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  • 1
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    Online Resource
    Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 12 ( 2009-06-15), p. 4138-4146
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 12 ( 2009-06-15), p. 4138-4146
    Abstract: Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts and to seek biomarkers predictive of activity. Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using the K-Top Scoring Pairs (K-TSP) method. Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth & lt;50% compared with control tumors (100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair (LRRC19 and IGFBP2) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity in an independent test set that consists of eight xenograft cases. Conclusions: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair (LRRC19 and IGFBP2) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for pancreatic tumor sensitivity to AZD0530.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-3021
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
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    Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 21 ( 2018-11-01), p. 5368-5380
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 21 ( 2018-11-01), p. 5368-5380
    Abstract: Purpose: Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance. Experimental Design: Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti–PD-L1 or anti–TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody. Results: We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti–TIM-3 concurrently with anti–PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory. Conclusions: These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. Clin Cancer Res; 24(21); 5368–80. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-1038
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Overcoming IGF1R/IR Resistance through Inhibition of MEK Signaling in Colorectal Cancer Models
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 22 ( 2013-11-15), p. 6219-6229
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 22 ( 2013-11-15), p. 6219-6229
    Abstract: Purpose: Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single-agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor, OSI-906, in combination with a mitogen–activated protein (MAP)–ERK kinase (MEK) 1/2 inhibitor based on evidence that the MAP kinase pathway was upregulated in colorectal cancer cell lines that were resistant to OSI-906. Experimental Design: The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126 were analyzed both as single agents and in combination in 13 colorectal cancer cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. In addition, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) was evaluated in vivo using human colorectal cancer xenograft models. Results: The combination of OSI-906 and U0126 resulted in synergistic effects in 11 of 13 colorectal cancer cell lines tested. This synergy was variably associated with apoptosis or cell-cycle arrest in addition to molecular effects on prosurvival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib. Conclusions: Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with an MEK 1/2 inhibitor in colorectal cancer cell line models both in vitro and in vivo, which supports the rational combination of OSI-906 with an MEK inhibitor in patients with colorectal cancer. Clin Cancer Res; 19(22); 6219–29. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0145
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 1225457-5
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  • 4
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    Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 7 ( 2017-04-01), p. 1710-1721
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 7 ( 2017-04-01), p. 1710-1721
    Abstract: Purpose: Antiendocrine therapy remains the most effective treatment for estrogen receptor–positive (ER+) breast cancer, but development of resistance is a major clinical complication. Effective targeting of mechanisms that control the loss of ER dependency in breast cancer remains elusive. We analyzed breast cancer–associated fibroblasts (CAF), the largest component of the tumor microenvironment, as a factor contributing to ER expression levels and antiendocrine resistance. Experimental Design: Tissues from patients with ER+ breast cancer were analyzed for the presence of CD146-positive (CD146pos) and CD146-negative (CD146neg) fibroblasts. ER-dependent proliferation and tamoxifen sensitivity were evaluated in ER+ tumor cells cocultured with CD146pos or CD146neg fibroblasts. RNA sequencing was used to develop a high-confidence gene signature that predicts for disease recurrence in tamoxifen-treated patients with ER+ breast cancer. Results: We demonstrate that ER+ breast cancers contain two CAF subtypes defined by CD146 expression. CD146neg CAFs suppress ER expression in ER+ breast cancer cells, decrease tumor cell sensitivity to estrogen, and increase tumor cell resistance to tamoxifen therapy. Conversely, the presence of CD146pos CAFs maintains ER expression in ER+ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146neg CAFs correlate with inferior clinical response to tamoxifen and worse patient outcomes. Conclusions: Our data suggest that CAF composition contributes to treatment response and patient outcomes in ER+ breast cancer and should be considered a target for drug development. Clin Cancer Res; 23(7); 1710–21. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-2851
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
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    Inhibiting Translation Elongation with SVC112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 5 ( 2020-03-01), p. 1183-1198
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 5 ( 2020-03-01), p. 1183-1198
    Abstract: Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. Significance: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-3232
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 410466-3
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  • 6
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    FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 19 ( 2015-10-01), p. 4356-4364
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 19 ( 2015-10-01), p. 4356-4364
    Abstract: Purpose: FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. Experimental Design: FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors. Results: Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. Conclusions: FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC. Clin Cancer Res; 21(19); 4356–64. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-3357
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 7
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    Abstract 5050: Biomarkers for sensitivity to gamma secretase inhibitors in mouse models of pancreatic adenocarcinoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5050-5050
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5050-5050
    Abstract: Background: The Notch pathway is important in carcinogenesis and maintenance of pancreatic adenocarcinoma through its effects on cancer stem cells, cell differentiation and neoangiogenesis. RO4929097 is a novel oral inhibitor of the Notch pathway through its effects on γ-secretase, a key enzyme in this pathway. Several clinical trials are currently in progress with RO4929097 including a CTEP sponsored phase II trial in gemcitabine resistant metastatic pancreas cancer by our group. However, there are no biomarkers of sensitivity available currently for therapy with RO4929097 or other γ-secretase inhibitors (GSIs). Methods: We intend to treat 12 human pancreas cancer cell line mouse xenografts and 6 human primary pancreas tumor explants with RO4929097 (alone or in combination with gemcitabine) to identify sensitive (defined as tumors with ≥ 50% relative tumor growth inhibition with treatment) and resistant tumors. Subsequently, we propose to identify differences in gene expression by RT-PCR (Notch pathway), gene array or gene copy number by FISH between the resistant and sensitive tumors as potential biomarkers. Results: Of the eight pancreas cell line xenografts treated so far, four are sensitive to RO4929097. Comparison between sensitive and resistant tumors by gene array suggests that the sensitive cell lines exhibit higher levels of mesenchymal markers. In addition, two of the four human primary pancreatic explants treated thus far show intermediate sensitivity. RO4929097 in combination with gemcitabine in the four explants reveals a significant decrease in tumor growth inhibition for the combination compared to RO4929097 alone but the additive effect appears to be entirely due to gemcitabine. Similar effects were observed on tumor regrowth, upon observation after an initial period of treatment with either agents alone or in combination. In addition, future experiments to identify stem cell and/or angiogenesis specific biomarkers are also planned. Updated results will be presented at the meeting. Acknowledgements: This work was supported by Roche Pharmaceuticals 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 5050. doi:10.1158/1538-7445.AM2011-5050
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5050
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 8
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    Homeoprotein Six2 Promotes Breast Cancer Metastasis via Transcriptional and Epigenetic Control of E-Cadherin Expression
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 24 ( 2014-12-15), p. 7357-7370
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 24 ( 2014-12-15), p. 7357-7370
    Abstract: Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin. Cancer Res; 74(24); 7357–70. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0666
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
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  • 9
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    Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 20 ( 2015-10-15), p. 4398-4406
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 20 ( 2015-10-15), p. 4398-4406
    Abstract: The FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with a single TKI represents a logical step toward personalized cancer therapy, but intrinsic and acquired resistance mechanisms limit their long-term benefit. In this study, we deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and head and neck squamous cell cancer (HNSCC) cells to ponatinib, a multikinase FGFR-active inhibitor. We identified and validated a synthetic lethal interaction between MTOR and ponatinib in non–small cell lung carcinoma cells. In addition, treatment with MTOR-targeting shRNAs and pharmacologic inhibitors revealed that MTOR is an essential protein kinase in other FGFR1-expressing cancer cells. The combination of FGFR inhibitors and MTOR or AKT inhibitors resulted in synergistic growth suppression in vitro. Notably, tumor xenografts generated from FGFR1-dependent lung cancer cells exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547, but when combined with the MTOR inhibitor, AZD2014, significantly attenuated tumor growth and prolonged survival. Our findings support the existence of a signaling network wherein FGFR1-driven ERK and activated MTOR/AKT represent distinct arms required to induce full transformation. Furthermore, they suggest that clinical efficacy of treatments for FGFR1-driven lung cancers and HNSCC may be achieved by combining MTOR inhibitors and FGFR-specific TKIs. Cancer Res; 75(20); 4398–406. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-0509
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
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  • 10
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    AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non–Small Cell Lung Cancer Cells Following EGFR Inhibition
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 6 ( 2017-03-15), p. 1531-1541
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 6 ( 2017-03-15), p. 1531-1541
    Abstract: Purpose: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non–small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors. Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results: In combination with EGFR inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model. Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC. Clin Cancer Res; 23(6); 1531–41. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-1179
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
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