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  • American Association for Cancer Research (AACR)  (16)
  • 1
    Online Resource
    Online Resource
    Abstract CT156: A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT156-CT156
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT156-CT156
    Abstract: Therapeutic vaccination with tumor antigen-encoding RNAs is being investigated in various clinical trials. Typically, the RNA vaccine is administered intradermally, subcutaneously or intranodally with the intention to get expression of the encoded antigens in local antigen-presenting cells (APCs). We have developed a novel class of RNA-lipoplex (RNA(LIP)) immunotherapeutics for intravenous application, which allow systemic targeting of APCs. RNA(LIP) is a novel nanoparticulate formulation of lipid-complexed mRNA which selectively delivers the functional mRNA to APCs in lymphoid compartments body-wide for efficient mRNA uptake and expression of the encoded antigen by APCs. Moreover, this formulation has intrinsically strong adjuvant activity, mimics a systemic viral infection and induces synchronized activation of potent adaptive as well as type-I-IFN-mediated innate immune responses (Kranz et al., Nature 2016). The first-in-human phase I/II dose escalation Lipo-MERIT trial (NCT02410733) conducted in four German study centers assesses the safety, tolerability, and biological efficacy of RNA(LIP) immunotherapy in patients with stage IIIB/C and IV melanoma. This trial is the first to investigate intravenous administration of a RNA-based cancer vaccine. Following antigen expression stratification on routinely collected tumor samples, eligible patients are treated with repeated dosing of the tetravalent Lipo-MERIT vaccine composed of RNA(LIP) products encoding the shared melanoma-associated antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTE. Pharmacodynamic activity and immunogenicity of the vaccine is investigated by concerted immune monitoring and correlative biomarker studies. Clinical activity is assessed following imaging according to irRECIST1.1. As of January 2018, & gt;50 patients have been treated with escalating or constant dosing under the guidance of an independent data safety and monitoring board. The Lipo-MERIT vaccine was generally well-tolerated and no dose-limiting toxicities (DLTs) were observed so far. Further patient enrollment is continuing. Preliminary data on the assessment of vaccine-induced immune responses and clinical responses from the first patients treated will be presented. Citation Format: Robert A. Jabulowsky, Carmen Loquai, Heidrun Mitzel-Rink, Jochen Utikal, Christoffer Gebhardt, Jessica C. Hassel, Roland Kaufmann, Andreas Pinter, Evelyna Derhovanessian, Christine Anft, Sebastian Attig, Alexandra Deubel, Mustafa Diken, Maike Gold, Claudia Guertler, Heinrich Haas, Ludwig Heesen, Alexandra Kemmer-Brück, Lena M. Kranz, Klaus Kuehlcke, Andreas Kuhn, Peter Langguth, Ulrich Luxemburger, Daniel Maurus, Martin Meng, Felicitas Müller, Richard Rae, Fatih Sari, Katharina Schreeb, Doreen Schwarck-Kokarakis, Malte Stein, Dirk Jäger, Stephan Grabbe, Sebastian Kreiter, Christoph Huber, Özlem Türeci, Ugur Sahin. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma [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 CT156.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-CT156
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Abstract CT202: IVAC MUTANOME: Individualized vaccines for the treatment of cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT202-CT202
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT202-CT202
    Abstract: Cancer arises from the accumulation of genomic alterations and epigenetic changes that constitute a hallmark of cancer. Owing to the molecular heterogeneity in cancer, only a minor fraction of patients profit from approved therapies. Available targeted therapies can only address alterations common to a particular type of cancer and induce transient effects due to the generation of resistant sub-clones. In contrast, the IVAC MUTANOME project aims to immunologically target multiple cancer mutations uniquely expressed in a given patient's tumor. The IVAC MUTANOME approach should be applicable to the majority of patients irrespective of the tumor entity and offers the potential to exploit the whole tumor mutanome of a given patient using a multi-target approach. The IVAC approach is supported by (i) the availability of technologies that allow fast discovery and validation of individual mutations based on sequencing of whole exome and (ii) an innovative vaccine platform based on RNA-technology supporting fast manufacturing and release of patient-specific vaccines targeting multiple immunogenic mutations within weeks. The phase I study to test the individualized cancer immunotherapeutics for the treatment of malignant melanoma was approved and initiated in 2013 (NCT02035956). With that, the IVAC MUTANOME trial is the first trial in Europe that introduces a fully personalized mutanome vaccine for cancer. The objectives of the clinical trial are to study the feasibility, safety, tolerability and immunogenicity of the IVAC MUTANOME approach for malignant melanoma. Feasibility will be shown by the proven ability to provide the fully personalized IVAC MUANOME vaccine to patients. Recruitment of a patient in the trial repetitively triggers the IVAC MUTANOME process covering (i) the receipt of tumor and blood sample specimens, (ii) the identification, prioritization and confirmation of mutations, (iii) testing of pre-existing immunity against private tumor mutations, (iv) the final selection of mutated sequences, (iv) design, production of a DNA lead structure, (v) GMP manufacturing and release of the patient-specific mRNA, (vi) shipment to the clinical trial site, and (vii) the administration of the IMP to patients. The IVAC MUTANOME recruitment status, manufacturing experiences and treatment status of this first-in-class clinical trial as well as novel data on the immune assessment incl. vaccine-induced mutation-specific T cell responses of the first patients treated will be presented. Citation Format: Bjoern-Philipp Kloke, Cedrik M. Britten, Carmen Loquai, Martin Löwer, Sebastian Attig, Valesca Bukur, Nicole Bidmon, Evelyna Derhovanessian, Jan Diekmann, Mustafa Diken, Angela Filbry, Stephan Grabbe, Sandra Heesch, Christoph Hoeller, David Langer, Uli Luxemburger, Matthias Miller, Felicitas Mueller, Tina Mueller-Brenne, Inga Ortseifer, Burkhard Otte, Anna Paruzynski, Sebastian Petri, Richard Rae, Christine Seck, Kristina Spieß, Arbel D. Tadmor, Jochen Utikal, Klaus Kuehlke, John Castle, Alexandra Kemmer-Brueck, Isabel Vogler, Andreas N. Kuhn, Sebastian Kreiter, Oezlem Tuereci, Ugur Sahin. IVAC MUTANOME: Individualized vaccines for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American As sociation for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT202. doi:10.1158/1538-7445.AM2015-CT202
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-CT202
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Abstract 910: Amanitin-based ADCs targeting PSMA as novel therapeutic modality for prostate cancer therapy
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 910-910
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 910-910
    Abstract: Background: Antibody-targeted amanitin conjugates (ATACs) comprise a new class of antibody-drug conjugates (ADCs) using amanitin as toxic payload. Amanitin binds to the RNA pol II and thereby efficiently inhibits the cellular transcription process. In the current study, in vitro and in vivo data of an ATAC targeting PSMA (prostate specific membrane antigen) are presented. PSMA is a type II integral membrane glycoprotein and used as tumor marker due to its predominant expression on malignant prostate cells in prostate carcinoma. As PSMA expression increases with tumor aggressiveness, metastatic and disease recurrence, it is considered an ideal target for amanitin-based ADCs. Material and methods: Cell lines: PSMA+ cell lines: LNCap, 22RV1; PSMA- cell line: PC3 Antibody: cysteine engineered monoclonal anti-PSMA antibody (Albert Ludwig University Freiburg, medical center; derivatization and production at Heidelberg Pharma) Toxic warhead: Cysteine reactive amanitin-linker constructs were synthesized at Heidelberg Pharma and conjugated site-specifically to engineered cysteine residues of the anti-PSMA antibody yielding ATACs with a DAR of 2. Cell proliferation assay: Quantitative determination of cell viability was performed by BrdU-based chemiluminescent cell proliferation ELISA (Roche). Animal models: Subcutaneous Mouse xenograft tumor models with PSMA-positive cell lines 22RV1 and LNCap were performed in single-dose experiments. Tolerability was assessed in mice and non-human primates (NHP). Results: All anti-PSMA ATACs with optimized amanitin-linker variants for use in solid tumors showed favorable in vitro cytotoxicity with nano- to picomolar activity on PSMA+ cell lines and no cytotoxic activity on PSMA- cells. In mouse xenograft models, the optimized anti-PSMA ATACs caused dose-dependent tumor regression in LNCap s.c. xenografts. Complete remission was achieved after a single i.v. dose of ¼ MTD with 100% overall survival for the full duration of the studies ( & gt;160 days). The tolerability of the tested ATACs in mice differed between 15 and & gt; 80 mg/kg Safety profiling in Cynomolgus monkeys revealed a good tolerability and therapeutic index for all selected amanitin-linker variants. Hematology and clinical chemistry parameters were unaffected except liver enzymes and LDH: A moderate and transient increase was observed. Low off target toxicity was confirmed by a non-binding ATAC. Conclusions: Targeted cytotoxic drug delivery to PSMA positive cell lines was achieved by using anti-PSMA ATACs optimized for the use in solid tumors. The mode of action of the payload amanitin led to an efficient anti-tumor potential in vitro and in vivo with good tolerability in non-human primates. Using ATACs in the therapy of PSMA positive prostate cancer is a promising approach, especially by using a cytotoxic agent whose mode of action differs from other commonly used toxins. Citation Format: Alexandra Braun, Aniko Palfi, Christoph Mueller, Torsten Hechler, Andreas Pahl, Michael Kulke. Amanitin-based ADCs targeting PSMA as novel therapeutic modality for prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 910.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-910
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
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    Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 23 ( 2018-12-01), p. 5939-5947
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 23 ( 2018-12-01), p. 5939-5947
    Abstract: Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials. Experimental Design: We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center. Results: Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit. Conclusions: Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0412
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Abstract 545: Plasma-based diagnostics for detection of EML4-ALK fusion transcripts in NSCLC patients
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 545-545
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 545-545
    Abstract: Introduction: The EML4-ALK (echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase) translocation represents a predictive driver mutation in non-small cell lung cancer (NSCLC). As EML4-ALK is both associated with resistance to EGFR inhibitors and druggability with FDA approved ALK kinase inhibitors, molecular profiling of the respective fusion transcripts is an important prerequisite for therapy. Ongoing clinical trials and development of new ALK inhibitors for personalized treatment also emphasize the need for development of accompanying diagnostics. Today's determination of EML4-ALK fusions is based on biopsies and fine-needle aspirates. These techniques are constrained by surgical complications, availability of tissue and sample heterogeneity. To overcome these challenges, the mutational analysis of fusion transcripts in plasma is expected to be a valuable benefit for non-surgical and longitudinal monitoring of EML4-ALK positive NSCLC patients. Experimental procedures: Using our proprietary column-based method to isolate vesicle-derived RNA from a few ml of patient plasma from NSCLC patients, we were able to consistently and reproducibly isolate sufficient amounts of high quality exoRNA. The purified exoRNA was subjected to RT-qPCR screening for EML4-ALK fusion transcripts, with assays designed to independently detect fusion transcripts of EML4-ALK variants v1, v2 and v3. During development of the qPCR, assay performance was characterized on synthetic nucleic acid oligos spiked into plasma of healthy human donors. The diagnostic assay was finally validated on time-matched tissue and plasma samples derived from NSCLC patients. Summary: Our data demonstrates the ability to detect rare predictive mutations in exosomal and other vesicular-derived RNA transcripts isolated from patient plasma. Here, NSCLC samples were characterized by monitoring their expression profile of EML4-ALK variants. The qPCR assays specifically detected the three major fusion transcript variants representing more than 70% of all EML4-ALK positive cases. The assay displayed high selectivity over wild type background and data showed correlation with tissue analysis. Iterative modeling of the assay significantly improved specificity and sensitivity towards its application as a diagnostic test. Conclusions: Liquid biopsies represent a low-risk and comprehensive method to screen for predictive cancer markers in plasma of NSCLC patients during longitudinal monitoring. The efficient isolation of exosomal/vesicle-derived RNA via spin column enables subsequent analysis of rare fusion transcripts for diagnostic development. As a proof of concept, we implemented a qPCR-based assay to determine EML4-ALK translocations in plasma from NSCLC patients, indicating the feasibility of developing a diagnostic test, which could facilitate effective personalized treatment. Citation Format: Kay Brinkmann, Daniel Enderle, Tina Koestler, Stefan Bentink, Jennifer Emenegger, Alexandra Spiel, Romy Mueller, Vincent O'Neill, Johan Skog, Mikkel Noerholm. Plasma-based diagnostics for detection of EML4-ALK fusion transcripts in NSCLC patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 545. doi:10.1158/1538-7445.AM2015-545
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-545
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 6
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    Abstract CT032: A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles for potent cancer immunotherapy in patients with malignant melanoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT032-CT032
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT032-CT032
    Abstract: Immunotherapeutic approaches have evolved as promising and valid alternatives to available conventional cancer treatments. Amongst others, vaccination with tumor antigen-encoding RNAs by local administration is currently successfully employed in various clinical trials. To allow for a more efficient targeting of antigen-presenting cells (APCs) and to overcome potential technical challenges associated with local administration, we have developed a novel RNA immunotherapeutic for systemic application based on a fixed set of four liposome complexed RNA drug products (RNA(LIP)), each encoding one shared melanoma-associated antigen. The novel RNA(LIP) formulation was engineered (i) to protect RNA from degradation by plasma RNases and (ii) to enable directed in vivo targeting of APCs in lymphoid compartments, thus (iii) allowing for intravenous administration of multiple RNA products advancing from local to systemic targeting of APCs. Here, RNA(LIP) products trigger a Toll-like receptor (TLR)-mediated Interferon-α (IFN-α) release from plasmacytoid dendritic cells (DCs) and macrophages stimulating DC maturation and hence inducing innate immune mechanisms as well as potent vaccine antigen-specific immune responses. Notably, BioNTech RNA Pharmaceuticals′ RNA(LIP) formulation is a universally applicable potent novel vaccine class for intravenous APC targeting and the induction of potent synchronized adaptive and type-I interferon-mediated innate immune responses for cancer immunotherapy. Similar to other liposomal drugs, the ready-to-use RNA(LIP) products are prepared individually in a straight-forward manner directly prior to use from three components, namely solutions containing RNA drug product, NaCl diluent, and liposome excipient, that are provided as a kit. A multi-center phase I/II trial to clinically validate this pioneering RNA(LIP) formulation for the treatment of malignant melanoma was initiated in 2015 (NCT02410733). The objective of the clinical trial is to study the feasibility, safety, tolerability, immunogenicity and evaluate potential clinical activity of the RNA(LIP) immunotherapy concept. Detailed information on the ongoing trial, the recruitment and treatment status as well as data on the assessment of vaccine-induced immune responses will be presented. Citation Format: Robert A. Jabulowsky, Carmen Loquai, Mustafa Diken, Lena M. Kranz, Heinrich Haas, Sebastian Attig, Nicole Bidmon, Janina Buck, Evelyna Derhovanessian, Jan Diekmann, Daniel Fritz, Veronika Jahndel, Alexandra Kemmer-Brueck, Klaus Kuehlcke, Andreas N. Kuhn, Peter Langguth, Ulrich Luxemburger, Martin Meng, Felicitas Mueller, Richard Rae, Fatih Sari, Doreen Schwarck-Kokarakis, Christine Seck, Kristina Spieß, Meike Witt, Jessica C. Hassel, Jochen Utikal, Roland Kaufmann, Sebastian Kreiter, Christoph Huber, Oezlem Tuereci, Ugur Sahin. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles for potent cancer immunotherapy in patients with malignant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT032.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-CT032
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    A Hypermutation Phenotype and Somatic MSH6 Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 8 ( 2006-04-15), p. 3987-3991
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 8 ( 2006-04-15), p. 3987-3991
    Abstract: Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers. (Cancer Res 2006; 66(8): 3987-91)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-0127
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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  • 8
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    Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 9 ( 2022-05-03), p. 1818-1831
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 9 ( 2022-05-03), p. 1818-1831
    Abstract: T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the argonaute RISC catalytic component 2 (AGO2) gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a protumorigenic key regulator of miRNA (miR) processing. Here, in primary tumor material and cell line models, AGO2 overrepresentation associated (i) with higher disease burden, (ii) with enhanced in vitro viability and growth of leukemic T cells, and (iii) with miR-omes and transcriptomes that highlight altered survival signaling, abrogated cell-cycle control, and defective DNA damage responses. However, AGO2 elicited also immediate, rather non–RNA-mediated, effects in leukemic T cells. Systems of genetically modulated AGO2 revealed that it enhances TCR signaling, particularly at the level of ZAP70, PLCγ1, and LAT kinase phosphoactivation. In global mass spectrometric analyses, AGO2 interacted with a unique set of partners in a TCR-stimulated context, including the TCR kinases LCK and ZAP70, forming membranous protein complexes. Models of their three-dimensional structure also suggested that AGO2 undergoes posttranscriptional modifications by ZAP70. This novel TCR-associated noncanonical function of AGO2 represents, in addition to TCL1A-mediated TCR signal augmentation, another enhancer mechanism of this important deregulated growth pathway in T-PLL. These findings further emphasize TCR signaling intermediates as candidates for therapeutic targeting. Significance: The identification of AGO2-mediated activation of oncogenic T cells through signal amplifying protein–protein interactions advances the understanding of leukemogenic AGO2 functions and underlines the role of aberrant TCR signaling in T-PLL.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-1908
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 19 ( 2016-10-01), p. 4837-4847
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 19 ( 2016-10-01), p. 4837-4847
    Abstract: Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models. Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS. Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837–47. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-1915
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 10
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    Abstract 2633: Radiogenomics of breast cancer using DCE-MRI and gene expression profiling
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2633-2633
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2633-2633
    Abstract: The utilization of radiomics (high-throughput extraction and analysis of imaging features) to abstract underlying genomic features of an evolving malignancy is an emerging field that has the potential to detail biological information of a tumor in a non-invasive and more accessible manner. Furthermore, applying radiomics confers a comprehensive spatial view of the tumor, a potential advantage over the limitations of sampling a small region of tissue that may not accurately represent the underlying complexity of the entire tumor. Most studies to date that incorporate radiogenomics in the analysis of breast cancers have focused on few basic clinical data or individual genetic mutations such as BRCA or HER2 status. Here, we use an automated quantitative radiomics analysis platform developed at the University of Chicago that enables computerized feature extraction of tumors to analyze magnetic resonant imaging scans of 50 breast cancer patients (mean age of diagnosis [range]: 54 [24-89] ; receptor status: HER2+: 14, Triple negative: 7; stage [1 through 4]: 10%, 40%, 42%, 8%) who have had comprehensive gene expression profiling performed using Agilent Human Gene Expression arrays. Our imaging platform extracts 38 features across six major phenotypes (size, shape, morphology, enhancement texture, kinetic curve assessment, and enhancement variance kinetics) (see Table for listing of 24 selected features). Existing radiomic analysis derived from a TCGA/TCIA dataset suggests that there are many correlations between imaging phenotypes and various genetic pathways, such as VEGF signaling and volume of enhancing voxels, base excision repair and enhancement texture entropy, and TGF-beta signaling and enhancement texture variance. We confirm these relationships as well as establish novel associations using a robust imaging dataset. By associating specific radiomic features with gene expression profile of tumors, we have the opportunity to extract detailed biological information non-invasively through clinical imaging. Selected imaging phenotypes extracted from MRI scansPhenotype categoryImage phenotypeDescriptionSizeVolumeVolume of lesionSizeEffective diameterDiameter of a sphere with the same volume as the lesionSizeSurface areaLesion surface areaShapeSphericitySimilarity of the lesion shape to a sphereShapeIrregularityDeviation of the lesion surface from the surface of a sphereShapeSurface area / volumeRatio of surface area to volumeMorphologyMargin sharpnessMean of the image gradient at the lesion marginMorphologyVariance of margin sharpnessVariance of the image gradient at the lesion marginMorphologyVariance of radial gradient histogramDegree to which the enhancement structure extends in a radial pattern originating from the center of the lesionEnhancement TextureContrastLocal image variationsEnhancement TextureEntropyRandomness of the gray-levelsEnhancement TextureDifference varianceVariations of difference of gray-levels between voxel-pairsEnhancement TextureAngular second momentImage homogeneityEnhancement TextureMaximum correlation coefficientNonlinear gray-level dependenceEnhancement TextureSum averageOverall brightnessEnhancement TextureSum of squaresSpread in the gray-level distributionKinetic Curve AssessmentMaximum enhancementMaximum contrast enhancementKinetic Curve AssessmentTime to peakTime at which the maximum enhancement occursKinetic Curve AssessmentUptake rateUptake speed of the contrast enhancementKinetic Curve AssessmentCurve shape indexDifference between late and early enhancementKinetic Curve AssessmentTotal rate variationHow rapidly the contrast will enter and exit from the lesionEnhancement-Variance KineticsMaximum variance of enhancementMaximum spatial variance of contrast enhancement over timeEnhancement-Variance KineticsTime to peak maximum varianceTime at which the maximum variance occursEnhancement-Variance KineticsEnhancement variance increasing rateRate of increase of the enhancement-variance during uptake Citation Format: Albert C. Yeh, Stephanie McGregor, Hui Li, Yuan Ji, Yitan Zhu, Tatyana Grushko, Alexandra Edwards, Fan Lui, Jing Zhang, Qiu Niu, Yonglan Zheng, Toshio Yoshimatsu, Galina Khramtsova, Karen Drukker, Gregory Karczmar, Hiroyuki Abe, Jeffrey Mueller, Maryellen Giger, Olufunmilayo Olopade. Radiogenomics of breast cancer using DCE-MRI and gene expression profiling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2633.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2633
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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