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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. e17103-e17103
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 5591-5591
    Abstract: 5591 Background: Studies have shown that adjuvant therapy increases progression free survival, but does not affect overall survival in patients with high-intermediate risk (H-IR) endometrial cancer (EMCA). Our objective was to develop a gene expression signature that may help identify H-IR EMCA patients with the highest risk of recurrence to help guide treatment strategies. Methods: Data was collected on all patients that met H-IR EMCA criteria diagnosed between 2000-2010 at UAB (n = 292). Of the patients that did not receive adjuvant treatment, 13 patients that recurred were matched to 13 patients that did not recur and original tumor was compared. Of those that recurred, 5 patients had original and recurrent tumor available for analysis. Gene expression data was collected using the Nanostring nCounter PanCancer Pathway 770 gene panel. Data was analyzed using nSolver Advanced Analysis Software. A fold change (FC) of ≥ ± 2 (p 〈 0.05) was used to identify genes with a significant expression difference. Results: Comparing the 13 patients that recurred to the 13 that did not, there were 5 genes with FC ≥ +2: BAIAP3, PLCB1, IL1R1, NOS3 and RAD50. There were 29 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -10) were: BMP7, FGF18, WNT7A. Genes in the Cell Cycle (CC) pathway were significantly different in the patients that recurred (p = 0.02). There were 61 genes with FC ≥ +2 when comparing the original tumor to recurrent tumor; the top 3 genes with increased expression (FC ≥ 10) were: FGF18, CCND1, HIST1H3H (p 〈 0.05). There were 50 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -1000) were: HOXA11, LEFTY2 and SFRP4. Wnt, Hedgehog, Chromatin Modification, DNA repair, TGF-β, MAPK, and CC pathways were significantly different in the recurrent samples compared to the original tumor (p 〈 0.05). Conclusions: Our data suggests that gene expression panels could better identify patients that warrant adjuvant treatment. The CC pathway, which is significantly different in the original tumor from those that recurred and those that did not, was further altered in the recurrent tumor samples. Additional studies are on-going to validate these findings and to further investigate DNA mutation differences in larger cohort of patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 5566-5566
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e14514-e14514
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e14514-e14514
    Abstract: e14514 Background: The Wnt/B-catenin pathway is associated with a “cold” phenotype in the gynecologic malignancy tumor microenvironment (TME), resulting in immunosuppression. Research is limited regarding this pathway’s effects on TME myeloid cell populations. We aimed to characterize the impact of Wnt pathway modulation on macrophage activity in ovarian cancer. Methods: Syngeneic murine models harboring ID8 parental (ID8par) tumors were treated with DKN-01 and CGX-1321 as single agents or in sequence (DKN-01 followed by CGX-1321.) Flow cytometry analyses were performed on harvested omenta and blood. Ascites from 10 high grade serous epithelial ovarian cancer patients were treated with DKN-01 (Wnt activator) or CGX-1321 (Wnt inhibitor) for 48 hours; multiplex cytokine array was performed to determine changes in cytokine/chemokine expression. Lastly, we performed co-culture analyses on the effects of ID8par and ID8p53-/- isolated cell media on murine macrophage (RAW264.7) activity. Results: In the ID8par model, sequential DKN-01/CGX-1321 resulted in the greatest macrophage influx into the TME. CGX-1321 monotherapy increased the M2:M1 macrophage ratio (pro-tumor) while DKN-01 monotherapy resulted in decreased M2:M1 ratio (anti-tumor.) In human ascites, DKN-01 increased macrophage colony stimulating factor (M-CSF) expression. Of note, ascites from a patient harboring a p53 mutation demonstrated an increase in M1 polarization cytokines IFNy and TNFa in response to DKN-01; CGX-1321 treatment resulted in increased M2 polarization cytokines IL-4 and IL-13. In co-culture analysis, ID8par isolated media increased RAW264.7 migration and polarization towards an M2 phenotype; ID8p53-/- isolated media polarized towards an M1 phenotype. Conclusions: Macrophage activity influences immune responses and tumor behavior. For example, M2 macrophages are pro-tumor and can enhance tumor growth and immune evasion. In our studies, we demonstrated that macrophage recruitment and polarization (M1 vs M2) are influenced by genetic alterations that can be modified by treatment. The ID8par model positively influenced M2 macrophage activity; ID8p53-/- cells positively influenced M1 macrophage activity. Importantly, DKN-01 treatment reverses the M2-dominant phenotype in ID8par model towards M1. These results suggest that p53 mutation and/or DKN-01 treatment in ovarian cancer influences M1 anti-tumor macrophage activity, and posits a novel targetable pathway. Further studies should investigate Wnt/B-catenin modulation on macrophage activity for immunotherapy in gynecologic malignancies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e17078-e17078
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e17078-e17078
    Abstract: e17078 Background: Alterations in the Wnt/β-catenin pathway have been associated with tumor progression in multiple cancers. Gene expression profiling in ovarian cancer has correlated Wnt upregulation to patterns of immune evasion in the tumor microenvironment (TME). We investigated effects of in vitro Wnt inhibition in a murine ovarian cancer cell line with p53 knocked out as a model to mimic human ovarian carcinoma. Methods: We used a small molecule inhibitor, CGX-1321, in C57Bl6 mice, an immunocompetent mouse model, injected intraperitoneally with either ID8 cells, a murine ovarian cancer cell line, or ID8-p53 -/- cells. Mouse omentums were collected and weighed for evaluation of tumor growth. Representative histology slides were stained for H & E. Western blots for β-catenin baseline levels were performed on the cell lines. TopFlash Assays with WNT3A stimulation were used for analysis of cell line nuclear β-catenin levels. Flow cytometry was performed on mouse omentums for TME evaluation. Results: Treatment with CGX-1321 decreased tumor size via omentum weight with both cell lines, p = 0.0098 with ID8 cells and p = 0.0855 with ID8-p53 -/- cells. H & E slides revealed a decreased tumor progression. Western blots confirmed a difference in baseline β-catenin levels between these two cell lines. However, TopFlash assays showed a response to stimulation. Changes in the TME between treated samples with ID8-p53 -/- cells did now show significant differences via flow cytometry. Conclusions: In the syngeneic mouse model with a murine ovarian cancer cell line, with p53 knocked out, tumor size and proliferation were decreased with treatment with Wnt inhibition. Surprisingly, the TME changes were inconclusive via flow cytometry. Perhaps these cells do not rely upon the Wnt/ β-catenin pathway as heavily, as seen in changes to baseline β-catenin levels, or perhaps tumors progress quicker and the critical time point of TME change is being overlooked. More investigation needs to be performed to further elucidate these differences.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e18041-e18041
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e18041-e18041
    Abstract: e18041 Background: Epithelial ovarian cancers (EOC) are immunologically “cold” tumors and consequently have seen limited success with immunotherapy. Wnt-beta/catenin signaling is dysregulated in multiple cancers, including EOC, and is characterized by immune exclusion. Porcupine (PORCN) is the enzyme necessary for secretion of Wnt ligands, which is required for activation of Wnt/beta-catenin signaling. Up-regulation of the Wnt/beta-catenin pathway leads to increased levels of the target gene DKK1, which plays a role in immune exclusion. Our goal is to improve the tumor immune response via targeting Wnt-signaling in EOC. Methods: We utilized a syngeneic murine model (ID8 cell line) deficient in p53 (ID8p53 −/− ) with and without the addition of a Luciferase tag (Luc+/-) to assess the effect of treatment with a PORCN inhibitor, CGX-1321, with and without DKN-01, a monoclonal antibody targeting DKK1. Mice were treated with vehicle/control, CGX-1321, DKN-01, or CGX-1321/DKN-01. Treatment was given for either 14 or 31 days. In Luc+ mice, bioluminescence imaging was performed weekly. Following mouse sacrifice, omental weights and ascites volume were measured. Omental tumor was used for flow cytometry and representative samples were sent for NanoString analysis. Results: Treatment with CGX-1321 for 14 days reduced omental weight and ascites volume in Luc- mice only (p = 0.02); however, earlier and extended treatment with CGX-1321 and CGX-1321/DKN-01 in Luc+ mice decreased omental weight (p = 0.008 and 0.0025); mice treated with CGX did not develop any ascites with the same treatment schedule. While treatment with DKN-01 alone did not decrease omental weight, treatment with DKN-01 and combination CGX-1321/DKN-01 increased total percentage of NK cells (p = 0.0192 and 0.0070). CGX-1321 and DKN-01 alone and in combination increased the total percentage of CD8+ T cells in omental tumors (p = 0.0238, 0.037, and 0.0127). Conclusions: CGX-1321 decreased omental weight and ascites volume, while DKN-01 increased the cellular percentage of NK cells. Both DKN-01 and CGX-1321 increased CD8+ T cells. Wnt-inhibition is therapeutically promising in EOC, and the combination of a PORCN inhibitor with DKN-01 could improve the response to immune checkpoint blockage and further investigation is warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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