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  • American Association for Cancer Research (AACR)  (12)
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  • American Association for Cancer Research (AACR)  (12)
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  • 1
    Online Resource
    Online Resource
    Tislelizumab for Relapsed/Refractory Classical Hodgkin Lymphoma: 3-Year Follow-up and Correlative Biomarker Analysis
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 6 ( 2022-03-15), p. 1147-1156
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 6 ( 2022-03-15), p. 1147-1156
    Abstract: Tislelizumab is an anti–programmed cell death protein 1 (anti–PD-1) monoclonal antibody specifically designed to minimize binding to Fcγ receptors (FcγR). Patients and Methods: Here, we present the extended 3-year follow-up of a phase II study of tislelizumab in 70 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who failed or were ineligible for autologous stem cell transplantation. Results: With a median follow-up of 33.8 months, the overall response rate by the independent review committee was 87.1%, and the complete response (CR) rate was 67.1%. Responses were durable as shown by a median duration of response of 31.3 months, and median progression-free survival (PFS) of 31.5 months. The 3-year PFS and overall survival rates were 40.8% and 84.8%, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 97.1% of patients; the grade ≥3 TRAE rate was low (31.4%), and only 8.6% of patients experienced adverse events leading to treatment discontinuation. Correlative biomarker analysis showed that FcγRΙ-expressing macrophages had no observed impact on either the CR rate or PFS achieved with tislelizumab, which may be potentially related to its engineered Fc region. Conclusions: With extended follow-up, tislelizumab yielded long-term benefits and demonstrated a favorable safety profile for patients with relapsed/refractory cHL. This trial was registered at clinicaltrials.gov as NCT03209973.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-2023
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Abstract B24: High-dimensional genomic data integration and bias correction using MANCIE
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 2_Supplement ( 2016-01-15), p. B24-B24
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 2_Supplement ( 2016-01-15), p. B24-B24
    Abstract: Most genomic and epigenomic experimental data are presented as high-dimensional matrices. Integrative analysis of such high-dimensional genomic data is challenging due to noises and biases in the high-throughput experiments from different platforms. We present MANCIE (Matrix Analysis and Normalization by Concordant Information Enhancement), a computational method for integrating two genomic datasets based on a Bayesian supported principal component analysis (PCA) approach. We demonstrate that data integration using MANCIE can reduce biases and improve the identification of tissue specificity from the Encyclopedia of DNA Elements (ENCODE) data, improve prognostic prediction from The Cancer Genome Atlas (TCGA) data, and improve the identification of genetic correlation in the Cancer Cell Line Encyclopedia (CCLE) data. MANCIE has broad applications in genomic and epigenomic data analysis in cancer research. Citation Format: Chongzhi Zang, Tao Wang, Ke Deng, Bo Li, Sheng'en Hu, Qian Qin, Tengfei Xiao, Shihua Zhang, Clifford A. Meyer, Housheng Hansen He, Myles Brown, Jun S. Liu, Yang Xie, Xiaole Shirley Liu. High-dimensional genomic data integration and bias correction using MANCIE. [abstract] . In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B24.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.CHROMEPI15-B24
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Online Resource
    Abstract P4-01-04: FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P4-01-04-P4-01-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P4-01-04-P4-01-04
    Abstract: How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodeling leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenografts (PDX) models. Collectively, these findings reveal a novel feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provide new therapeutic strategies to overcome this mechanism of resistance. Citation Format: Yihao Li, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee Geck Geck, Alok Tewari, Kin-Hoe Chow, Tengfei Xiao, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X Liu, Alex Toker, Myles Brown. FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer [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 P4-01-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P4-01-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    Abstract 1210: A patient derived xenograft tumor model platform for “mouse trials”
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1210-1210
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1210-1210
    Abstract: From Chinese cancer patients, close to 600 patient derived xenograft (PDX) tumor models have been established ( & gt; P3, three passages in mice) at GenenDesign through serial passages in the immune-compromised nude mice. The major collection of GenenDesign PDX tumor model platform represents cancer types that are prevalent in Asian patients, including gastric cancer ( & gt; 200 models), esophageal cancer ( & gt;100 models), liver cancer (∼50 models), pancreatic cancer ( & gt;60 models) and lung cancer ( & gt; 80 models). Establishment of variant PDX models from the same patient tumor is on-going to support translational studies of tumor heterogeneity. Initial characterization indicates that the mouse PDX models have captured the major histopathological characteristics of the original human tumors. Reproducible growth curves for PDX models ( & gt;P3) support their usage in efficacy analysis of anti-cancer therapeutic agents. Response curves to SoC (standard of care) chemotherapies such as Paclitaxel for lung cancer, FOLFOX for gastric cancer and Sorafenib for liver cancer have been established in the PDX tumor models, providing a baseline for further investigation of novel therapies in a combination setting. On-going molecular characterization including oncogene mutational analysis and target specific IHC and FISH analysis has identified panels of PDX tumor models with aberrations in key oncogenic signaling pathways, including lung panels with EGFR overexpression or KRAS mutations, gastric panels with FGFR2 amplification or being HER2 positive, lung and gastric panels with cMET overexpression. Testing of Herceptin in the gastric HER2 positive tumor panel resulted in observations similar to that from the ToGA trial. At the same time, Herceptin resistant PDX tumor variants (de novo or acquired) were identified or established. The PDX tumor model panels facilitate translational studies in a “mouse trial” format in a setting similar to clinical trials to test patient stratification strategies and drug response predictive biomarkers for emerging therapeutic modalities. Citation Format: Ying Yan, Tengfei Yu, Wei Du, Guosheng Tong, Yuefei Yang, Tingting Tan, Xuqin Yang, Zhenhua Liu, Jiali Gu, Liang Hua, Wei Zhang, Xin K. Ye, Zhenyu Gu. A patient derived xenograft tumor model platform for “mouse trials”. [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 1210. doi:10.1158/1538-7445.AM2014-1210
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1210
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 5
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    A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-κB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 5 ( 2021-03-01), p. 1361-1374
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 5 ( 2021-03-01), p. 1361-1374
    Abstract: AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis, however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In this study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis in vitro and in vivo. AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC. Significance: These findings elucidate a novel AKR1C3-driven signaling loop that regulates proliferation and metastasis in HCC, providing potential prognostic and therapeutic targets in this disease.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-20-2480
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract LB514: CD8 T cells and macrophage abundances associated with clinical benefit of tislelizumab in various tumor types
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB514-LB514
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB514-LB514
    Abstract: Background: Functionally activated immune cells (ICs) in the tumor microenvironment (TME) are critical to antitumor efficacy. Here, we report association between ICs and the clinical efficacy of tislelizumab (TIS), an anti-programmed cell death protein 1 monoclonal antibody, by examining tumor tissues from various tumor types in three pooled Phase 1/2 studies (NCT02407990, NCT04068519, NCT04004221). Methods:Available baseline tumor tissues from patients (pts) with advanced solid tumors who received TIS were tested with either multiplex-immunohistochemistry (m-IHC) (n=67, Opal automation Multiplex IHC kit) or gene expression profile (n=629, HTG EdgeSeq Precision Immuno-Oncology Panel). High/low cell density/signature scores were defined per median score, respectively. Median overall survival (OS) was estimated by the Kaplan-Meier method and log rank test was used to compare survival curves between pts with different biomarker levels. Results: Pts with a high CD68 density (CD68Hi) (n=34) had a longer OS compared with pts who had a low CD68 density (n=33), with a median OS of 15.0 vs 10.4 months, p=0.11. A weak association was observed between survival and CD8 cell density. When the two cell types were combined as a composite biomarker, pts with high CD8 (CD8Hi) and CD68Hi showed the longest OS (Table). A consistent finding was confirmed in the gene expression population (Table). Further TME analysis revealed that pts with CD8Hi and CD68Hi signature showed most elevated CD8 T cell cytotoxicity (CD8A, GNLY, GZMA, GZMB), T cell trafficking (CXCL9, CXCL10, CCL4, CCL5), MHCI antigen presentation (TAP1, TAP2, HLA.A/B/C) signatures/genes, and enriched expression of pro-inflammatory macrophage polarization pathway (STAT1, SLAMF7/8, ISG15). Conclusion: Co-enrichment of CD8 T cells and macrophages were associated with survival benefit and an immune-activated TME in pts with various tumor types treated with TIS. This observation warrants further investigation. Association between ICs and the clinical efficacy of TIS m-IHC analysis CD8Hi/CD68 Hi (n=24) CD8 Hi/CD68Lo (n=10) CD8 Lo/CD68Hi (n=10) CD8 Lo/CD68Lo (n=23) Median OS, months (95% CI) 15.7 (8.5, NA) 5.1 (0.8, 10.8) 6.3 (1.8, NA) 11.2 (4.0, 17.6) Gene expression analysis CD8Hi/CD68 Hi (n=202) CD8 Hi/CD68Lo (n=113) CD8 Lo/CD68Hi (n=113) CD8 Lo/CD68Lo (n=201) Median OS, months (95% CI) 14.9 (11.2, 19.2) 11.1 (7.1, 13.5) 7.7 (5.6, 11.4) 9.8 (7.4, 11.6) p value* 0.00033 *p value obtained from log-rank test CI, confidence interval; Hi, high density; IC, immune cell; m-IHC, multiplex immunohistochemistry; Lo, low density; NA, not available; OS, overall survival; TIS, tislelizumab Citation Format: Wei Shen, Tengfei Liu, Yang Shi, Jingwen Shi, Dan Wang, Liang Liang, Silu Yang, Xiaopeng Ma, Wei Jin, Pei Zhang, Ruiqi Huang, Yun Zhang, Zhirong Shen. CD8 T cells and macrophage abundances associated with clinical benefit of tislelizumab in various tumor types [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 LB514.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract 6124: Interleukin-1β and exosomal M6PR secreted by serglycin-overexpressing esophageal cancer cells instigate fibroblasts and endothelial cells to promote esophageal cancer progression
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6124-6124
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6124-6124
    Abstract: Non-tumor cells can be recruited and educated by cancer cells to facilitate cancer progression. Previously, we found that serum serglycin (SRGN), a secretory proteoglycan, was an independent prognostic marker for patients with esophageal squamous cell carcinoma (ESCC), and that the autocrine pro-invasive effect of SRGN on ESCC cells was mediated by midkine (MDK). Here, we investigated the effects of cancer cell-derived SRGN on human esophageal fibroblasts (HEF) and human umbilical vein endothelial cells (HUVECs). We found that conditioned medium from SRGN-overexpressing ESCC cells (SRGN-CM) promoted the migration and proliferation of HEF. After SRGN-CM treatment, HEF showed increased expression of fibroblast activation protein alpha (FAP), hepatocyte growth factor (HGF) and amphiregulin, and could enhance tumor growth in vivo. In addition, exosomes derived from SRGN-overexpressing ESCC cells (SRGN-Exo) enhanced the tube formation ability of HUVECs. We found that the effects of SRGN-CM on activation, migration and proliferation of HEF were mediated by MDK. To elucidate the mechanisms by which SRGN upregulates HGF and amphiregulin, and promotes endothelial tube formation, cytokine array and mass spectrometry were performed to analyze differentially expressed proteins in SRGN-CM and SRGN-Exo respectively. The results showed upregulated secretion of interleukin (IL)-1β, IL-18 and tumor necrosis factor-α in SRGN-CM, as well as enriched cation-dependent mannose-6-phosphate receptor (M6PR), integrin alpha-5, teneurin-2 and neurogenic locus notch homolog protein 2 in SRGN-Exo, which were validated by Western blot. These effects were dependent on the glycosaminoglycan chains on SRGN. Our data also showed that the enhanced secretion of IL-1β promoted the expression of HGF in HEF by activating extracellular signal-regulated kinase/activating protein-1. Treatment with SU11274, a c-Met (the receptor of HGF) inhibitor, attenuated the proliferation of ESCC cells co-cultured with HEF, which further indicates that IL-1β-induced HGF from HEF plays a significant role in the tumor microenvironment. In addition, the upregulated exosomal M6PR was found to mediate the enhancing effect of SRGN-Exo on endothelial tube formation ability. Notably, the expression level of M6PR in serum samples of patients with ESCC was positively correlated with that of SRGN and with poor survival. Taken together, SRGN overexpression in ESCC cells created a tumor-promoting microenvironment by altering the ESCC cell secretome including exosomes to exert influence on HEF and HUVECs. [This study was supported by Research Grants Council of the Hong Kong SAR, China, GRF Project No. 17100819] Citation Format: Dongdong Yan, Di Cui, Yun Zhu, Cecilia Ka Wing Chan, Chung Hang Jonathan Choi, Tengfei Liu, Sai Wah Tsao, Stephanie Ma, Annie Lai-Man Cheung. Interleukin-1β and exosomal M6PR secreted by serglycin-overexpressing esophageal cancer cells instigate fibroblasts and endothelial cells to promote esophageal cancer progression [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 6124.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6124
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    An Imageable Metastatic Treatment Model of Nasopharyngeal Carcinoma
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 13 ( 2007-07-01), p. 3960-3967
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 13 ( 2007-07-01), p. 3960-3967
    Abstract: Purpose: Nasopharyngeal carcinoma is highly prevalent in southern China and is often resistant to current treatment options. Experimental Design: Clinically relevant mouse models are necessary for further understanding and drug discovery in this disease. Two nasopharyngeal carcinoma cell lines, stably expressing green fluorescent protein (GFP), 5-8F-GFP and 6-10B-GFP, were established. The cells were orthotopically injected into the nasopharynx or ectopically into the subcutis of nude mice. Whole-body fluorescence imaging was used to monitor the growth of the primary tumor as well as angiogenesis and metastasis. Results: The metastatic behavior of 5-8F and 6-10B were distinct in the orthotopic model. Orthotopic implantation of highly metastatic 5-8F cells resulted in brain invasion, cervical lymph node metastases, and pulmonary metastases similar to what is often observed in patients. Cell line 6-10B was less metastatic, which occasionally resulted in pulmonary metastasis. GFP enabled imaging of micrometastasis. Neither 5-8F nor 6-10B were metastatic in the s.c. site. These results indicated that, in addition to the cancer cell type, the host microenvironment was critical for metastasis to occur consistent with the “seed-and-soil” hypothesis. 5-8F was highly sensitive to 5-fluorouracil (5-FU), whereas 6-10B was moderately sensitive. Conclusions: The imageable orthotopic model should play a critical role in elucidating the mechanisms involved in the growth, progression, metastasis, and angiogenesis of nasopharyngeal carcinoma and for evaluation of novel compounds with potential efficacy.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-0089
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 9
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    Abstract 755: Supporting precision cancer treatment decision with functional evaluation of cancer gene mutations and variants
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 755-755
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 755-755
    Abstract: Precision oncology requires identifying and understanding of cancer genome changes in a patient tumor tissue and finding the best cancer therapy targeting the changes. Although many cancer gene targets have been validated so far, next-generation genomic profile analyses have uncovered much more cancer gene variants with unconfirmed functions. Developing methods to functionally evaluate mutations/variants and understand their roles in cancer development and drug responses, such as drug resistance or synthetic lethality, will be critical in cancer treatment decision support. In addition, in some clinical cases, multiple treatment choices such as multiple drug combinations exist. Developing cancer models which can test multiple treatments will provide direct comparison of those therapies and select the best options. At GenenDesign, we have performed drug tests on mouse “avatars”, which are also known as Patient-Derived Xenograft (PDX) models. They are personalized cancer models derived from patient tumor samples with cancer mutation profiles and drug responses very similar to the corresponding cancer patients. Drug screenings were carried out in avatars by testing chemotherapies or targeted drugs against specific cancer gene mutations and variants. Selected drugs or drug combinations from avatar studies have been applied to corresponding patients with highly consistent treatment outcome. From genomic profile analysis of our near 1500 PDX tumor models in cancer types such as lung, colorectal, gastric, liver, and esophageal, we are able to identify a large number of cancer gene mutations/variants, gene fusions, as well as gene copy number and RNA expression changes in major cancer signal pathways such as EGFR, Her2, c-Met/ALK, Ras/Raf, FGFRs, PI3K/Akt, Wnt, Notch, DNA repair, cell cycle regulation, angiogenesis. Many of these gene aberrations are potential drug targets and have been functionally tested in PDX models with approved drugs or clinical drug candidates. The mutation/variant information and drug response information generated from PDX models have been organized into our Precision Cancer Information Lab database. Patient tumor DNA test results have been used for searching genetically matched PDX models in our database. Once matched PDX models are identified, the available drug response information can be used as evidence for clinical treatment decision. In addition, the matched PDX models can also been used to test more treatment options such as different combinations and new clinical drug candidates. Citation Format: Jingjing Jiang, Zhongguang Luo, Jia Wei, Guanglei Zhuang, Song Yi, Ying Yan, Tengfei Yu, Wei Du, Tingting Tan, Ling Qiu, Jiali Gu, Xin K. Ye, Jie Liu, Zhenyu Gu. Supporting precision cancer treatment decision with functional evaluation of cancer gene mutations and variants [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 755. doi:10.1158/1538-7445.AM2017-755
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-755
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    Abstract P108: In vivo CRISPR screens identify E3 ligase COP1 as a modulator of macrophage infiltration and cancer immunotherapy target
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 12_Supplement ( 2021-12-01), p. P108-P108
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 12_Supplement ( 2021-12-01), p. P108-P108
    Abstract: Despite remarkable clinical efficacies of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits in triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that inhibition of the E3 ubiquitin ligase COP1 in cancer cells decreases the secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances tumor immunity and ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed COP1 functions through proteasomal degradation of the C/ebpδ protein. COP1 substrate TRIB2 functions as a scaffold linking COP1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. COP1 inhibition stabilizes C/ebpδ to suppress the expression of macrophage chemoattractant genes. Our integrated approach implicates COP1 as a target for improving cancer immunotherapy efficacy by regulating chemokine secretion and macrophage infiltration in the TNBC tumor microenvironment. Citation Format: Xiaoqing Wang, Collin Tokheim, Shengqing S. Gu, Binbin Wang, Qin Tang, Yihao Li, Nicole Traugh, Zexian Zeng, Yi Zhang, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford Meyer, Peng Jiang, Paloma Cejas, Klothilda Lim, Henry Long, Myles Brown, X. Shirley Liu. In vivo CRISPR screens identify E3 ligase COP1 as a modulator of macrophage infiltration and cancer immunotherapy target [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P108.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-21-P108
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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