bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5127: Significance of Trop-2 in HER2-positive breast cancer
Authors: Liu Chun-Yu , Chen Ji-Lin , Chu Pei-Yi , Huang Chun-Teng , Wang Wan-Lun , Huang Chi-Cheng , Lin Po-Han , Tseng Ling-Ming 
Published: June 2022

Abstract
Purpose: The glycoprotein Trop-2 is frequently overexpressed in human malignancies and linked to worse outcome. A Trop2-targeting antibody-drug conjugate, sacituzumab govitecan, has been approved by the FDA for patients with unresectable locally advanced or metastatic triple-negative breast cancer. Trop-2 enhances Akt phosphorylation in numerous cancer cell lines, while the opposite findings are also reported suggesting the cell context-dependent effect of Trop-2. Blockade of PI3K/Akt pathway mediates anti-tumor mechanism of anti-HER2 agents. In this study, we aim to investigate the role of Trop-2 in HER2-positive breast cancer.
Experimental design: The archival samples comprising different breast cancer subtypes were analyzed using immunohistochemical staining. The public databases, including, Metabric, KM plotter, ROC plotter, were used to verify the prognostic role and clinical significance of Trop-2 in HER2-positive breast cancer. In vitro tumor models, the transwell migration, invasion and sphere assays, were applied for evaluation of cancer progression. The apoptotic cells were determined by flow cytometry using Annexin V/propidium iodide double staining.
Results: We analyzed a cohort of 986 breast cancer patients and found that HER2-positive breast cancer harbored higher Trop-2 protein expression than other breast cancer subtypes. Higher levels of Trop-2 and phospho-Akt in HER2-positive breast cancer tissues compared with normal tissues. Trop-2 expression was correlated with tumor stage and phospho-Akt level. HER2-positive breast cancer patients with high level of Trop-2 protein were linked to worse recurrence-free survival. Consistently, data from the public databases exhibited patients with higher level of Trop-2 transcript had shorter recurrence-free survival and overall survival of HER2-positive breast cancer. Overexpression of Trop-2 increased cell migration, invasion and sphere number in SK-BR-3 and BT-474 cells. In contrast, knockdown of Trop-2 suppressed cell motility and sphere formation. Trop-2-expressing cells had better cell viability compared to control cells in the presence of lapatinib or neratinib treatment. Lapatinib- and neratinib-induced cell apoptosis was rescued by Trop-2 overexpression. Notably, patients responded to anti-HER2 therapy had lower Trop-2 transcript expression than non-responders.
Conclusion: These results suggested that the oncogenic role of Trop-2 in HER2-positive breast cancer and Trop-2 expression might confer resistance to anti-HER2 therapy.
Citation Format: Chun-Yu Liu, Ji-Lin Chen, Pei-Yi Chu, Chun-Teng Huang, Wan-Lun Wang, Chi-Cheng Huang, Po-Han Lin, Ling-Ming Tseng. Significance of Trop-2 in HER2-positive breast cancer [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 5127.
Abstract 5147: The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer
Authors: Zhang Xiaojun , Kang Bowon , Karim Mazharul , Zhang Jianying , Song Jae Yun , Kim In-San , Al-Hilal Taslim A. 
Published: June 2022

Abstract
Ovarian cancer has a dire prognosis with an overall 5-year survival rate of ~40%, whereas stage III and IV has a survival rate of only 3-19%. Failure to detect early contributes highly to the poor survival rate of ovarian cancer. Thus, early detection of EOCs is likely to translate into mortality benefit. Two tests used clinically to detect ovarian cancer are serum cancer antigen-125 (CA-125) and transvaginal ultrasound. Both have limitations of specificity and sensitivity. CA-125 along with other biomarkers that are in clinical trials express both in the ovaries and serum of healthy females. Thus, the specific detection among cancer-free controls versus ovarian cancer cases remains highly variable. We hypothesize to assess the Doppel (PRND gene) as a serum biomarker in the detection of epithelial ovarian cancers (EOC) at the early stages. Doppel, a prion-like protein first identified in 1996, is known to express in testis and appears to regulate male fertility. Previously, we and others reported that Doppel is a highly specific tumor endothelium marker. In this study, to validate the potential of Doppel as an EOC serum biomarker, using ELISA, we detected Doppel concentration in the sera of 76 sera samples from patients with stage and histopathology information, and in 18 normal human sera (NHS). Doppel level was significantly higher in sera of EOC patients than NHS (0.720 vs 6.653 ng/ml, p&lt;0.0001); 72 out of 76 patients were positive for Doppel expression (cut off value was calculated as Mean+3×SEM = 1.296 ng/mL) while only 3 out of 18 cases were positive for NHS. Receiver operating characteristic (ROC) analysis showed that Doppel can differentiate EOC patients from normal individuals with AUC of 0.957, sensitivity of 90.8%, and specificity of 90%. Doppel was markedly higher in all stages of EOC than NHS (Stage I, 6.261 ng/mL; Stage II, 8.045 ng/ml; Stage III, 7.040 ng/mL; and Stage IV, 5.726 ng/ml vs NHS 0.720 ng/ml; p&lt;0.001). Interestingly, serum Doppel level was higher among EOC of serous adenocarcinoma (7.020 ng/mL; n = 39), mucinous (10.780 ng/mL; n = 8), and endometroid (7.295 ng/mL; n = 7) than clear cell (3.114 ng/mL; n = 7) or other types (4.855 ng/mL; n = 15). Together, our study showed the potential of Doppel as a serological biomarker for EOC detection.
Citation Format: Xiaojun Zhang, Bowon Kang, Mazharul Karim, Jianying Zhang, Jae Yun Song, In-San Kim, Taslim A. Al-Hilal. The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer [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 5147.
Abstract 5190: Case report: long-term response to combination of Sintilimab, Bevacizumab and chemotherapy in a heavily pretreated refractory colon cancer patient with microsatellite stability
Authors: Cui Zhi , Wang Qi , Deng Muhong , Meng Erhong , Liu Sheng , Han Quanli 
Published: June 2022

Abstract
Background: Unlike patients with advanced colorectal cancer (CRC) with deficient DNA mismatch repair or microsatellite instability-high (dMMR/MSI-H) tumors, most patients with advanced CRC with proficient DNA mismatch repair or microsatellite-stability (pMMR/MSS) tumors are not sensitive to immune checkpoint inhibitor (ICI) therapy. The current challenge is to find out innovative therapeutic combinations with ICIs for such patients.
Case Presentation: In this study, we report a case of heavily pretreated refractory colon cancer with MSS but high-tumor mutation burden (TMB-H) tumors. After experiencing five lines of therapy, including chemotherapy and targeted therapy with anti-angiogenic inhibitor as well as anti-EGFR antibody, she received sixth-line therapy with combination of Sintilimab, Bevacizumab and chemotherapy, and obtained a durable clinical benefit. The patient’s progression-free survival (PFS) of sixth line therapy was about 9 months and overall survival (OS) has been over 4.6 years.
Conclusion: To the best of our knowledge, this study represented the longest PFS of response to combination of ICI with other agents with different mechanisms of action in a heavily pretreated refractory colon cancer patient with MSS.
Citation Format: Zhi Cui, Qi Wang, Muhong Deng, Erhong Meng, Sheng Liu, Quanli Han. Case report: long-term response to combination of Sintilimab, Bevacizumab and chemotherapy in a heavily pretreated refractory colon cancer patient with microsatellite stability [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 5190.
Abstract 5192: Efficacy and safety of second-line therapy by S-1 combined with Sintilimab and Anlotinib in pancreatic cancer patients with liver metastasis: A single-arm, phase II clinical trial
Authors: Du Juan , Qiu Xin , Lu Changchang , Sha Huizi , Zhu Yahui , Kong Weiwei , Li Xing , Qian Xiaoping , Liu Baorui 
Published: June 2022

Abstract
Background: The mortality of pancreatic cancer is increasing year by year, and the prognosis of pancreatic cancer with liver metastasis is worse. There is still no recognized effective second-line treatment strategy. In this trial, the efficacy and safety of the triple-drug regimen by S-1 chemotherapy combined with anti-PD-1 McAb (Sintilimab) and anti-angiogenic drug (Anlotinib) were evaluated in pancreatic cancer patients with liver metastasis.
Methods: Pancreatic cancer patients with liver metastases and ECOG 0~2 were recruited. These patients had never been given 5-FU, anti-PD-1 McAb and/or anti-angiogenic drugs in first-line treatment. S-1 was administered orally at 25 mg/m2 bid from day 1 to day 14, Sintilimab was administered intravenously at 200 mg on day 1, and Anlotinib was administered orally 12mg qd from day 1 to day 14. This method were repeated every 21 days till disease progression. The therapeutic effect was evaluated every 3 cycles. Progression-free survival (PFS) and overall survival (OS) were estimated via the K-M method. Some patients’ tumor tissues have done high-throughput sequencing and the relationship between with effect has been analyzed.
Results: From March 2020 to June 2021, a total of 23 patients were enrolled in this study and 19 patients had objective efficacy evaluation. Two patient (10.5%) had confirmed partial response and eight patients (42.1%) had stable disease. Median PFS and OS were 3.53 months and 7.15 months. Grade 3 adverse events were 26.3%, and there were no grade 4 or above adverse events. The tumor tissues of 16 patients have done high-throughput sequencing, and genetic test results show that 6 patients were evaluated as HRD-High and 10 patients as HRD-Low. Patients with HRD-H had shorter PFS than those with HRD-L (2.43 vs. 5.45 months; p = 0.043), However, OS was not significantly different between these two groups (4.43vs.9.35 months; P = 0.11).
Conclusions: This study suggests that S-1 chemotherapy combined with anti-PD-1 McAb (Sintilimab) and anti-angiogenic drug (Anlotinib) is efficacy and safety as a second-line treatment for pancreatic cancer patients with liver metastasis. Subgroup analysis showed that patients with HRD-L had longer PFS. HRD-H were found to be related to worsen PFS, which may indicate that other therapies should be explored regarding to these patients.
Citation Format: Juan Du, Xin Qiu, Changchang Lu, Huizi Sha, Yahui Zhu, Weiwei Kong, Xing Li, Xiaoping Qian, Baorui Liu. Efficacy and safety of second-line therapy by S-1 combined with Sintilimab and Anlotinib in pancreatic cancer patients with liver metastasis: A single-arm, phase II clinical trial [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 5192.
Abstract 5201: Enhanced production of IL-2 from anti CD3-stimulated mouse spleen cells by artepillin C, a major component of Brazilian green propolis
Authors: Kondoh Nobuo , Kamiya Masako , Tsuruta Hanemi , Takahashi Moe , Ikeno Kumiko , Ueno Kyohei , Umemura Naoki , Takayama Eiji , Kawaki Harumi , Nakamura Genjiro , Nikaido Toru , Muramatsu Yasunori , Ando Megumi 
Published: June 2022

Abstract
Objectives: It has been reported that Brazilian green propolis (BGP) possesses anti-tumor and chemo-preventive properties against prostate cancer (Szliszaka E, 2011). And bioactive components from propolis have been shown to have anti-cancerous effects upon hepatocellular carcinoma (Liu X, 2021). These observations revealed that propolis can be an anti-cancer drugs, however the immunological effects upon tumor microenvironments of these naturally occurring components has not been elucidated. In this report, we attempt to clarify immune modulatory effects of BGP and the major component, artepillin C, by observing cytokine production from activated T cells.
Methods: The mouse spleen cell stimulated by anti-CD3 monoclonal antibody were co-cultured with BGP, artepillin C and HC030031, an antagonist of TRPA1 Ca2+ channel. The productions of IFN-γ, IL-6, IL-17, IL-4, IL-10 and IL-2 was assayed by ELISA.
Results: Our results demonstrated the production of IL-2 was markedly enhanced, while the production of IL-4 and IL-10 was not significantly affected; by contrast, the production of IFN-γ, IL-6 and IL-17 were markedly reduced, in the highly viable stimulated spleen cells treated with BGP. These effects were also reproduced in the cells treated with artepillin C, a major component of BGP. The enhancement of IL-2 production by artepillin C was significantly alleviated by adding 10 HC030031, an antagonist of TRPA1 Ca2+ channel, suggesting the enhancement of the cytokine production by artepillin C could be mediated by Ca2+ influx.
Conclusions: The artepillin C, a major component of BGP, is an important regulator of activated T lymphocytes and specifically augmented the expression of IL-2 vie Ca2+-permeable cation channel, TRPA1. These effects may exert immunomodulatory effects upon tumor microenvironments.
Citation Format: Nobuo Kondoh, Masako Kamiya, Hanemi Tsuruta, Moe Takahashi, Kumiko Ikeno, Kyohei Ueno, Naoki Umemura, Eiji Takayama, Harumi Kawaki, Genjiro Nakamura, Toru Nikaido, Yasunori Muramatsu, Megumi Ando. Enhanced production of IL-2 from anti CD3-stimulated mouse spleen cells by artepillin C, a major component of Brazilian green propolis [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 5201.
Abstract 5204: Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity
Authors: Zhang Richard , Lin Haishan 
Published: June 2022

Abstract
CD47 is a well-studied target for cancer immunotherapy. Blocking of CD47 binding to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. Several monoclonal anti-CD47 antibodies are currently in various stages of clinical development. However, since CD47 is also expressed on normal cells such as red blood cells and platelets, anti-CD47 antibodies also caused on-target side effects during clinical evaluations, such as anemia and red blood cell hemagglutination. To minimize the on-target side effects of anti-CD47 antibodies, we have generated anti-CD47 prodrugs. By screening a phage peptide library, we identified peptides that can specifically block the anti-CD47 antibody binding activity. These peptides were fused to the humanized anti-CD47 antibody via a linker containing protease substrate sequences to derive the anti-CD47 antibody prodrug. We demonstrated that these anti-CD47 antibody prodrugs had significantly diminished CD47 binding activity and were unable to block CD47:SIRPα interaction. Upon cleavage of the anti-CD47 antibody prodrug with proteases, the antibody regained full activities in both binding to CD47 and blocking CD47:SIRPα interaction. Importantly, we showed that the anti-CD47 antibody prodrug had minimal hemagglutination and RBC binding activities. Since different tumors may have different types of protease activities, anti-CD47 prodrugs with different types of protease substrates have been generated to demonstrate that the anti-CD47 prodrug can be used for treating various tumor types. These data suggest that novel anti-CD47 antibody prodrugs are promising candidates for the next generation anti-CD47 therapeutics with improved safety profile.
Citation Format: Richard Zhang, Haishan Lin. Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity [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 5204.
Abstract 5253: SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC
Authors: Cai Jinlin , Fan Dandan , Chen Yaoxu , Huang Mengli 
Published: June 2022

Abstract
Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. SMO, a gene encodes Smoothened protein, which is an important signal converter in Sonic Hedgehog (SHH) signal pathway. Studies have shown that CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring SMO mutation, suggested that SMO may be related to immune microenvironment and tumor immunity, but the association between SMO mutation and TMB or survival in metastatic Colorectal Cancer(mCRC) is unknown.
Methods: Genomic and survival data of mCRC patients administrated with ICIs were retrieved from publicly accessible data (Pancancer.Samstein2018.NGS.1661) and the association between SMO mutation overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. The association between SMO mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 149 patients with Rectum Adenocarcinoma (READ) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and SMO mutation status was further analyzed by CIBERSORT. Statistical significance was set at p=0.05.
Results: 7.3% (8/109) patients in the clinical cohort harbored SMO mutation. Survival analysis in the public cohort demonstrated that SMO mutation resulted in significantly longer OS (10.5 vs 8 months; HR, 0; p=0.035) in mCRC patients treated with ICIs. Moreover, SMO mutation is associated with higher TMB in public cohort (p&lt;0.0001). Furthermore, the correlation analysis between immune infiltration and SMO mutation status in mCRC which was analysed in TCGA shows that M1 macrophages, CD8 T cells, Gamma Delta T cells increased significantly (p=0.048, p=0.043, p=0.002).
Conclusions: This study shows that SMO mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages, CD8 T cells, as well as the Gamma Delta T cells may be another potential mechanism for the better efficacy of ICIs in patients with SMO mutation.
Citation Format: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang. SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC [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 5253.
Abstract 5278: Cancer WHIRI research: Improving the early cancer pathway for indigenous NZ peoples
Authors: Scott Nina , Ruka Myra , Jones Amy R. 
Published: June 2022

Abstract
Background: Māori, Indigenous peoples of New Zealand (NZ) are twice as likely to die after a diagnosis of cancer compared to non-Māori. Cancer pathways are not designed for Māori health gain and are not pandemic resilient. Māori receive delayed poorer quality treatment and those with comorbidities are undertreated [1]. Existing inequities from time of referral to cancer services through to treatment were exacerbated by the COVID-19 response in Aotearoa NZ. Coordination of care is crucial for Māori patients and whānau (family), but poorly developed along this early part of the cancer pathway. In addition, care quality is not well monitored, and the current pathway is vulnerable to changes created by pandemic conditions.
Aims: This study seeks to co-design, implement and evaluate a holistic cultural and clinical cancer service that is patient and whānau centred; the Whānau Hauora Integrated Response Initiative (WHIRI) programme. This comprehensive, pandemic resilient, racism-free, hauora (wellbeing) enhancing and responsive model of care will be designed for the early part of the secondary care cancer pathway.
Design and Method: The WHIRI programme includes navigation, a holistic whānau/family hauora assessment tool, proactive management by a team of clinicians and a team responsible for making systems changes. WHIRI was launched mid-pandemic (early 2020) for kaumātua (elderly Māori) with long-term conditions and ran for 3 months. During COVID we found that WHIRI had the potential to change hospital systems and improve experiences for patients and whānau. WHIRI ensures the provision of best-practice timely treatment for Māori patients and could make large gains in closing the survival gap between Māori and non-Māori in the short- to medium-term, leading to reductions in Māori cancer deaths. We plan to redesign WHIRI into a cancer programme that functions effectively in all COVID levels using qualitative Kaupapa Māori methodology. Key to this methodology is partnerships with patients, whānau, cancer clinicians, Māori navigators and The Cancer Control Agency New Zealand. We will present our methods and co-design model of cancer care. We will outline the potential to expand the model nationally with reach from primary care all the way through to palliative care. It will also provide a platform for future research to measure the impact of WHIRI on cancer and whānau care. 1. Hill S, Sarfati D, Blakely T, Robson B, Purdie G, Chen J, et al. Survival disparities in Indigenous and non-Indigenous New Zealanders with colon cancer: the role of patient comorbidity, treatment and health service
Citation Format: Nina Scott, Myra Ruka, Amy R. Jones. Cancer WHIRI research: Improving the early cancer pathway for indigenous NZ peoples [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 5278.
Abstract 5286: RNase7-guided anti-ROS1 targeted therapy for hepatocellular carcinoma
Authors: Liu Chunxiao , Zha Zhengyu , Zhou Chenhao , Yu Dihua , Ren Ning , Hung Mien-Chien 
Published: June 2022

Abstract
Oncogenic activation of c-ros oncogene 1 (ROS1) kinase due to gene fusion by chromosomal rearrangements was found in multiple cancers. The anti-ROS1 fusion gene is a successful therapeutic target with a 72% objective response rate in ROS1-rearranged NSCLC patients. However, it has yet to be determined whether wild-type ROS1 plays a role in cancer development or could serve as a therapeutic target as its ligand was unknown. Our study unexpectedly identified that RNase7, a RNase superfamily protein, is specifically pulled down by ROS1 and acts as a ROS1 ligand. In HCC patient-derived xenograft and an orthotopic mouse model of HCC, we found that crizotinib, an FDA-approved ROS1 inhibitor, exhibits potent anti-tumor activity in the mice harboring RNase7-expressing tumors. In addition, clinical data analysis indicated that ROS1 and RNase7 co-expression occurs in about 30% of HCC patients and is highly correlated with poorer survival. The plasma level of RNase7 is positively correlated with phosphorylated ROS1 in HCC patients. Our current report provides a rationale to choose RNase7 as a potential plasma biomarker to stratify HCC patients for anti-ROS1 targeted therapy.
Citation Format: Chunxiao Liu, Zhengyu Zha, Chenhao Zhou, Dihua Yu, Ning Ren, Mien-Chien Hung. RNase7-guided anti-ROS1 targeted therapy for hepatocellular carcinoma [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 5286.