bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT189: A phase I study of BAT1006, a novel anti-HER2 antibody, in patients with locally advanced/metastatic solid tumors
Authors: Mei Xingxing , Tang Weijia , Song Shuqiang , Wang Hao , Cao Chuanqi , Feng Cuiying , Thomas Bert E. , Li Shengfeng , Yu Jin-Chen 
Published: April 2023

Abstract
Purpose: BAT1006 is a HER2 extracellular domain II-targeted monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect aiming for Her2-positive locally advanced/metastatic solid tumors. Previous studies have shown that de-fucosylated antibody binds to FcγRIIIa with increased affinity and can thus trigger FcγRIIIa-mediated effector functions more efficiently than native antibody. BAT1006 was expressed in an FUT8-knockout CHO cell line, resulting in antibody completely devoid of fucose modification. With approximate 5-fold higher level of ADCC effect compared to Pertuzumab, BAT1006 also exhibited potent anti-tumor activity in HER2 positive Calu-3 xenograft mice model. The ongoing phase I, open-label, first-in-human study is evaluating the safety, pharmacokinetics (PK), immunogenicity and preliminary efficacy of BAT1006 to determine the Maximum-Tolerated Dose (MTD) and/or recommended phase II dose (RP2D).
Methods: Patients with locally advanced/metastatic solid tumors received escalating doses of BAT1006 (3, 6, 10, 15 mg/kg), administered intravenously (IV) once every three weeks. Patients must have had documented HER2 positivity defined as 3+ by validated immunohistochemistry or amplified on in situ hybridization (ISH). Assessments include archival tumor molecular status, PK, and efficacy by Response Evaluation Criteria in Solid Tumors (RECIST).
Results: Fifteen patients [with 2-9 prior lines of therapy] have been treated with BAT1006. All patients had metastatic breast cancer and had received previous HER2-targeted therapies including Trastuzumab, Pertuzumab, T-DM1 and Pyrotinib. No treatment related ≥ Grade 3 AEs have been observed. Of 9 patients at 10mg/kg and 15mg/kg, 1 in 3 patients had CR at 10mg/kg, 2 in 6 patients had PR at 15mg/kg.
Conclusion: BAT1006 was well tolerated and showed promising anti-tumor activity in patients with heavily pre-treated HER2-positive cancers. Based on the safety and efficacy results, one additional dose level (20 mg/kg) will be added to the escalation phase and combination therapy with other HER2-based therapy will also be initiated.
Citation Format: Xingxing Mei, Weijia Tang, Shuqiang Song, Hao Wang, Chuanqi Cao, Cuiying Feng, Bert E. Thomas, Shengfeng Li, Jin-Chen Yu. A phase I study of BAT1006, a novel anti-HER2 antibody, in patients with locally advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT189.
Abstract CT232: Safety, efficacy, and tolerability of FHND9041 capsules as first-line treatment in patients with EGFR sensitive mutations or second/third-line treatment in patients with T790M+ advanced non-small cell lung cancer (NSCLC): results from a phase I/II single-arm, multi-center, open-label study
Authors: Zhu Yongqiang , Shang Minghong , Wang Jia , Yang Nong , Dong Xiaorong 
Published: April 2023

Abstract
Background: FHND9041 is a third-generation EGFR inhibitor independently developed by Nanjing Chuangte Pharmaceutical Technology Co., Ltd. It irreversibly binds to EGFR protein, and demonstrates strong inhibitory effect on EGFR T790M mutations as well as EGFR sensitive mutations. This is the first single-arm, multi-center, open-label phase I/II study of FHND9041 capsule, which evaluates the safety, tolerability and preliminary efficacy of FHND9041 capsule in initial treatment of NSCLC with EGFR sensitive mutations or treatment of T790M+ advanced NSCLC who progressed after prior EGFR-TKI therapy.
Methods: 124 subjects tested for EGFR mutations and eligible for evaluation were randomized to dose groups of 40 mg, 80 mg (first-line treatment or second/third-line treatment with T790M+), 120 mg and 180 mg. The primary endpoint is objective response rate (ORR), and key secondary endpoints are progression-free survival (PFS), disease control rate, duration of response, and safety.
Results: The ORR of FHND9041 capsule 80 mg (recommended phase 2 dose, RP2D) is 71.43% in patients newly diagnosed of NSCLC with EGFR sensitive mutations, and 63.64% in patients with T790M+ NSCLC who had progressed after prior EGFR-TKI therapy. No DLT occurred in all dose groups, 40 mg, 80 mg and 120 mg, which demonstrated satisfactory tolerability and safety of FHND9041. Detailed efficacy data of each dose group is shown in the table below.
Conclusion: FHND9041 capsule 80 mg shows significant antitumor activity with favorable efficacy and safety profile in patients for both initial treatment and treatment of T790M+ NSCLC who progressed after prior therapy. For futher research of the capsule, a multicenter, randomized, positive-controlled phase III clinical research is ongoing with recommended dose of 80 mg.
Group Dosage(mg) Evaluable Subjects(n) ORR% Second/Third-line T790M+ 40mg 3 33.33 80mg 39 63.64 120mg 42 58.33 180mg 3 100.00 First-line 80mg 37 71.43
Citation Format: Yongqiang Zhu, Minghong Shang, Jia Wang, Nong Yang, Xiaorong Dong. Safety, efficacy, and tolerability of FHND9041 capsules as first-line treatment in patients with EGFR sensitive mutations or second/third-line treatment in patients with T790M+ advanced non-small cell lung cancer (NSCLC): results from a phase I/II single-arm, multi-center, open-label study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT232.
Abstract LB004: Ultra-sensitive targeted DNA panel for very low-frequency mutation detection in circulating cell-free DNA
Authors: Baird Michelle , Ashraf Mariam , Chistensen Emil , Haldrup Christa , Wu Zhong , Lader Eric 
Published: April 2023

Abstract
Due to its noninvasive nature and being readily available in peripheral blood and other bodily fluids, analysis of cell-free DNA (cfDNA) has become a promising application in cancer diagnosis, prognosis and treatment monitoring. However, disease-relevant cfDNA is present in a very limited amount in the huge background of normal cfDNA. This remains a challenge for any detection technology. Many currently available target enrichment and library preparation methods use regular DNA polymerase and amplification processes that introduce substantial bias and artifacts. This results in artifactual errors that greatly limit the detection of true low-frequency variants below 0.5% in heterogeneous samples, such as cfDNA. Here, we present a new targeted cfDNA workflow that overcomes challenges such as biases and artifacts. The workflow uses a highly optimized, high-fidelity reaction chemistry and incorporates UMIs into a single gene-specific, primer-based targeted enrichment process. Compared to regular DNA polymerase, this high-fidelity chemistry resulted in a five- to ten-fold decrease in base substitution error. An individual cancer panel was designed to specifically cover cancer-relevant hotspots and copy number genes with a dense primer design to accommodate the short length of cfDNA. Due to its high-fidelity chemistry and optimal panel design, our streamlined workflow can be completed in a single day. We also report consistent panel performance across different samples. Detection sensitivity and specificity were evaluated on a reference cfDNA sample and a simulated cfDNA sample by mixing enzyme-digested Genome in a Bottle samples, NA12878 and NA24385. We achieved close to 90% detection sensitivity and above 99.9% specificity for 0.1% variant. In addition, copy number variation could be successfully detected with a 1.5-fold difference over normal control samples. These results demonstrate an efficient targeted cfDNA panel workflow that enables cancer-relevant mutation detection with high sensitivity and accuracy. The applications presented here are for research use only. Not for use in diagnostic procedures.
Citation Format: Michelle Baird, Mariam Ashraf, Emil Chistensen, Christa Haldrup, Zhong Wu, Eric Lader. Ultra-sensitive targeted DNA panel for very low-frequency mutation detection in circulating cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB004.
Abstract LB005: Insights of renal cell carcinoma from multiomic perspective
Authors: Bartha Aron , Darula Zsuzsanna , Munkacsy Gyongyi , Klement Eva , Fenyo David , Nyirady Peter , Gyorffy Balazs 
Published: April 2023

Abstract
Introduction: Clear cell renal carcinoma is the most frequent form of renal malignancy, with an increasing incidence rate worldwide. In this study we used a multi-omic approach to differentiate normal and tumor tissues in clear cell Renal Cell Carcinoma (ccRCC).
Methods: Using transcriptomic data of patients with malignant and adjacent normal tissue samples from gene chip and RNA-Seq cohorts, we identified the top genes over-expressed in ccRCC. We collected surgically resected ccRCC specimens to further investigate the transcriptomic results on the proteome level. The differential protein abundance was evaluated using targeted mass spectrometry (MS).
Results: We assembled a database of more than 600 renal tissue samples from NCBI GEO and TCGA and used these to uncover the top genes with higher expression in ccRCC. For protein level analysis 162 malignant and normal kidney tissue samples have been acquired. The most consistently upregulated genes were IGFBP3, PLIN2, PLOD2, PFKP, VEGFA, and CCND1 (p&lt;1E-05 for each gene). Mass spectrometry further validated the differential protein abundance of these genes (IGFBP3, p = 7.53E-18; PLIN2, p = 3.9E-39; PLOD2, p = 6.51E-36; PFKP, p = 1.01E-47; VEGFA, p = 1.40E-22; CCND1, p= 1.04E-24). We also identified proteins correlating with overall survival.
Conclusions: We used transcriptomic and proteomic data to identify a minimal panel of proteins highly specific for clear cell renal carcinoma tissues. The introduced gene panel could be used as a promising tool in the clinical setting.
Citation Format: Aron Bartha, Zsuzsanna Darula, Gyongyi Munkacsy, Eva Klement, David Fenyo, Peter Nyirady, Balazs Gyorffy. Insights of renal cell carcinoma from multiomic perspective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB005.
Abstract LB010: LY6K depletion modulates TGF-β and EGF signaling
Authors: Yang Young , Park Sujeong 
Published: April 2023

Abstract
Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol-anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) signaling through clathrin- and caveolin-1 (CAV-1)-mediated endocytosis. LY6K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression-free survival, and disease-free survival. LY6K-depletion in HeLa and SiHa cancer cells suppressed EGF-induced proliferation and TGF-β-enhanced migration and invasion. Both TGF-β receptor-I (TβRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TβRI irrespective of the presence of TGF-β; however, LY6K did not bind EGFR. LY6K-depleted cells showed impaired SMAD2 phosphorylation upon TGF-β treatment and lower proliferation rates following long-term treatment with EGF. We revealed the atypical movement of TβRI and EGFR from plasma membrane upon ligand stimulation in LY6K-depleted cells and an impaired movement of the endocytic proteins clathrin and CAV-1. Subsequently, transmission electron microscopy showed no clathrin and CAV-1-coated vesicles in LY6K-depleted cells. Our study demonstrates the key role of LY6K in both clathrin- and CAV-1-mediated endocytic pathways regulated by TGF-β and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival.
Citation Format: Young Yang, Sujeong Park. LY6K depletion modulates TGF-β and EGF signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB010.
Abstract LB029: AWT030: a first-in-class bi-functional IL-21 fusion protein selectively activates tumor infiltrated CD8 T cells and suppresses Treg cells
Authors: Ye Fan , Huang Jianing , Chen Sandra , Li Ella , Jiang Jenny , Lin Hanna , Hua Michael , Huang Danny , Huang Zoey , Kwan Joyce , Cheng Lili , Zhong Ziyang 
Published: April 2023

Abstract
The tumor microenvironment (TME) has been identified as a significant obstacle to the success of immunotherapy, including anti-PD-1 therapy. The TME comprises several factors that limit the response rate to immunotherapy, including immunosuppressive cells such as regulatory T cells (Tregs), which directly or indirectly interact with effector cells and undermine the tumor recognition, activation, proliferation, and survival of the effector cells, thereby promoting tumor growth. To overcome suppressive TME, we designed AWT030, a first-in-class bi-functional IL-21 fusion protein that comprises a stability and potency optimized IL-21 mutein and an engineered functional domain that targets T cells. AWT030 is designed to selectively activate tumor-infiltrating CD8 T cells and suppress Tregs while avoiding the potential suppressive effect of IL-21 on dendritic cells.Compared to wild-type IL-21, mAWT030 greatly enhances the tolerability, half-life, and anti-tumor activity. In anti-PD-1 therapy resistant breast cancer EMT6 model, fibrosarcoma MCA205 model, and anti-PD-1 therapy responsive colon cancer MC38 model, mAWT030 achieved 100% complete response without noticeable toxicity, demonstrating a powerful synergy between tumor specific CD8 T cell activation axis and Treg suppression axis induced simultaneously by mAWT030. In addition, mAWT030 also exhibited a strong synergistic effect with anti-PD-1 antibody. Immunophenotyping revealed that AWT030 had minimal impact on circulating lymphocytes while altering the suppressive TME, with a significantly increased CD8 T cell population and suppressed Treg population. In summary, AWT030 is a novel bi-functional IL-21 fusion protein with high tumoral specificity, the excellent safety and antitumor activity of mAWT030 observed preclinically supports clinical development, focusing on treating PD-1 resistant/relapsed patients or combining with anti-PD-1 therapy.
Citation Format: Fan Ye, Jianing Huang, Sandra Chen, Ella Li, Jenny Jiang, Hanna Lin, Michael Hua, Danny Huang, Zoey Huang, Joyce Kwan, Lili Cheng, Ziyang Zhong. AWT030: a first-in-class bi-functional IL-21 fusion protein selectively activates tumor infiltrated CD8 T cells and suppresses Treg cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB029.
Abstract LB036: IRF8 regulates tumor cell sensitivity to intrinsic ferroptosis by repressing p53
Authors: Poschel Dakota , Kehinde-Ige Mercy , Klement John , Yang Dafeng , Merting Alyssa , Savage Natasha , Shi Huidong , Liu Kebin 
Published: April 2023

Abstract
Tumor cell resistance to ferroptosis, which is a recently discovered CTL induced cell death pathway, remains incompletely understood. We report here that interferon regulatory factor 8 (IRF8) functions as a regulator of tumor cell intrinsic ferroptosis. Genome-wide gene expression profiling identified ferroptosis pathway as an IRF8-regulated pathway in tumor cells. IRF8.KO tumor cells are resistant to intrinsic ferroptosis induction and also exhibit decreased ferroptosis in response to tumor specific CTL killing. Loss of IRF8 increases p53 express in tumor cells and knocking out Tp53 in IRF8.KO cells restored tumor cell sensitivity to intrinsic ferroptosis induction. We were able to show that treating tumor-bearing mice with IRF8-encoding plasmid NTC9385R-mIRF8 encapsulated in a DOTAP-cholesterol lipid nanoparticle significantly reduced tumor growth and increased the percentage of dead cells in the tumor. Our data therefore determine that IRF8 represses p53 expression to maintain tumor cell sensitivity to intrinsic ferroptosis.
Citation Format: Dakota Poschel, Mercy Kehinde-Ige, John Klement, Dafeng Yang, Alyssa Merting, Natasha Savage, Huidong Shi, Kebin Liu. IRF8 regulates tumor cell sensitivity to intrinsic ferroptosis by repressing p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB036.
Abstract LB039: Ovarian cancer cell-derived exosomal UCA1 reprograms glucose metabolism in stromal fibroblasts
Authors: Nadhan Revathy , Ha Ji Hee , Jayaraman Muralidharan , Kashyap Srishti , Dhanasekaran Danny N. 
Published: April 2023

Abstract
Tumor progression is stringently regulated by the co-ordinated signaling between the tumor cells and the tumor microenvironment (TME) through diverse autocrine, paracrine and exocrine signaling mechanisms. Recent studies have shown that the exosomes that play a crucial role in the transfer of oncogenic macromolecules and oncometabolites to different cellular components of the TME can be targeted for therapy. Therefore, with the focus on identifying the exosomal long non-coding RNA (lncRNA) that can be therapeutically targeted, we investigated the profile of ovarian cancer cell derived lncRNAs and their functional role in ovarian cancer pathophysiology. Analysis of exosomes derived from a panel of high grade serous ovarian cancer cell lines indicated that UCA1 (Urothelial Cancer Associated 1) is the most abundantly packaged lncRNA in the exosomes. Similarly, exosomes from patient-derived ovarian cancer cells exhibited higher levels of UCA1. Ascites from ovarian cancer patients also indicated high levels of UCA1 in the ascites-derived exosomes. Results using PKH67-labelled ovarian cancer cell-derived exosomes and MRC5 fibroblast cell line indicated the exosomal transfer of UCA1 to the fibroblasts. Since paracrine signaling has been shown to induce metabolic reprogramming of peritumoral fibroblasts, we interrogated whether exosomal transfer of UCA1 could reprogram the glucose metabolism in the fibroblasts. Results from the Agilent Seahorse glycolytic stress assay indicate that the exosomal UCA1 promotes reprogramming of glucose metabolism in fibroblast cells while depleting of UCA1 in the exosomes failed to induce such metabolic reprogramming. Results from the analysis of the key glycolytic enzymes in the stromal fibroblasts, post-exosomal UCA1 uptake also corroborate this conclusion. Thus our results provide primary evidence that the exosomal-UCA1 induces pro-tumorigenic metabolic reprogramming in peri-tumoral fibroblasts. Together with the known oncogenic role of UCA1 in many different cancer cells, our findings indicate that targeting UCA1 could form a productive precision cancer strategy in ovarian cancer, targeting both the tumor cells and tumor stromal cells. This research was supported by the Department of Defense Ovarian Cancer Research Program Award W81XWH-18-1-0066, W81XWH-22-1-0415, the National Institute of General Medical Sciences grant P20 GM103639 and The National Cancer Institute of the National Institutes of Health grant P30 CA225520.
Citation Format: Revathy Nadhan, Ji Hee Ha, Muralidharan Jayaraman, Srishti Kashyap, Danny N. Dhanasekaran. Ovarian cancer cell-derived exosomal UCA1 reprograms glucose metabolism in stromal fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB039.
Abstract LB040: P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype
Authors: Thoms Hazel , Stark Lesley 
Published: April 2023

Abstract
Advanced age is one of the most significant risk factors for malignancy. One mechanism proposed for age-associated cancer risk is the accumulation of senescent cells in ageing tissue. These cells secrete a cocktail of pro-tumorigenic factors known as the senescence associated secretory phenotype (SASP). The SASP is driven by the NF-κB transcription factor. However, the initial triggers of NF-κB in senescence remain unclear. Here we describe a novel mechanism that triggers NF-κB and the SASP. Using multiple in vitro and in vivo models, we demonstrate accumulation and cytoplasmic to nuclear translocation of the PolI complex component, TIF-IA, upon senescence induction. siRNA knockdown revealed TIF-IA is not required for the cell cycle effects of senescence but is essential for transcription of SASP factors, nucleolar enlargement (a characteristic of senescence and marker of organismal ageing) and full senescence. We make the novel observation that in steady state, TIF-IA is targeted for autophagosomal degradation by the cargo receptor, p62, which is inhibited in senescence and promoted by inactivation of the DNA repair protein, ATM. Based on these data, we propose a model whereby the P62-TIF-IA interaction is lost downstream of DNA damage and ATM activation, which causes TIF-IA accumulation, the SASP and senescence. Using tissue from the well characterized nfkb1− / − mouse model of aging, and old and young mice, we show that TIF-IA accumulates in colonic mucosa with age, which is further enhance by nfkb1 deletion. These exciting new data identify a new role for TIF-IA and have considerable relevance to age-related cancer.
Citation Format: Hazel Thoms, Lesley Stark. P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB040.