovery of β-catenin
    Mesh-Begriff(e) Animals ; Antigens, CD/metabolism ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomarkers, Tumor/metabolism ; Biopsy, Large-Core Needle ; Cadherins/metabolism ; Carcinoma/drug therapy ; Carcinoma/pathology ; Cell Line, Tumor ; Cell Plasticity/drug effects ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Epithelial-Mesenchymal Transition/drug effects ; Female ; Humans ; Indazoles ; Male ; Mice ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/pathology ; Paclitaxel/pharmacology ; Paclitaxel/therapeutic use ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Vimentin/metabolism ; Xenograft Model Antitumor Assays ; beta Catenin/metabolism
    Chemische Substanzen Antigens, CD ; Biomarkers, Tumor ; CDH1 protein, human ; CTNNB1 protein, human ; Cadherins ; Indazoles ; Pyrimidines ; Sulfonamides ; VIM protein, human ; Vimentin ; beta Catenin ; pazopanib (7RN5DR86CK) ; nilotinib (F41401512X) ; Paclitaxel (P88XT4IS4D)
    Sprache Englisch
    Erscheinungsdatum 2019-11-15
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Observational Study ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-18-3539
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Uh III Zs.135/5: Hefte anzeigen Standort:
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  5. Artikel ; Online: The root causes of pharmacodynamic assay failure.

    Ferry-Galow, Katherine V / Makhlouf, Hala R / Wilsker, Deborah F / Lawrence, Scott M / Pfister, Thomas D / Marrero, Allison M / Bigelow, Kristina M / Yutzy, William H / Ji, Jiuping J / Butcher, Donna O / Gouker, Brad A / Kummar, Shivaani / Chen, Alice P / Kinders, Robert J / Parchment, Ralph E / Doroshow, James H

    Seminars in oncology

    2016  Band 43, Heft 4, Seite(n) 484–491

    Abstract: Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable ...

    Abstract Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. This is especially true in the evaluation of pre- and post-dose tumor biopsies, which suffer from high levels of tumor insufficiency due to variations in biopsy collection techniques and significant specimen heterogeneity within and across patients. Developing methods to assess heterogeneous biopsies is necessary in order to evaluate a majority of tumor biopsies collected for pharmacodynamic biomarker studies. Improved collection devices and standardization of methods are being sought in order to improve the tumor content and quality of tumor biopsies. In terms of reagent variability, we have found that stringent initial reagent qualification and quality control of R&D-grade reagents is critical to minimize lot-to-lot variability and prevent assay failures, especially for clinical pharmacodynamic questions, which often demand assay performance that meets or exceeds clinical diagnostic assay standards. Rigorous reagent specifications and use of appropriate assay quality control methodologies help to ensure consistency between assay runs, laboratories and trials to provide much needed pharmacodynamic insights into the activity of investigational agents.
    Mesh-Begriff(e) Antineoplastic Agents/pharmacokinetics ; Biomarkers, Tumor/analysis ; Biopsy ; Humans ; Indicators and Reagents ; Neoplasms/pathology ; Reproducibility of Results ; Specimen Handling/methods ; Specimen Handling/standards
    Chemische Substanzen Antineoplastic Agents ; Biomarkers, Tumor ; Indicators and Reagents
    Sprache Englisch
    Erscheinungsdatum 2016-08
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 189220-4
    ISSN 1532-8708 ; 0093-7754
    ISSN (online) 1532-8708
    ISSN 0093-7754
    DOI 10.1053/j.seminoncol.2016.06.006
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1348: Hefte anzeigen Standort:
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