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  • American Association for Cancer Research (AACR)  (13)
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  • American Association for Cancer Research (AACR)  (13)
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  • 1
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    Online Resource
    Abstract CT184: First-Line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT184-CT184
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT184-CT184
    Abstract: Background: Overall survival (OS) for advanced or metastatic HER2-negative GC/GEJC with standard 1L chemo remains poor (median OS & lt; 1 year). CheckMate 649 is the largest randomized, global phase 3 study of 1L programmed death (PD)-1 inhibitor-based therapies in GC/GEJC/EAC (NCT02872116). Results from this study demonstrated superior OS, along with progression-free survival (PFS) benefit and an acceptable safety profile with 1L NIVO + chemo vs chemo alone (Moehler et al. Ann Oncol 2020). We present the pre-planned subgroup analysis from CheckMate 649 in Chinese pts.Methods: Adults with previously untreated, unresectable advanced or metastatic GC/GEJC/EAC were enrolled regardless of PD ligand 1 (PD-L1) expression. Pts with known HER2-positive status were excluded. Pts were randomized to receive NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded central review in pts with PD-L1 combined positive score (CPS) ≥ 5.Results: 208 Chinese pts were concurrently randomized to NIVO + chemo or chemo, including 156 pts (75%) with PD-L1 CPS ≥ 5. Median age was 60 years; 88% had GC; 12% had GEJC; no pts had EAC. At minimum follow-up of 12 months (mo), NIVO + chemo demonstrated clinically meaningful improvement in OS and PFS vs chemo in pts with PD-L1 CPS ≥ 5 (OS, HR 0.54 [95% CI 0.36-0.79]; PFS, HR 0.52 [0.34-0.77] ; Table), consistent with the overall study population. OS benefit was also observed in pts with PD-L1 CPS ≥ 1 and the all-randomized population (Table). No new safety signals were identified. Conclusions: NIVO + chemo demonstrated a clinically meaningful improvement in OS and PFS and an acceptable safety profile vs chemo alone in previously untreated Chinese pts, consistent with the overall study population with advanced GC/GEJC/EAC from CheckMate 649. TableEfficacyNIVO + chemoChemoPD-L1 CPS ≥ 5N = 75N = 81Median OS (95% CI), mo15.5 (11.9-25.5)9.6 (8.0-12.1)HR (95% CI)0.54 (0.36-0.79)Median PFS (95% CI), mo8.5 (5.9-12.4)4.3 (4.1-6.5)HR (95% CI)0.52 (0.34-0.77)ORR (95% CI), %63 (51-74)43 (32-55)PD-L1 CPS ≥ 1N = 89N = 94Median OS (95% CI), mo14.3 (11.5-17.5)9.9 (8.1-12.1)HR (95% CI)0.62 (0.43-0.87)All randomizedN = 99N = 109Median OS (95% CI), mo14.3 (11.5-17.5)10.3 (8.1-12.1)HR (95% CI)0.61 (0.44-0.85)Safety: Treatment-related adverse events, n (%)All treatedN = 99N = 106Any grade98 (99)100 (94)Grade 3-464 (65)53 (50)Leading to discontinuation50 (51)27 (25)Deaths1 (1)1 ( & lt;1) Citation Format: Lin Shen, Yuxian Bai, Xiaoyan Lin, Wei Li, Jufeng Wang, Xiaochun Zhang, Hongming Pan, Chunmei Bai, Li Bai, Ying Cheng, Jingdong Zhang, Haijun Zhong, Yi Ba, Wenwei Hu, Ruihua Xu, Weijian Guo, Shukui Qin, Nong Yang, Jianwei Lu, Kohei Shitara, Ming Lei, Mingshun Li, Nicole Bao, Tian Chen, Tianshu Liu. First-Line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT184.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT184
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    Abstract A009: Distinct activity of androgen receptor splice variants in promoting prostate cancer metastasis
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 11_Supplement ( 2023-06-02), p. A009-A009
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 11_Supplement ( 2023-06-02), p. A009-A009
    Abstract: Introduction: Constitutively active androgen receptor splice variant 7 (AR-V7) correlates with the adaptation to androgen receptor signaling inhibition treatment in prostate cancer (PCa) patients. Despite intensive studies of AR-V7, it is still unclear how the distinct genomic and epigenomic characteristics of AR-V7-dependent cistrome and transcriptome are distinct from full-length AR (AR-FL) and whether AR-V7 may play a role in promoting the metastatic progression of castration-resistant PCa (CRPC). Experiments: To accurately compare the activity of AR-V7 with AR-FL, we generated lentiviral stable cell lines with inducible overexpression of AR-V7 or AR-FL using AR-V7 negative LNCaP and C4-2 cell lines. We assessed the in vivo impact of AR-V7 or AR-FL expression on PCa metastasis by injecting cells in zebrafish embryos and the tibias of castrated male mice. ChIP-seq analyses of AR-V7, AR-FL, FOXA1, and H3K27ac, ATAC-seq analysis, and RNA-seq analysis were conducted in to characterize the global cistrome and transcriptome activity of AR-V7 in comparison with AR-FL. In addition, we also examined how a posttranslational modification, Ser81 phosphorylation, affects AR-V7 activity by generating an S81A mutant of AR-V7 and using S81-phosphorylation inhibitors. Results: Our in vivo study revealed that overexpressed-AR-V7, but not AR-FL, strongly promotes tumor cell invasion into blood vessels and induces osteoblastic bone lesions. Through integrated ChIP-, ATAC- and RNA-seq analysis, we determined that AR-V7 has a “pioneer factor-like” ability to bind to androgen-responsive elements (AREs) located at compact chromatin regions and activates the enhancers by increasing the chromatin accessibility. This mechanism leads to a unique AR-V7-regulated transcriptional program that is completely independent of AR-FL activity and is highly enriched for genes mediating epithelial-mesenchymal transition and metastatic functions. We then identified a subset of AR-V7-specific targets with significant overexpression in CRPC tumor samples and associated with poor clinical outcomes. In particular, we found that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7, and its protein expression was dramatically upregulated at AR-V7-induced bone lesions. Furthermore, we found that the pro-metastasis function of AR-V7 can be enhanced by Ser81 phosphorylation through chromatin-binding-independent mechanisms, and that targeting this phosphorylation by CDK9 inhibitors can block AR-V7-induced SOX9 expression and impair AR-V7-mediated metastasis function. Conclusion: Our study provides novel molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC. In specific, these data have demonstrated the distinctive transcriptional program of AR-V7 from AR-FL, identified critical AR-V7 targets, and determined the function of Ser81 phosphorylation on AR-V7. Our data also suggest a new therapeutic strategy to target AR-V7-induced metastasis cascade in CRPC by using CDK9 inhibitor treatment. Citation Format: Maryam Labaf, Dong Han, Yawei Zhao, Jude Owiredu, Songqi Zhang, Kavita Venkataramani, Jocelyn S. Steinfeld, Wanting Han, Muqing Li, Mingyu Liu, Zifeng Wang, Anna Besschetnova, Susan C. Patalano-Salsman, Jill A. Macoska, Xin Yuan, Steven P. Balk, Stephen R. Plymate, Shuai Gao, Kellee R. Siegfried-Harris, Ruihua Liu, Gabrielle Foxa, Mary M. Stangis, Piotr J. Czernik, Bart Williams, Kourosh Zarringhalam, Xiaohong Li, Changmeng Cai. Distinct activity of androgen receptor splice variants in promoting prostate cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A009.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2023-A009
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Upregulation of Cytosolic Phosphoenolpyruvate Carboxykinase Is a Critical Metabolic Event in Melanoma Cells That Repopulate Tumors
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 7 ( 2015-04-01), p. 1191-1196
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 7 ( 2015-04-01), p. 1191-1196
    Abstract: Although metabolic defects have been investigated extensively in differentiated tumor cells, much less attention has been directed to the metabolic properties of stem-like cells that repopulate tumors [tumor-repopulating cells (TRC)]. Here, we show that melanoma TRCs cultured in three-dimensional soft fibrin gels reprogram glucose metabolism by hijacking the cytosolic enzyme phosphoenolpyruvate carboxykinase (PCK1), a key player in gluconeogenesis. Surprisingly, upregulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including in the serine and glycerol-3-phosphate pathways. Moreover, this retrograde glucose carbon flow strengthened rather than antagonized glycolysis and glucose consumption. Silencing PCK1 or inhibiting its enzymatic activity slowed the growth of TRCs in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled metabolic features of TRCs in melanoma that have implications for targeting a unique aspect of this disease. Cancer Res; 75(7); 1191–6. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-2615
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
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    Abstract 4266: Potential role of reactive oxygen species in affecting tumorigenicity of glioblastoma stem cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4266-4266
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4266-4266
    Abstract: Glioblastoma multiforme (GBM) is a common and highly aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used two lines of stem-like cancer cells (GSC11 and GSC23) derived from the tumor tissues of two GBM patients by classical neurosphere culture system, and showed that addition of serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and eventual cell death. Although both GBM stem-like cell lines showed high percentage of CD133-positive cells (20% in GSC11 and 70% in GSC23), exposure to serum only caused a moderate decrease of CD133 expression at later time points. Several methods were used to further test the role of ROS in affecting the stemness of the GSC cells and their self-renewal capacity. Addition of 5% FBS or removal of the antioxidant supplements (B27) from the culture medium caused the spheroid GSC cells to attach to the culture surface, exhibit differentiation morphology, decrease expression of certain stem-cell markers, and eventually die within two weeks. Serum exposure also resulted in a decrease of the GSC ability to form colonies in soft agar assay and to grow tumors in a mouse xenograft model. Although an increase of general cellular ROS could be detected when GSC cells were exposed to FBS, the mitochondrial superoxide appeared to be prominent and likely to be a primary event, which led to a compensatory increase of the mitochondrial SOD2 expression and upregulation of glutathione synthesis. Interestingly, addition of the antioxidant N-Acetylcysteine to the FBS-containing medium partially blocked the FBS-induced aberrant differentiation and improved cell viability and self-renewal capacity, suggesting that ROS may play an important role in affecting stemness and differentiation status of the cancer stem cells. We postulate that during tumor development, only the progeny cells that acquire the ability to counteract the impact of ROS increase induced by serum may eventually proliferate and grow as the tumor bulk, and that proper redox-modulation may be a potential novel strategy to block tumor formation and possibly kill the stem-like cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4266.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4266
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
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    Cell-free Tumor Microparticle Vaccines Stimulate Dendritic Cells via cGAS/STING Signaling
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Immunology Research Vol. 3, No. 2 ( 2015-02-01), p. 196-205
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 3, No. 2 ( 2015-02-01), p. 196-205
    Abstract: Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell–derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP–loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications. Cancer Immunol Res; 3(2); 196–205. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-14-0177
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 6
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    Overexpression of GOLPH3 Promotes Proliferation and Tumorigenicity in Breast Cancer via Suppression of the FOXO1 Transcription Factor
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 15 ( 2012-08-01), p. 4059-4069
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 15 ( 2012-08-01), p. 4059-4069
    Abstract: Purpose: Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in various biologic processes. The clinical significance and biologic role of GOLPH3 in breast cancer, however, remains unknown. Experimental Design: Expression of GOLPH3 in normal breast cells, breast cancer cells, and 6-paired breast cancer and adjacent noncancerous tissues were quantified using real-time PCR and Western blotting. GOLPH3 protein expression was analyzed in 258 archived, paraffin-embedded breast cancer samples using immunohistochemistry. The role of GOLPH3 in breast cancer cell proliferation and tumorigenicity was explored in vitro and in vivo. Western blotting and luciferase reporter analyses were used to investigate the effect of GOLPH3 overexpression and silencing on the expression of cell-cycle regulators and FOXO1 transcriptional activity. Results: GOLPH3 was significantly upregulated in breast cancer cells and tissues compared with normal cells and tissues. Immunohistochemical analysis revealed high expression of GOLPH3 in 133 of 258 (51.6%) breast cancer specimens. Statistical analysis showed a significant correlation of GOLPH3 expression with advanced clinical stage and poorer survival. Overexpression and ablation of GOLPH3 promoted and inhibited, respectively, the proliferation and tumorigenicity of breast cancer cells in vitro and in vivo. GOLPH3 overexpression enhanced AKT activity and decreased FOXO1 transcriptional activity, downregulated cyclin-dependent kinase (CDK) inhibitor p21Cip1, p27Kip1, and p57Kip2, and upregulated the CDK regulator cyclin D1. Conclusion: Our results suggest that high GOLPH3 expression is associated with poor overall survival in patients with breast cancer and that GOLPH3 overexpression increases the proliferation and tumorigenicity of human breast cancer cells. Clin Cancer Res; 18(15); 4059–69. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-3156
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 7
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    Abstract B037: Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 11_Supplement ( 2023-06-02), p. B037-B037
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 11_Supplement ( 2023-06-02), p. B037-B037
    Abstract: Prostate cancer (PCa) patients’ 5-year survival is only ~30% when metastases develop. Most PCa metastases happen in bone. We seek to identify gene signatures unique for bone-metastatic PCa cells and explore potential drug candidates to specifically target PCa bone metastases (bone met). Using public RNA-Seq datasets, we defined differentially expressed genes (DE) intrinsic to PCa bone met by analyzing the DE between bone mets (MET500) and primary tumors (TCGA) and filtering out the genes shown as the DE between normal bone marrow and prostate (GTex). Similarly, we got DE intrinsic to liver met. These two intrinsic DE were further compared and functional annotation for bone met only DE was performed. We found that the bone met only up-regulated DE were significantly enriched for mitochondrial OXPHOS and electron transport chain (ETC). In contrast, no mitochondria-related terms were enriched in PCa liver met, PCa lymph node met or breast cancer bone met, suggesting unique elevated mitochondrial activities in PCa bone met. We further performed RNA-Seq analyses and determined the DE unique in intratibial xenografts (mimicking bone mets), compared to C4-2B PCa primary tumors, i.e., orthotopic or subcutaneous xenografts. OXPHOS was also positively enriched in the intratibial DE, suggesting that pre-clinical animal models recapitulate functional signatures of PCa patients and can be used for drug testing. Therefore, we hypothesized that inhibiting mitochondrial OXPHOS or ETC complex blocks PCa bone metastases. Excitingly, we found that mitochondrial ETC complex I inhibitor, IACS-010759, showed high potency and specificity in suppressing PCa cell growth without affecting osteoblasts in vitro, and significantly inhibited metastatic development of PCa cells in vivo. In summary, elevated mitochondrial activity appears to be a unique signature and phenotype for PCa bone met and mitochondria-interrupting drugs selectively suppress the growth of PCa cells without affecting normal cells in the bone microenvironment such as osteoblasts. Blocking mitochondria hyperactivation is a potential approach against PCa bone met. Citation Format: Shang Su, Ke Liu, Jing Xing, Yawei Zhao, Ruihua Liu, Bin Chen, Xiaohong Li. Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B037.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2023-B037
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Notch1 Signaling Promotes Primary Melanoma Progression by Activating Mitogen-Activated Protein Kinase/Phosphatidylinositol 3-Kinase-Akt Pathways and Up-regulating N-Cadherin Expression
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 8 ( 2006-04-15), p. 4182-4190
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 8 ( 2006-04-15), p. 4182-4190
    Abstract: Cellular signaling mediated by Notch receptors results in coordinated regulation of cell growth, survival, and differentiation. Aberrant Notch activation has been linked to a variety of human neoplasms. Here, we show that Notch1 signaling drives the vertical growth phase (VGP) of primary melanoma toward a more aggressive phenotype. Constitutive activation of Notch1 by ectopic expression of the Notch1 intracellular domain enables VGP primary melanoma cell lines to proliferate in a serum-independent and growth factor–independent manner in vitro and to grow more aggressively with metastatic activity in vivo. Notch1 activation also enhances tumor cell survival when cultured as three-dimensional spheroids. Such effects of Notch signaling are mediated by activation of the mitogen-activated protein kinase (MAPK) and Akt pathways. Both pathways are activated in melanoma cells following Notch1 pathway activation. Inhibition of either the MAPK or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway reverses the Notch1 signaling-induced tumor cell growth. Moreover, the growth-promoting effect of Notch1 depends on mastermind-like 1. We further showed that Notch1 activation increases tumor cell adhesion and up-regulates N-cadherin expression. Our data show regulation of MAPK/PI3K-Akt pathway activities and expression of N-cadherin by the Notch pathway and provide a mechanistic basis for Notch signaling in the promotion of primary melanoma progression. (Cancer Res 2006; 66(8): 4182-90)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-3589
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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  • 9
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    Abstract 2014: Radiopathomics strategy combining multiparametric MRI with whole-slide image for pretreatment prediction of tumor regression grade to neoadjuvant chemoradiotherapy in rectal cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2014-2014
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2014-2014
    Abstract: Backgrounds: Tumor regression grade (TRG) reflects the chemoradiosensitivity of rectal cancer patients undergone neoadjuvant treatment, and relates to distinct probabilities of cancer recurrence and survival. However, in clinical practice, it is significantly challenging to rely solely on radiographic or clinical diagnostic information to obtain a patient's pathological response pre-treatment for treatment optimization. The aim was combining both the tumor information of macroscopic radiological and microscopic pathological images to develop and validated a more accurate signature for pretreatment prediction of TRG to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) on a multicenter dataset. Materials and Methods: We prospectively enrolled 981 patients (303 in the primary cohort, 678 in three external validation cohort) with clinicopathologically confirmed LARC treated with nCRT followed by surgery between Aug 2007 and Nov 2017, and collected their pretreatment multi-parametric MRI (mp-MRI), whole-slide image (WSI) of biopsy specimen, and pathologic response according to AJCC TRG system as well as clinical outcomes. Briefly, an artificial intelligence model integrating quantitative imaging features of mp-MRI and WSI was proposed to predict each nCRT treated patient into a particular 4-category TRG. The signature from the model (hereafter Rp-Grade) was further assessed in three independent validation cohort. Results: Rp-Grade yielded an overall ACC of 87.76% and revealed significant improvement than signature generating from model with mp-MRI or WSI features alone in all validation cohorts (P & lt;0.0.5) (Table). Performance of radiopathomics signature for predicting 4-category AJCC/CAP TRGMetrics (%) [95% CI]Validation Cohort1 (N=480)Validation Cohort2 (N=150)Validation Cohort3 (N=48)Accuracy87.76 [84.86-90.66] 79.71 [72.52-84.9]81.24 [70.15-92.34] PPV (TRG=0)94.58 [90.48-98.69]93.52 [84.68-100.0] 83.09 [61.19-100.0]PPV (TRG=1)92.02 [86.19-97.85] 70.26 [56.42-84.1]70.26 [56.42-84.1] PPV (TRG=2)83.9 [79.6-88.19]74.24 [63.57-84.92] 71.49 [52.04-90.94]PPV (TRG=3)-92.54 [78.21-100.0] -Sensitivity (TRG=0)96.49 [93.03-99.95]96.62 [89.92-100.0] 91.3 [74.73-100.0]Sensitivity (TRG=1)96.49 [93.03-99.95] 75.57 [61.75-89.4]63.39 [42.96-83.82] Sensitivity (TRG=2)97.16 [95.02-99.29]100.0 [100.0-100.0] 100.0 [100.0 100.0]Sensitivity (TRG=3)-35.55 [19.99-51.12] -Note: The evaluation results were represented by ‘-' when the number of categories was insufficient in the independent cohort test. Conclusions: Combining the macroscopic radiological information of the whole tumor and microscopic pathological information of local lesions from biopsy, radiopathomics was a potential strategy for the pretreatment prediction of the TRG in patients with LARC who underwent nCRT. Citation Format: Lizhi Shao, Zhenyu Liu, Lili Feng, Xiaoying Lou, Zhenhui Li, Xiao-Yan Zhang, Xuezhi Zhou, Kai Sun, Da-Fu Zhang, Lin Wu, Guanyu Yang, Ying-Shi Sun, Ruihua Xu, Xiangbo Wan, Xinjuan Fan, Jie Tian. Radiopathomics strategy combining multiparametric MRI with whole-slide image for pretreatment prediction of tumor regression grade to neoadjuvant chemoradiotherapy in rectal cancer [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 2014.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2014
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 10
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    Abstract 5681: Design, synthesis and study of small molecules with both AR degradation and AKR1C3 inhibitory activities
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5681-5681
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5681-5681
    Abstract: Prostate cancer is the most common cancer in men and it is estimated that 32,000 men in the US alone will die of this cancer in 2019. Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer therapy. However, most of the patients will progress to castration resistance prostate cancer (CRPC) after several years of treatment. The current treatment of CRPC includes chemotherapeutic agents (docetaxel) and agents that target androgen signaling (abiraterone, enzalutamide and apalutamide). Ultimately, however, most patients develop resistance to the treatments. Two of the mechanisms of resistance involve the expression of constitutively active androgen receptor variant (AR-V7) and the increase in intra-tumoral biosynthesis of androgens. Several treatment strategies targeting AR-V7 have been reported. For the intra-tumoral biosynthesis of androgens, one of the enzymes, AKR1C3, plays a critical role in the development of CRPC and has been reported to be consistently elevated in CRPC patients who are resistant to abiraterone and enzalutamide. We have been involved in the development of agents to treat CRPC and overcome drug resistance of CRPC patients. We reported that niclosamide, an FDA-approved anthelminthic agent, could degrade AR-V7. We also reported that niclosamide, as well as an AKR1C3 inhibitor, indomethacin, were able to overcome enzalutamide and abiraterone resistance in several prostate cancer cell lines, suggesting that niclosamide is also an AKR1C3 inhibitor. By examining the reported structures of AKR1C3 inhibitors, niclosamide was found to contain the core scaffold of 4-Hydroxy-1-(4-methoxybenzyl)-N-(3-(trifluoromethyl) phenyl)-1H-1,2,3-triazole-5-carboxamide. Using this knowledge, we designed a series compounds with dual AR degrading and AKR1C3 inhibitory activities. Preliminary studies showed the compounds caused AR-V7 degradation and to a lesser extent AR full length degradation. The compounds also inhibited AKR1C3 and caused a dose dependent growth inhibition of several prostate cancer cell lines. Citation Format: Enming Xing, Xiaotian Kong, Wei Lou, Ruihua Shi, Xiaolin Cheng, Allen C. Gao, Pui Kai Li. Design, synthesis and study of small molecules with both AR degradation and AKR1C3 inhibitory activities [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 5681.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5681
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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