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  • American Association for Cancer Research (AACR)  (52)
  • 1
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    Abstract A44: Predictive biomarkers of efficacy to the hedgehog pathway inhibitor, GDC-0449, in advanced basal cell carcinoma and medulloblastoma in phase I studies
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. A44-A44
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. A44-A44
    Abstract: The Hedgehog (Hh) signaling pathway has been directly implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma (MB). Constitutive Hh signaling, most often due to underlying loss of function mutations in the inhibitory receptor Patched1 (PTCH1), has been demonstrated in a majority of common localized BCCs and approximately 25–30% of sporadic MB cases. In this study, we examined molecular correlatives of clinical efficacy in locally-advanced / metastatic BCC and MB patients treated with GDC-0449, an inhibitor of the Hh pathway that targets the serpentine receptor Smoothened (SMO). An analysis of Hh pathway transcriptional target gene expression in archival tissue biopsies provided evidence for active Hh signaling in patients exhibiting clinical benefit (objective response or disease stabilization) on therapy. This was further supported by the identification of either loss of function or activating mutations in PTCH1 or SMO, respectively. We were unable to provide evidence for active Hh signaling in 2 patients with progressive disease as best response, potentially underlying the reason for lack of efficacy in these patients. In addition to providing molecular support for Hh pathway activity in patients exhibiting treatment benefit, this is the first evidence for Hh pathway dysregulation in the previously uncharacterized, advanced BCC setting. Furthermore, the results begin to support the utility of transcriptional-based tests as a strategy to potentially select the subset of MB patients with Hh-driven disease that would likely benefit on GDC-0449. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A44.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-A44
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
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    Abstract LB-353: Mutational profile of metastatic breast cancers using whole-exome sequencing: a retrospective analysis of 216 samples from SAFIR01 / 02 / SHIVA / MOSCATO trials
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-353-LB-353
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-353-LB-353
    Abstract: Background: Major advances have been achieved in the understanding of breast cancer biology using high throughput technologies at the DNA and RNA levels. Most of these advances were made in early breast cancers (eBC) which are cured in about 80% of the cases. Nevertheless, little is known about metastatic breast cancers (mBC) which remain lethal in most of the cases. Methods: Whole-exome sequencing was performed on 216 tumour-normal pairs from mBC patients who underwent a biopsy in the context of the SAFIR01/SAFIR02/SHIVA or MOSCATO prospective trials. TCGA dataset (n = 772) was used to assess frequency of mutations in eBC. Findings: Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, CDKN2A) were identified as drivers using MutSig algorithm (FDR & lt;0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, AGRN) were more frequently mutated in mBC as compared to eBC (TCGA, FDR & lt;0.01). HR+/Her2- mBC presented a high prevalence (6.3%) of mutations on genes located on mTOR pathway (TSC1, TSC2) as compared to HR+/Her2- eBC (0.7%, p = 0.0004). A subset of HR+/Her2- mBC (n = 17, 12%) presented a high mutational load ( & gt;150 non-synonymous mutations). This subset was observed in 2% of early breast cancers (TCGA, p = 7.1e?06). The prevalence of this subset increased with the time from diagnosis of metastasis to biopsy. Highly mutated HR+/Her2- mBC (n = 17) presented higher rate of PIK3CA mutations (n = 12, 70%), high number of neoantigens, an APOBEC mutational signature and a poor outcome (multivariate analysis, HR = 4.68, 95%CI: 1.8-12.1, p = 0.001). Interpretation: Whole exome sequencing of metastatic breast cancers identifies a subset of HR+/Her2- mBC who present a high mutational load. RB1, PALB2 and TSC1/2 mutations were found enriched in either mBC or HR+ mBC. Fundings: Breast Cancer Research Foundation, Fondation ARC, Fondation Lombard-Odier “Philanthropia”, Odyssea, Operation Parrains Chercheurs, Dassault Foundation, French NCI: INCa-DGOS-INSERM 6043 Citation Format: Maud Kamal, Celine Lefebvre, Thomas Bachelot, Thomas Filleron, Marion Pedrero, Mario Campone, Jean-Charles Soria, Christophe Massard, Christelle Levy, Monica Arnedos, Julie Garrabey, Yannick Boursin, Marc Deloger, Yu Fu, Frederic Commo, Veronique Scott, Ludovic Lacroix, Emmanuel Martin, Veronique Dieras, Anthony Goncalves, Jean-Marc Ferrero, Gilles Romieu, Laurence Vanlemmens, Marie-Ange Mouret-Reynier, Jean-christophe Thery, Pierre Kerbrat, Severine Guiu, Florence Dalenc, Gilles Clapisson, Hervé Bonnefoi, Martha Jimenez, Christophe Le Tourneau, Fabrice Andre. Mutational profile of metastatic breast cancers using whole-exome sequencing: a retrospective analysis of 216 samples from SAFIR01 / 02 / SHIVA / MOSCATO trials. [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 LB-353.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-LB-353
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Preclinical and Clinical Evidence that Deoxy-2-[18F]fluoro- D -glucose Positron Emission Tomography with Computed Tomography Is a Reliable Tool for the Detection of Early Molecular Responses to Erlotinib in Head and Neck Cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 17 ( 2010-09-01), p. 4434-4445
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 17 ( 2010-09-01), p. 4434-4445
    Abstract: Purpose: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[18F]fluoro-d-glucose positron emission tomography with computed tomography (18FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. Experimental Design: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in 18FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the 18FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. Results: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in 18FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. Conclusion: These results show that the 18FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma. Clin Cancer Res; 16(17); 4434–45. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-2795
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 4
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    Abstract PD8-02: Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD8-02-PD8-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD8-02-PD8-02
    Abstract: Background: The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) demonstrated efficacy in heavily pretreated HER2-over- and HER2-low expressing ABC (1, 2). We aimed to assess the activity of T-DXd in HER2-over-, HER2-low and HER2-nul expressing ABC, to describe the drug mechanisms of action in the 3 cohorts and to identify biomarkers associated to drug response or resistance. Study Description: DAISY is a multicenter, open-label phase II trial designed to assess the efficacy of single agent T-DXd at 5.4 mg/kg dose in ABC with extensive biomarkers analysis. Three cohorts of patients were included: Cohort 1 (HER2 over-expressing: HER2 3+ on immunohistochemistry (IHC) or HER2 IHC2+/in situ hybridization [ISH]+), Cohort 2 (HER2 low-expressing: IHC1+ or IHC2+/ISH-) and cohort 3 (HER2-nul: IHC0+). Biopsy of metastatic sites was performed: at baseline, on treatment (mandatory for cohort 1, optional for cohort 2/3) and at tumor progression; blood samples for ctDNA were collected at baseline. The primary endpoint was the Best Overall Response (BOR) in each cohort, according to the investigator assessment. Secondary endpoints were BOR by central assessment, clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Results:185 women and 1 man were enrolled between November 2019 and March 2021. Among the patients enrolled in the safety population (see Table 1), median (range) age was 55 (24-82) years, all received at least one prior line of therapy and 12 patients were TN. Table 2 shows investigator-reported T-Dxd activity in the 3 cohorts at a median follow-up of 10.1 months [95%CI: 9.2-11.1] . A total of 170 patients (95%) had at least one treatment-related toxicity. Key grade ≥3 treatment-related toxicities included neutropenia (10.6% of patients), fatigue (5.6%), leucopenia (4.5%), vomiting (4.5%) and anemia (3.4%). A total of 4 patients had drug-related interstitial lung disease or pneumonitis (grade 1 in 3 patients and grade 2 in 1 patient), 11 patients discontinued treatment due to treatment-related adverse events. No drug-related deaths occurred. Conclusions: T-DXd showed clinically meaningful activity in patients with HER2-overexpressing ABC and interestingly also in those with HER2low and HER2-nul ABC. Safety profile was consistent with previous reports. 1.Modi S et al N Engl J Med 2020 2.Mosi S et al J Clin Oncol 2020 Table 1.Analysis populationsTotalCohort 1 (HER2 over-expressing)Cohort 2 (HER2 low-expressing)Cohort 3 (HER2 non-detected)Enrolled population186727440Safety population*179687338 (including 12 TN)Full analysis Set**176687236TN: Triple Negative. *: safety population = enrolled population except 7 patients who did not receive at least one dose of study drug. **: Full Analysis Set = safety population except 3 patients (2 who did not have a valid first post-baseline assessment of disease status or who did not have progressive disease and 1 who did not have at least one radiologically measurable lesion according to RECIST v1.1) Table 2.T-DXd activity in the three cohorts according to investigator assessmentTotalCohort 1Cohort 2Cohort 3BOR confirmedn/N82/176 (46.6%)47/68 (69.1%)24/72 (33.3%)11/36 (30.6%)[95%CI][39.1; 54.2] [56.7; 79.8][22.7; 45.4] 16.3; 48.1]Median DORmonths7.69.97.66.8[95%CI] [6.2; 9.7][5.4; NR] [4.4; 8.7][2.8; 8.3] Median PFSmonths6.911.16.74.2[95%CI][6.7; 8.7] [8.4; NR][4.6; 8.5] [2.1; 6.9]NR: Not Reached Citation Format: Véronique Diéras, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret, Christelle Levy, Laura Salabert, Fanny Le Du, Florence Dalenc, Christelle Jouannaud, Laurence Venat-Bouvet, Jean-Philippe Jacquin, Xavier Durando, Thierry Petit, Céline Mahier - Aït Oukhatar, Thomas Filleron, Maria Fernanda Mosele, Magali Lacroix-Triki, Agnès Ducoulombier, Fabrice André. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-PD8-02
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    Abstract C30: A KRAS pathway activation index predicting response to MEK inhibitors in patient-derived tumor xenografts.
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. C30-C30
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. C30-C30
    Abstract: Introduction: MEK 1/2 inhibitors (MEKi) are promising compounds for the treatment of cancer due to frequent activation of the RAS/MAPK/ERK oncogenic pathway. CI-1040 and PD0325901 are newly developed MEKi that are currently being tested in clinical trials. In the present study, we investigated MEKi response in different tumor types and we determined whether an index of KRAS pathway activation (K-PAI) could predict response to MEKi. Material and Methods: CI-1040 and PD0325901 were tested using an ex vivo 3D Tumor Clonogenic Assay (TCA) in a panel of 63 patient-derived tumor xenografts (PDX) covering 15 tumor histotypes. The K-PAI was determined by identifying gene expression patterns (Affymetrix HGU133 plus 2.0 arrays) associated with activation of the pathway and KRAS mutational status (determined by Sanger sequencing). Results: The absolute activities (IC50) of CI-1040 and PD0325901 correlated in most of the tumor models tested (r=0.87). Most of the melanomas were sensitive to both MEKi tested, whereas variable response profiles were observed in colon cancers and non-small cell lung cancers (NSCLC). Ovarian and pancreatic cancer xenografts displayed in most instances weak responses. The KRAS and BRAF statuses were significantly associated with MEKi IC50 (p=0.0001 and p=0.0002, respectively). The melanomas which frequently displayed BRAF mutations (13/21), were highly sensitive to MEKi treatment, whereas ovarian and pancreatic tumors, which frequently harbored KRAS mutations (1/3 and 2/2), were resistant. Moreover, we found that the K-PAI correlated significantly with MEKi IC50 (r & gt;0.5, p & lt;0.0001 for CI-1040 and PD0325901).= Melanomas with low K-PAI values were highly sensitive to MEKi treatment whereas ovarian and pancreatic tumors with high K-PAI values were resistant. Interestingly, the K-PAI was also predictive of response to MEKi treatment for tumors expressing wild-type BRAF and KRAS.Conclusion: This large ex vivo PDX study showed that tumor sensitivity to MEKi is related to histology and to RAS pathway activation. KRAS and BRAF mutations were predictive of MEKi response (resistance and sensitivity, respectively). These results are consistent with published data on cell lines and on small patient cohorts and demonstrate that PDX are adequate models to test targeted drugs such as MEKi. The correlation of tumor sensitivity to MEKi and the RAS pathway activation level (K-PAI) should be further evaluated in ex vivo 3D assays utilizing PDXs or with an in vivo study, to be able to better stratify patients when testing the predictive potential of K-PAI in clinical trials. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C30. Citation Format: Anne-Lise Peille, Armin Maier, Frederic Foucault, Rebekka Krumbach, Tim Kees, Torsten Giesemann, Thomas Metz, Thomas Metcalfe, Heinz-Herbert Fiebig, Vincent Vuaroqueaux. A KRAS pathway activation index predicting response to MEK inhibitors in patient-derived tumor xenografts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C30.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-13-C30
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Discovery Vol. 9, No. 6 ( 2019-06-01), p. 796-811
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 9, No. 6 ( 2019-06-01), p. 796-811
    Abstract: The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. Significance: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors. This article is highlighted in the In This Issue feature, p. 681
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-18-0873
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 7
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    Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 14 ( 2021-07-15), p. 3806-3821
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 14 ( 2021-07-15), p. 3806-3821
    Abstract: Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAFV600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. Significance: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-20-2114
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 15 ( 2009-08-01), p. 6249-6255
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 15 ( 2009-08-01), p. 6249-6255
    Abstract: We have reported previously that the interaction of αE(CD103)β7 integrin, expressed on a CD8+ tumor-infiltrating lymphocyte (TIL) clone but not on a peripheral blood lymphocyte (PBL) counterpart, with the epithelial marker E-cadherin on human lung tumor cells plays a crucial role in T-cell receptor–mediated cytotoxicity. We show here that both TIL and PBL clones are able to migrate toward autologous tumor cells and that chemokine receptor CCR5 is involved in this process. Adoptive transfer of the PBL clone in the cognate tumor engrafted in nonobese diabetic/severe combined immunodeficient mice and subsequent coengagement of T-cell receptor and transforming growth factor-β1 receptor triggers CD103 expression on T-cell surface resulting in strong potentiation of antitumor lytic function. Moreover, interaction of αEβ7 integrin with E-cadherin, but not lymphocyte function-associated antigen-1 with intercellular adhesion molecule-1, promotes CCR5 recruitment at the immunologic synapse formed between TIL and tumor cells, leading to inhibition of T-cell sensitivity to CCL5 chemotactic gradient. These results provide evidence for a role of tumor microenvironment, namely MHC class I–restricted antigen presentation and transforming growth factor-β1 secretion, in regulating the effector phase of tumor-specific CTL response. They also suggest a unique role of CD103 in T-cell retention at the tumor site by a CCR5-dependent mechanism. [Cancer Res 2009;69(15):6249–55]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-3571
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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    Abstract 4435: Discovery, biological characterization and oral antitumor activity of polo-like kinase 1 (Plk1) selective small molecule inhibitors
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4435-4435
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4435-4435
    Abstract: We have identified novel inhibitors of Polo-like kinase 1 (Plk1) that exhibit strong single agent activity in solid tumor and leukemia xenograft models after oral dosing. Plk1 is a serine / threonine protein kinase thought to regulate cell division through promotion of mitotic entry, control of spindle assembly, orchestration of mitotic progression and initiation of cytokinesis. Plk1 has been reported to phosphorylate and deactivate the tumor suppressors p53, p63 and p73 thereby inhibiting apoptosis. Furthermore this repression of p53 family members may be responsible for the survival and tumorigenesis of liver cancer stem cells. Cancer cell proliferation is blocked in vitro and in vivo by antisense oligonucleotides and siRNAs to Plk1. Overexpression of Plk1 is associated with tumor development and many human cancers express elevated Plk1 levels compared to surrounding normal tissue. Numerous studies have shown that Plk1 expression levels correlate with disease progression, invasiveness and poor patient prognosis. Collectively, these observations support the selection of Plk1 as an attractive target for cell cycle-directed cancer therapy. We have employed high throughput screening, in silico screening and de novo ligand design approaches to select an inhibitor scaffold for lead optimization. We have selected a set of ATP-competitive Plk1 inhibitors that exhibit high selectivity for Plk1 and inhibit growth of a broad range of tumor cell lines in vitro with IC50s in the low nanomolar range. Structure-activity relationships (SAR) were determined through iterative targeted analogue synthesis and in vitro testing with SAR rationalized against x-ray crystallographic data. We observed selectivity of the inhibitor scaffold for Plk1 against a panel of over 200 kinases. Treatment of tumor cells with our Plk1 inhibitors induced a phenotype consistent with inhibition of Plk1, accumulation of cells in mitosis and induction of apoptosis. The extent of cytotoxicity was dependent on proliferation as determined by comparative viability of cells arrested in the G1 phase versus proliferating cells. Compound evaluation using a cell-based activity assay for inhibition of Plk1 and pharmacokinetic profiling informed lead optimization studies to generate potential drug candidates with high oral bioavailability and which induce tumor stabilization, regression and tumor-free cures in solid tumor and leukemia xenograft models as single agents. For example, 6% T/C (p = 0.00001) was achieved in the HCT116 human colon carcinoma model. In summary, we describe a set of Plk1 inhibitors which act as potent antiproliferative agents suitable for further development as oral Plk1 selective inhibitors for the treatment of human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4435.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4435
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    Abstract 4466: Characterization of the pan class I PI3K inhibitor NVP-BKM120 mechanism of action across a broad range of concentrations
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4466-4466
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4466-4466
    Abstract: NVP-BKM120 is a pan class I PI3K inhibitor that has recently entered phase II clinical trials. The compound was shown to inhibit cell proliferation and survival of cancer models displaying PI3K pathway dependency, in a dose-dependent manner, and proportionally to the extent of pathway inhibition. To further characterize NVP-BKM120, we have investigated its mechanism of action across a broad range of relevant models and concentrations of the molecule and compared it to other PI3K inhibitors (e.g. GDC0941 and ZSTK474). The effects observed on phenotypical read-outs were similar for all compounds, when tested up to concentrations necessary to achieve near complete pathway inhibition (IC90 for Akt-S473P). More profound effects were however observed with NVP-BKM120, at higher concentrations ( & gt;2 micromolar), in PI3K-independent models, suggesting that at these dose levels, NVP-BKM120 might display inhibitory activities other than PI3K. In order to determine this potential off-target activity, a gene expression profiling study was performed in a PI3K insensitive model, comparing effects of GDC0941 and NVP-BKM120 at equipotent concentrations. Gene-Set Enrichment Analysis (GSEA) revealed that NVP-BKM120 at the highest dose only (3.6 micromolar, 2 fold above the S473-Akt IC90 of PI3K sensitive models), led to increased expression of genes involved in G2 and mitotic (M) phases. Subsequent FACS analysis showed that in contrast to the other pan-PI3K inhibitors, NVP-BKM120 was indeed able to induce a strong G2/M arrest in several PI3K non addicted cell lines when used at concentrations higher than 2 micromolar. DAPI and tubulin immuno-histochemistry studies showed that the NVP-BKM120 induced block was phenotypically similar to that of Nocodazole, suggesting effects on spindle dynamics in prometaphase. Indeed, in cellular or in in vitro purified systems, NVP-BKM120 greatly reduced microtubule polymerization.Based on analysis the antitumor activity observed in vivo in PI3K-dependent animal models, it appears that efficacy is solely due to pure PI3K inhibition, as these off-target activities are generally observed at concentrations (corrected for free fraction) that could not be achieved in animals. Based on modeling of human PK data, a similar conclusion can be reached for patients, as the exposure currently observed in plasma does predict sole coverage of PI3K inhibitory activities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4466. doi:10.1158/1538-7445.AM2011-4466
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-4466
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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