tbuckley/cabot-search huggingface dataset:
Abstract 6520: Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients
Authors: Wataru Goto, Hanae Matsuda, Saeko Henmi, Mariko Nishikawa, Asuka Kouchi, Rika Kouhashi, Akimichi Yabumoto, Koji Takada, Yukie Tauchi, Kana Ogisawa, Tamami Morisaki, Shinichiro Kashiwagi
Journal: Cancer Research (2024)

Abstract Background: Recently, some basic research has reported that the tumor immune microenvironment (TIME) is related to the therapeutic efficacy and prognosis of breast cancer patients, and that the regulation of metabolism can affect TIME and enhance antitumor immunity. Suppression of aromatase expression from adipose tissue is the standard adjuvant endocrine therapy for postmenopausal hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, but few studies have examined the impact of controlling lipid metabolism on TIME and cancer prognosis. Materials and Methods: Except for patients with ductal carcinoma in situ, 531 postmenopausal HR-positive/HER2-negative breast cancer patients treated with curative surgery between 2011 and 2017 were examined. Serum lipid levels and systemic immune-related markers were evaluated by blood samples, and tumor-infiltrating lymphocytes (TILs) in cancer tissue samples were investigated by immunohistochemistry. We also examined the relationship between lipid metabolism, TIME, and prognosis, respectively. Results: Good serum lipid control group was significantly correlated with low neutrophil- to-lymphocyte ratio (NLR) (p = 0.024) and high TILs (p = 0.039). The median follow-up time for the assessment of prognosis was 5.5 years, and 67 patients had recurrence. Only patients treated with aromatase inhibitor as adjuvant endocrine therapy showed significantly better recurrence-free survival (RFS) in the good lipid control group (p = 0.025, log-rank). Also, multivariate analyses showed that good serum lipid control was an independent prognostic factor for recurrence (HRs = 4.722, 95%CI: 1.006-22.161, p = 0.049). Patients with high CD8/FOXP3 ratio (CFR) had significantly better RFS (p=0.027, log-rank) and tended to have good lipid control. Conclusions: Good control of serum lipid metabolism may inhibit the acquisition of resistance to endocrine therapy by improving TIME and induce favorable outcome in postmenopausal HR-positive/HER2-negative breast cancer patients. Citation Format: Wataru Goto, Hanae Matsuda, Saeko Henmi, Mariko Nishikawa, Asuka Kouchi, Rika Kouhashi, Akimichi Yabumoto, Koji Takada, Yukie Tauchi, Kana Ogisawa, Tamami Morisaki, Shinichiro Kashiwagi. Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6520.
Abstract 2111: Impact of HER2 Expression on trastuzumab deruxtecan(T-DXd) efficacy
Authors: Wanyi Chen, Joshua Drago, Avantika Gupta, Bo Liu, Sarat Chandarlapaty
Journal: Cancer Research (2024)

Abstract Background: T-DXd is an FDA-approved anti-HER2 Antibody Drug Conjugate (ADC), which has shown clinical efficacy in breast cancers with either overexpression or low-level expression of HER2. The benefit of T-DXd across the spectrum of HER2 expression has called into question the relevance of HER2 expression level as relevant parameter for T-DXd sensitivity. We sought to experimentally address the relevance of HER2 expression level upon the degree of T-DXd response. Methods: A series of isogenic models was generated that expressed different levels of surface HER2 using a doxycycline-inducible promoter. These were analyzed for impact of differential expression level upon T-DXd internalization and drug response. Human breast cancer samples were analyzed for HER2 expression levels and association with clinical response to T-DXd under an IRB approved protocol. Results: Induction of different levels of HER2 at specified doxycycline concentrations was verified in multiple models using immunoblotting and FACS. These different levels appeared to correspond to clinical breast cancer immunohistochemistry (IHC) scoring levels to 0, 1+, 2+, and 3+. The models were analyzed for T-DXd response and showed increasing levels of HER2 led to increase lysosomal uptake of T-DXd (p&amp;lt;0.0001). Moreover, elevation of HER2 levels led to lower concentrations of T-DXd needed to suppress tumor growth. Analyses of the effects of increasing levels of HER2 upon xenograft response to T-DXd are ongoing. Finally, retrospective analyses of a cohort of 50 breast cancer patients treated with T-DXd revealed that higher levels of HER2 corresponded to longer time on treatment (time to progression). Conclusion: We observe a consistent relationship between elevated expression of HER2 and breast cancer response to T-DXd. The findings highlight the relevance of HER2 expression level as a biomarker of T-DXd response and support the potential value of therapeutic strategies that can induce HER2 surface expression levels to enhance response. Citation Format: Wanyi Chen, Joshua Drago, Avantika Gupta, Bo Liu, Sarat Chandarlapaty. Impact of HER2 Expression on trastuzumab deruxtecan(T-DXd) efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2111.
Abstract 6213: <i>De</i>termination of permissive and restraining <i>c</i>ancer-<i>a</i>ssociated <i>f</i>ibroblast (DeCAF) subtypes
Authors: Xianlu Laura Peng, Elena Kharitonova, Joseph Kearney, Yi Xu, Priscilla Chan, Changfei Luan, Brian Belt, Roheena Panni, Arthi Hariharan, Ian McCabe, Ashley Morrison, Ashley Cliff, David C. Linehan, Alina Iuga, Naim U. Rashid, Jen Jen Yeh
Journal: Cancer Research (2024)

Abstract Cancer-associated fibroblasts (CAFs) in pancreatic adenocarcinoma (PDAC) are known to play a significant role in regulating tumor progression, invasion, and metastasis. Multiple studies using experimental strategies, as well as single-cell RNA-sequencing (scRNAseq) technology, have shown the existence of subpopulations of PDAC CAFs, with divergent physical and biological characteristics. However, how these CAF subpopulations translate to clinical practice remains unclear. Using a combination of sc- and bulk RNAseq data, we present two CAF subtypes with permissive (permCAF) and restraining (restCAF) characteristics in patients, and developed a clinically usable single-sample classifier (DeCAF) using using 11 independent datasets with high reproducibility (AUC = 0.961). We found that the permCAF patients tend to be associated with a “myxoid” histological features, while restCAF samples were more “collagenized” (p = 0.018). Patients with permCAF tumors had a median overall survival (OS) of 18.5 m compared to 30.2 m for restCAF tumors, with a stratified HR = 1.66 (p &amp;lt; 0.001) for patients with permCAF tumors. Basal-like tumors were found to be associated permCAF subtype (p &amp;lt; 0.001). DeCAF and PurIST (basal-like/classical) subtypes were independently associated with OS (p &amp;lt; 0.001). Analysis of a phase Ib trial FOLFIRINOX in combination with a CCR2 inhibitor (PF-04136309; NCT01413022) , we found that in patients with classical tumors, increasing permCAF probability was associated with response (r = -0.688, p&amp;lt;0.001). Tumors with permCAF subtype are enriched in neutrophils using CIBERSORT and may explain the positive response to CCR2 inhibition. More intriguingly, we found similar associations with OS in kidney renal clear cell carcinoma (KIRC, p = 0.001) and mesothelioma (MESO, p = 0.019). DeCAF subtypes are associated with histological subtype in MESO (p = 0.021) and grade in KIRC (p = 0.056). Taken together, DeCAF subtypes explain the role of CAF subtypes in patients, provide a foundation for the translation of preclinical studies, and facilitate the design of future therapeutic approaches and clinical trials. Citation Format: Xianlu Laura Peng, Elena Kharitonova, Joseph Kearney, Yi Xu, Priscilla Chan, Changfei Luan, Brian Belt, Roheena Panni, Arthi Hariharan, Ian McCabe, Ashley Morrison, Ashley Cliff, David C. Linehan, Alina Iuga, Naim U. Rashid, Jen Jen Yeh. Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6213.
Abstract 6175: Deep learning-based survival prediction for hepatocellular carcinoma using whole slide images
Authors: Sung Hak Lee, Hyun-Jong Jang
Journal: Cancer Research (2024)

Abstract There is an increasing need for classifiers to effectively stratify prognosis in patients with hepatocellular carcinoma (HCC). Deriving interpretable prognostic features using deep-learning (DL)-based prognostic models from pathology images remains a challenge. In this study, we developed a computational approach based on DL to predict the overall survival (OS) of HCC patients from formalin-fixed paraffin-embedded histopathology whole slide images. A DL model for classifying good and poor prognosis was developed on a total of 460 patients with 2 independent cohorts from Seoul St. Mary's Hospital. The primary outcome was OS. The training set (SSM1, n = 292) included HCC patients that had undergone surgical resection. The classifier was then independently tested on the second HCC dataset (SSM2, n = 168). The area under the curve (AUC) for the receiver operating characteristic (ROC) curves was 0.850 and 0.781 for SSM1 and SSM2 datasets, respectively. In addition, we have tried to establish DL model for prediction of OS based on clinicopathological features, including Edmondson-Steiner grade, pT stage, vascular invasion, Ki-67 index, and cytokeratin 19 immunohistochemical expression. Random forest model was applied to classify the good and poor prognosis groups and The AUROCs for the random forest was 0.705 for the SSM1 dataset, which are inferior to that of DL prediction. These findings suggest that the DL techniques can be applied to refine the prognostic prediction of HCC patients. Citation Format: Sung Hak Lee, Hyun-Jong Jang. Deep learning-based survival prediction for hepatocellular carcinoma using whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6175.
Abstract 4302: ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer
Authors: Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M. Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J. Freedland, Edwin M. Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S. Nelson, Lauren Brady, Ramachandran Murali, Moray J. Campbell, Wei Yang, Beatrice S. Knudsen, Elahe A. Mostaghel, Huihui Ye, Isla P. Garraway, Sungyong You, Michael R. Freeman
Journal: Cancer Research (2024)

Abstract Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor (GR) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease. Citation Format: Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M. Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J. Freedland, Edwin M. Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S. Nelson, Lauren Brady, Ramachandran Murali, Moray J. Campbell, Wei Yang, Beatrice S. Knudsen, Elahe A. Mostaghel, Huihui Ye, Isla P. Garraway, Sungyong You, Michael R. Freeman. ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4302.
Abstract 4998: Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation
Authors: Shinkyo Yoon, Hyun-Min Ryu, Sang-We Kim, Kang-Seo Park, Dae Ho Lee
Journal: Cancer Research (2024)

Abstract Background: Oncogenic alteration in RET, representing 1-2% of non-small cell lung cancer (NSCLC), is one of the important targets. Pralsetinib is a selective RET inhibitor that targets RET fusions. We present a case series on opportunistic infections and the mechanism of immunosuppression. Methods: From October 2021 to March 2022, we administered pralsetinib to a total of 15 patients with NSCLC harboring RET fusion. We retrospectively analyzed the clinical efficacy and adverse event related to pralsetinib. To investigate the potential impact of pralsetinib on T-cells, we examined cytokine release from Jurkat T (JT) cells after pralsetinib treatment. To test if Stat5 bind to IL-2 promotor, we conducted Chromatin Immunoprecipitation (ChIP). Results: Out of a total of 18 patients with measurable disease, 14 patients (93%) achieved a partial response. With the median follow-up duration of 8.7 months, four cases of opportunistic infections were occurred. Notably, three patients (16.6%) experienced invasive pulmonary aspergillosis, and one patient (5.5%) experienced cytomegalovirus pneumonia. To mimic conditions akin to activated T cells, we treated JT cells with PMA and ionomycin, inducing IL-2 release through the binding of NFAT, AP-1, and NF-κB to the IL-2 promoter. Following approximately two weeks of pralsetinib treatment, a decrease of IL-2 releases, the inhibition of Jak3 and the reduced-expression of JunB and c-Jun was observed. Additionally, to investigate the direct correlation between Jak3 and IL-2 release, JT cells were treated with ritlecitinib, the Jak3-selective inhibitor, for approximately two weeks. Like pralsetinib, a reduction in IL-2 release was observed. Furthermore, based on the evidence that Stat5 inhibition leads to reduced IL-2 release, we also showed that the transcription factor Stat5, a direct downstream signaling component of Jak3, binds to the IL-2 promoter during the activation of Jurkat T cells. Conclusion: Pralsetinib inhibits additional IL-2 production by blocking Jak3/Stat5 activation triggered by IL-2 released during early T cell activation. As a result, the Jak3 inhibition induced by pralsetinib leads to a decrease in JunB/c-Jun expression and blocking Stat5 activation by reducing IL-2 release. Consequently, Pralsetinib-related opportunistic infections may be caused by inhibition of the JAK3 pathway and IL-2 release. Citation Format: Shinkyo Yoon, Hyun-Min Ryu, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4998.
Abstract 6900: Patient-derived xenografts from circulating cancer stem cells and their potential utility in personalized medicine of pancreatic cancer
Authors: Monika Pizon, Dorothea Schott, Andreas Ettner-Sittner, Benedikt J. Wagner, Katharina Pachmann, Thiha Aung, Christina Hackl, Silke Haerteis
Journal: Cancer Research (2024)

Abstract Background: Pancreatic cancer carries a poor prognosis in the majority of patients, with an overall 5-year survival rate of less than 10%. Therefore, the development of new therapies and preclinical models is crucial and urgently needed. Circulating cancer stem cells (cCSCs) are a subset of circulating cancer cells that have stem cell-like properties and play a significant role in tumor progression, metastasis, and treatment resistance. Patient-derived xenografts (PDX) reflect the genotypic and phenotypic landscape of patients' cancers and are useful for drug screening, biomarker development, and preclinical evaluation of personalized medicine strategies. In this study, we describe a fast, simple, and cost effective method to generate PDX on Chorioallantoic Membrane (CAM) from circulating cancer stem cells. Methods: In this study, primary cultures from circulating cancer stem cells were established using sphere-forming assays from 30 patients with newly diagnosed pancreatic cancer. Subsequently, tumorspheres were transplanted onto the CAM membrane of fertilized chicken eggs to form patient- derived xenografts. Results: For the identification of cCSCs from peripheral blood of pancreatic cancer patients, an innovative in vitro sphere-forming assay was established. The number of tumorspheres was correlated with clinicopathological parameters like tumor size, lymph node involvement and grading status of the primary tumor. Implantation of tumorspheres onto the CAM was successful in ~90 % of the applied samples. The histological analysis suggests that the PDX tumors were morphologically and pathologically identical to primary tumor tissue. Conclusions: The number of tumorspheres was associated with clinicopathological parameters. Further follow-up is needed to evaluate the prognostic significance of tumorsphere detection in pancreatic cancer. Generation of PDX from cCSCs on CAM has a high success rate and may become an integral part of the drug development arena, including drug screening and biomarker development. Citation Format: Monika Pizon, Dorothea Schott, Andreas Ettner-Sittner, Benedikt J. Wagner, Katharina Pachmann, Thiha Aung, Christina Hackl, Silke Haerteis. Patient-derived xenografts from circulating cancer stem cells and their potential utility in personalized medicine of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6900.
Abstract 6509: GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors
Authors: Xiaodan Hou, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren, Youzhi Tong
Journal: Cancer Research (2024)

Abstract Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is the central signal molecule in regulating cell growth, metabolism, angiogenesis, and survival. The first generation of mTOR inhibitors specifically inhibit mTORC1 but are insensitive to mTORC2 and cannot eliminate the downstream signaling cascade in cancer. GT0486, a second-generation mTORC1/2 dual inhibitor, can selectively suppress mTOR kinase activity while has no inhibitory effect on other kinase receptors. We investigate the anti-tumor efficacy of GT0486 in a variety of tumor cells and xenograft animal models in vitro and in vivo. The combination effects of GT0486 and BTKi (BTK inhibitor) were also evaluated. Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer). In B-cell lymphoma, compared with the CC-223, GT0486 shows greater inhibitory potency against TMD8, DoHH2 and WSU-DLCL2, with IC50 values of 85nM, 96nM and 83nM, respectively. Moreover, in the U87 and the PC-3 xenograft animal models, GT0486 strongly reduced tumor growth in dose dependent manner. High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells. In BTKi resistant DoHH2 cells, GT0486 also enhanced the drug sensitivity of BTKi. The possible biomarkers on the synergistic mechanism were further studied. GT0486 improves the role of BTKi on cell cycle arrest in phase G1. At the same time, the phosphorylation levels of mTOR downstream effectors AKT, 4EBP1 and S6 were dose-dependently downregulated after GT0486 treatment, and a significant reduction were observed when combined with BTKi. These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials. Citation Format: Xiaodan Hou, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren, Youzhi Tong. GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6509.