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  • American Association for Cancer Research (AACR)  (10)
  • 1
    Online Resource
    Online Resource
    Phase I Safety and Pharmacodynamic of Inecalcitol, a Novel VDR Agonist with Docetaxel in Metastatic Castration-Resistant Prostate Cancer Patients
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 17 ( 2014-09-01), p. 4471-4477
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 17 ( 2014-09-01), p. 4471-4477
    Abstract: Purpose: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. Experimental Design: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. Results: Eight dose levels (40–8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. Conclusion: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned. Clin Cancer Res; 20(17); 4471–7. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-3247
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
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    Abstract LB-201: MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-201-LB-201
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-201-LB-201
    Abstract: Disease recurrence following multi-modal therapy is the single most adverse event in medulloblastoma (MB). Currently & gt;90% of relapsing patients die, accounting for ∼10% of childhood cancer deaths. MB is heterogeneous at diagnosis, comprising four molecular subgroups with distinct clinicopathological and molecular features and outcomes. The relevance of these features at relapse is unknown, making characterisation, modelling and targeted therapy of relapse biology essential to improve outcomes. However, relapsed MBs are not routinely biopsied in clinical practice. We undertook a first comprehensive investigation of the molecular, clinical and pathological features of 29 relapsed MBs and paired tumour samples taken at diagnosis, including the assessment of features with established significance at diagnosis (e.g. chromosome 17 and TP53 pathway status, MYC family (MYC, MYCN) gene amplification, polyploidy, CTNNB1 mutation and molecular subgroup status). Molecular subgroup was concordant at diagnosis and relapse, however evidence of alteration of all other features examined was found in relapsed tumours, with the majority of changes (30/44) representing acquired high-risk events. Most notably, MYC family gene amplifications and TP53 pathway defects commonly emerged in combination at relapse following conventional multimodal treatment (P=0.02, 7/22, 32%) and predicted rapid progression to death (P=0.016). These observations suggested aberrant activation of MYC family genes synergizes with TP53 inactivation in the genesis of biologically aggressive MB. To investigate any such relationship, we examined Trp53 status in our transgenic mouse model of spontaneously-arising MYCN-driven MB (GTML; Glt1-tTA/TRE-MYCN-Luc). Somatic Trp53 mutations were found in 83% of tumors (n=10/12). Direct modelling of this interaction in GTML/Trp53KI/KI mice dramatically enhanced MB formation with 100% penetrance (43/43, median survival 47 days) in GTML/Trp53KI/KI versus 6% (3/50) in GTML; P & lt;0.0001), faithfully mimicked clinicopathological characteristics of TP53-MYC family gene-associated relapsed human tumors, and validated the essential role of TP53 in potentiating the growth of MYCN-driven MB. Finally, therapeutic inhibition of Aurora-A kinase using MLN8237 in these tumours, and in derived neurospheres in vitro, promoted degradation of MYCN, reduced tumor growth and prolonged survival. In summary, while subgroup status remains stable, MBs display altered molecular, pathological and clinical features at relapse, and the emergence of combined TP53-MYC family gene defects is common following conventional therapy. Their association with rapid demise, coupled with their biological validation as driving and therapeutically exploitable events in a novel mouse MB model, strongly support further investigation and routine biopsy of relapse disease to drive future individualised therapeutic strategies. Citation Format: Rebecca M. Hill, Sanne Kuijper, Janet Lindsey, Ed C. Schwalbe, Karen Barker, Jessica Boult, Daniel Williamson, Zai Ahmad, Albert Hallsworth, Sarra Ryan, Evon Poon, Simon Robinson, Ruth Ruddle, Florence Raynaud, Louise Howell, Colin Kwok, Abhijit Joshi, Sarah Nicholson, Stephen Crosier, Stephen Wharton, Tom Jacques, Keith Robson, Antony Michalski, Darren Hargrave, Barry Pizer, Simon Bailey, Fredrik J. Swartling, Kevin Petrie, William A. Weiss, Louis Chesler, Steve Clifford. MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-201. doi:10.1158/1538-7445.AM2014-LB-201
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-LB-201
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
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    Abstract 478: Predicting interactome networks perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 478-478
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 478-478
    Abstract: Genomic variations such point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and as therapeutic targets. However, predicting the functional impact of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes likely result in complex molecular interaction networks. Using as models three different chromosomal translocations ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and E2A-PBX1 (TCF3-PBX1) frequently found in B-cell acute lymphoblastic leukemia (B-ALL), we develop an approach to extract from gene expression changes, perturbed molecular interactions. We show that the Myc and JunD transcriptional circuits are specifically deregulated following TEL-AML1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and TEL-AML1 acute lymphoblastic leukemia. Note: This abstract was not presented at the meeting. Citation Format: Leon Hajingabo, Sarah Daakour, Maud Martin, Reinhard Grausenburger, Renate Panzer-Grümayer, Franck Dequiedt, Jacques Van Helden, Jean-Claude Twizere, Nicolas Simonis. Predicting interactome networks perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 478. doi:10.1158/1538-7445.AM2014-478
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-478
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
    Online Resource
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    Macrophage Scavenger Receptor 1 999C〉T (R293X) Mutation and Risk of Prostate Cancer
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 14, No. 2 ( 2005-02-01), p. 397-402
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 14, No. 2 ( 2005-02-01), p. 397-402
    Abstract: Background: Variants in the gene encoding the macrophage scavenger receptor 1 (MSR14) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C & gt;T (R293X) protein-truncating mutation may be associated with an increased risk for this disease. Methods: Using large case-control, cohort, and prostate cancer family studies conducted in several Western countries, we tested for the 999C & gt;T mutation in 2,943 men with invasive prostate carcinoma, including 401 males from multiple-case families, 1,982 cases unselected for age, and 575 men diagnosed before the age of 56 years, and in 2,870 male controls. Risk ratios were estimated by unconditional logistic regression adjusting for country and by a modified segregation analysis. A meta-analysis was conducted pooling our data with published data. Results: The prevalence of MSR1*999C & gt;T mutation carriers was 0.027 (SE, 0.003) in cases and 0.022 (SE, 0.002) in controls, and did not differ by country, ethnicity, or source. The adjusted risk ratio for prostate cancer associated with being a 999C & gt;T carrier was 1.31 [95% confidence interval (CI), 0.93-1.84; P = 0.16]. The modified segregation analysis estimated the risk ratio to be 1.20 (95% CI, 0.87-1.66; P = 0.16). The risk ratio estimated from the meta-analysis was 1.34 (95% CI, 0.94-1.89; P = 0.10). Conclusion: Our large-scale analysis of case and controls from several countries found no evidence that the 999C & gt;T mutation is associated with increased risk of prostate cancer. The meta-analysis suggests it is unlikely that this mutation confers more than a 2-fold increased risk.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-04-0202
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 5
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    Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 23 ( 2022-12-01), p. 5211-5220
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 23 ( 2022-12-01), p. 5211-5220
    Abstract: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1622
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract 902: Augmentation of anti-melanoma response by combining radiation-based in situ vaccination with GIFT4 B cell therapy
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 902-902
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 902-902
    Abstract: We have recently demonstrated the effectiveness of combining external beam radiation therapy (RT), intratumoral immunocytokine (IT-IC), and anti-CTLA4 (αCTLA4) in eliminating large (500mm3) B78 melanomas (MEL), prolonging survival and invoking T cell immune memory in mice. This highly translational therapy is currently being investigated in a phase I clinical trial. Despite the success of this regimen against large single subcutaneous MEL tumors, many mice with large tumors and intravenously (IV) injected metastatic MEL, receiving this same regimen, still die from metastatic disease. A recent report has shown that fusokine GIFT4, a recombinant chimera of GMCSF and IL4 programs B cells (GIFT4BC) to acquire a unique phenotype with augmented capacity for antigen presentation and anti-MEL activity. Herein, we report the preliminary results of studies combining RT+IC+αCTLA4 with intratumoral (IT) GIFT4BCs therapy. We hypothesized that GIFT4BCs enhance the anti-tumor and anti-metastatic efficacy of RT+IC+αCTLA4. C57BL/6 mice were engrafted with 2 × 106 B78 MEL intradermally in the flank. At a tumor volume of ~250mm3, mice were intravenously injected with 3.5 × 105 B16 MEL (a metastatic parental line of B78 MEL) to induce metastases. Mice were treated with 12 Gy RT on day 1 (D1), 1 × 107 IT- GIFT4BC on D4, IC (IT, 50ug) on D6-D10, and αCTLA4 (ip, 200ug) on D3, 6, and 9 (designated RT+IC+αCTLA4+GIFT4BC). Control groups received no treatment, GIFT4BCs alone, or RT+IC+αCTLA4. Tumor growth and survival were monitored. At the time of euthanasia for tumor burden or illness, necropsy was performed to quantify metastases. A pre-determined cohort of mice from each treatment group were euthanized on D12. From these, tumor-draining lymph nodes were fixed for histology and tumors were harvested for qPCR, histology, and flow cytometry. Preliminary results indicate that the addition of GIFT4BCs to RT+IC+αCTLA4 improves survival. Lungs from treated mice showed reduced metastatic burden in RT+IC+αCTLA4+GIFT4BC mice compared to controls. GIFT4BCs were identified in the tumor-draining lymph nodes using confocal microscopy in RT+IC+αCTLA4+GIFT4BC mice. qPCR analysis of tumor samples revealed an upregulation of interferon gamma (Ifny) in RT+IC+αCTLA4+GIFT4BC mice compared to control groups. Flow cytometry analysis show increased CD45+ tumor infiltrating lymphocytes in RT+IC+αCTLA4+GIFT4BC compared to RT+IC+αCTLA4 groups. Combination of RT+IC+αCTLA4+GIFT4BC displays anti-MEL activity that reduces metastatic burden and prolongs survival in murine MEL models. These preliminary findings support published hypotheses which postulate that GIFT4BC-mediated mechanisms may augment the T cell response through B cell antigen presentation and chemotactic cytokine production in vivo. Future studies will elucidate the mechanisms of anti-tumor efficacy of RT+IC+αCTLA4+GIFT4BC. Citation Format: Elizabeth G. Sumiec, Claire C. Baniel, Amber M. Bates, Sarah Emma, Erin Nystuen, Alexander L. Rakhmilevich, Amy K. Erbe, Pradyut Paul, Jacques Galipeau, Paul M. Sondel, Zachary S. Morris. Augmentation of anti-melanoma response by combining radiation-based in situ vaccination with GIFT4 B cell therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 902.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-902
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    Abstract B143: HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. B143-B143
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. B143-B143
    Abstract: Colorectal carcinoma (CRC) as well as other indications that have lost competence in mismatch repair and have a phenotype known as microsatellite instability (MSI), remain a significant unmet medical need. Large-scale functional genomics screens across cell line panels have identified the Werner Syndrome RecQ helicase (WRN) as being synthetic lethal with MSIhigh cancers. Thus, WRN inhibitors may offer a new therapeutic avenue in MSIhigh cancers. We report the preclinical characteristics of HRO761, a first-in-class, highly potent and selective inhibitor of WRN helicase, with optimized drug-like properties. We evaluated the pharmacokinetics and pharmacodynamics of HRO761 when administered orally once daily in MSIhigh and also assessed the efficacy as single agent across cell (CDX) and patient-derived (PDX) xenografts as well as in combination with irinotecan, a prodrug derivative of camptothecin which acts as topoisomerase I inhibitor. Daily oral administration of HRO761 was highly efficacious across the CDX and PDX models evaluated with a disease control rate of 70% across all indications. In the SW48 CDX model, tumor regression was sustained for 2 months at the highest dose followed by slow relapse. HRO761 also induced WRN degradation, activated the DNA damage response and induced p53 target genes in a dose dependent manner. In vitro combination with irinotecan deepened sensitivity to HRO761 with a more sustained response in MSIhigh CRC cell lines. Combining administration of HRO761 daily with irinotecan weekly was highly efficacious and beneficial over single agent in CDX and PDX models. In CDX models, the combination showed a robust benefit, translating into homogeneous, sustained regression leading to a dose-dependent tumor growth delay even after treatment discontinuation. Overall, we demonstrate that the novel, selective, first-in-class WRN inhibitor HRO761 is a promising therapeutic approach for the treatment of MSIhigh cancer patients either as single agent or in combination with irinotecan. Clinical development is currently ongoing to assess the safety, tolerability and preliminary anti-tumor activity in patients with MSIhigh colorectal cancer and other MSIhigh solid tumors [clinicaltrials.gov NCT05838768]. Citation Format: Stephane Ferretti, Isabel Jaco, Andrea Decker, Christelle Hemmerlin, Clemens Scheufler, Cornelia Quadt, Dario Sterker, Elena Gavioli, Eloisa Jimenez Nunez, Ernesta Dammassa, Fanny Schaeffer, Genevieve Albrecht, Giorgia Clementi, Hansjoerg Martus, Jacques Hamon, Juergen Hinrichs, Laurent Laborde, Marion Dourdoigne, Michele Moschetta, Ramona Stump, Rita Andraos-Rey, Sarah Welly, Stephanie Barbe, Vincent Romanet, Markus Reschke, Ruben De Kanter, Michael Jensen, Henrik Moebitz, Marta Cortes Cros. HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B143.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-B143
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Abstract LB080: Tipifarnib prevents emergence of resistance to osimertinib in EGFR-mutant NSCLC
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB080-LB080
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB080-LB080
    Abstract: Purpose: Drug-tolerant “dormant” cells (DTC) have emerged as one of the major non-genetic mechanisms driving resistance to targeted therapy in lung cancer, although the sequence of events leading to entry and exit from dormancy remain poorly described. Here, we provide a step-by-step phenotypic and molecular characterization of the different processes involved during the adaptive response to osimertinib using several EGFR-mutated lung cancer models. This strategy led to the identification of a common vulnerability of drug-tolerant cells which could be efficiently and safely targeted by a clinical stage drug. Experimental design: We used the FUCCI (fluorescence ubiquitination cell cycle indicator) system to determine the cell cycle dynamics in real time during the adaptive response to osimertinib in a panel of EGFR-mutated lung cancer cell lines. We performed scRNAseq on untreated and osimertinib-treated G1 and S/G2 sorted cells during early relapse to determine the molecular mechanisms underlying entry and exit from dormancy. We validated our observations in several in vitro and in vivo models as well as in publicly available patient data. Results: FUCCI labelling allowed the identification of a rare population of S/G2 cycling cells (referred to as early escapers) that emerged in the first hours of treatment amongst a majority of stably arrested and progressively dying G1 cells. scRNAseq data revealed that early escapers emerged from a differentiated alveolar type 1 (AT1) phenotype which was invariably associated with an increase in contractile-related gene signatures, F-actin polymerization and Rho/ROCK pathway activation. Using a screen of Rho-pathway inhibitors, we found that tipifarnib, a farnesyltransferase inhibitor (FTi), induced a complete clearance of DTC in vitro. Co-treatment with tipifarnib, a clinically active FTi, safely and durably prevented relapse to osimertinib in a PC9-xenograft model as well as in a PDX model of EGFRL858R/T790M lung cancer for up to 6 months with no evidence of toxicity. Several farnesylated targets were identified in both G1 and S/G2 treated cells, which could explain the high efficiency of tipifarnib in preventing the adaptive response to osimertinib. Finally, we observed that osimertinib + tipifarnib co-treatment completely suppressed the emergence of the AT1 phenotype, prevented mitosis of S/G2-treated cells and increased the apoptotic response through activation of the unfolded protein response (UPR) pathway. Conclusion: Our data strongly support the use of tipifarnib in combination with osimertinib in the clinic to effectively, durably and safely prevent relapse. Citation Format: Sarah Figarol, Célia Delahaye, Rémi Gence, Raghda Asslan, Sandra Pagano, Jacques Colinge, Jean-Philippe Villemin, Antonio Maraver, Isabelle Lajoie-Mazenc, Estelle Clermont, Anne Casanova, Anne Pradines, Julien Mazières, Olivier Calvayrac, Gilles Favre. Tipifarnib prevents emergence of resistance to osimertinib in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB080.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB080
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Abstract LB120: Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB120-LB120
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB120-LB120
    Abstract: Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the & gt;300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and & lt;70yrs (68%). Tumors were mainly non-squamous (79%) with & gt;1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p & lt;0.001). Among other biomarkers, Tregs (MV OR=0.44, p=0.018), NK cell subsets (MV OR≤0.44, p & lt;0.05), albumin (MV OR=0.4, p & lt;0.01) and PDL1 TC % (MV OR=0.27, p & lt;0.01) were decreased whereas alkaline phosphatase was increased (OR=3, p=0.018). & gt;65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary. Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB120
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Abstract 3340: Identification of CARM1/PRMT4 as a novel therapeutic target for AML
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3340-3340
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3340-3340
    Abstract: Chromatin modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs) have emerged as important targets in cancer. PRMT4, also known as CARM1, is overexpressed in a number of cancers, including breast, prostate, pancreatic, and lung cancer. Our lab reported the overexpression of PRMT4 in the context of acute myeloid leukemia (AML), showing that more than 70% of cytogenetically normal AML patients have up-regulation of PRMT4. Here, we investigated the role of PRMT4 in normal hematopoiesis and leukemia development. In order to study the role of PRMT4 in normal hematopoiesis, Prmt4-floxed mice were crossed with Vav1-cre mice purchased from the Jackson Laboratory. Inducible Prmt4 conditional KO mice were generated by crossing Prmt4-floxed mice with Mx1-Cre mice and Prmt4 gene excision was induced by poly(I:C). Using this hematopoietic specific knockout system, we show that loss of PRMT4 has little effect on normal hematopoiesis, but promotes the differentiation of hematopoietic stem and progenitor cells. Next we evaluated the role of PRMT4 in leukemia development using leukemia transplantation models driven by fusion oncoproteins. Strikingly, the knockout of PRMT4 completely abrogates leukemia initiation in fetal liver transplantation models driven by the AML1-ETO or MLL-AF9 fusion proteins. We further characterized the mechanism for the leukemia-specific dependence on PRMT4 using leukemia cell lines and found that knockdown of PRMT4 impairs cell cycle progression, decreases proliferation, and induces rapid apoptosis. To examine PRMT4 dependent changes in gene expression in a leukemia system, we used lentiviral vectors that express RFP and shRNAs directed against PRMT4. We knocked down PRMT4 in four leukemia cell lines or normal human cord-blood derived CD34+ cells. Gene set enrichment analysis showed that all four leukemia cell lines with knockdown of PRMT4 significantly down-regulated E2F target genes compared to the scrambled control. Chromatin immunoprecipitation analysis (ChIP) confirmed the presence of PRMT4 and H3R17 dimethylation at the promoter regions of E2F1 targets. The PRMT4 conditional knockout mice and PRMT4 knockdown experiments both suggest that the loss of PRMT4 protein has a selective effect on leukemia cells compared to normal hematopoietic stem and progenitor cells. Collectively, this work suggests that targeting PRMT4 through chemical inhibition may be an effective therapeutic strategy for AML and other cancers with up-regulation of PRMT4. Citation Format: Sarah M. Greenblatt, Pierre-Jacques J. Hamard, Takashi Asai, Na Man, Concepcion Martinez-Caja, Fan Liu, Stephen Nimer. Identification of CARM1/PRMT4 as a novel therapeutic target for AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3340. doi:10.1158/1538-7445.AM2017-3340
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3340
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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