bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5336: Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients
Authors: Xu Qi , Li Jingjing , Tang Haimeng , Bao Hua , Yan Junrong , Wu Xue , Shao Yang , Jin Jianying , Luo Cong , Weng Haimin , Ying Jieer 
Published: June 2022

Abstract
Introduction: The effect of trastuzumab in targeted therapy for HER2-positive gastric cancer (GC) is limited by the eventual development of resistance within patients. Although numerous studies have been published on this topic, both the mechanism of innate and acquired trastuzumab resistance are still not fully understood. In this study, we compare the mutational landscape of paired solid tumor samples before and after treatment in an effort to identify acquired events associated with resistance.
Methods: We performed whole-exome sequencing on 46 tumor and 23 whole blood samples from patients with stage IV gastric cancer were obtained from before treatment (n = 23) and at disease progression (PD) (n = 23). HER2 status was checked using immunohistochemistry and validated with florescence in situ hybridization (FISH). Correlation analysis was then conducted between the mutational profile and clinical data of patients.
Results: Comparisons between innate resistance samples and acquired resistance samples at baseline revealed three copy number variation events (CDK12 amplification, ERBB2 amplification, MECOM amplification) that occurs in significantly different proportions (p &lt; 0.05). In addition, for baseline samples, MECOM was shown to be associated with poor progression-free survival (PFS) (Hazard Ratio (HR), 12; 95% CI, 1.6 - 85; p = 0.027). Commonly acquired events (i.e., lacking in before treatment samples and present at PD) within patients include TP53 mutation, MYC amplification, MCL1 amplification, CDKN2A/2B deletion, and CCNE1 amplification. Of these, patients with MCL1 gene amplification had worse survival (HR, 4.8; 95% CI, 1.2 - 20; p = 0.050) than patients with wild-type MCL1. In addition, the NOTCH pathway acquired mutations in 4 of 23 patients and was found to be correlated with a worse PFS (HR, 5.1; 95% CI, 1.4 - 19; p = 0.023), indicating that this pathway is possibly involved with trastuzumab resistance to some degree.
Conclusion: Overall, our results show that comparisons of samples obtained before treatment and at PD can give insight about innate and acquired resistance mechanisms to trastuzumab in stage IV, HER2-positive GC patients.
Citation Format: Qi Xu, Jingjing Li, Haimeng Tang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Jianying Jin, Cong Luo, Haimin Weng, Jieer Ying. Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients [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 5336.
Abstract 5363: The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor
Authors: Drilon Alexander , Zhong Jun , Lu Ying , Liu Yongbo , Wang Hao , Chen Minchun , Chen Xiaohu , Zhu John , Lu Shun , Subbiah Vivek 
Published: June 2022

Abstract
Backgroud: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. The gatekeeper RET V804 mutation cannot be inhibited by selected next-generation RET inhibitors in development. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations.
Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models.
Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 &lt;15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 &lt; 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models. At 10 mg/kg BID, tumor regression was observed in these xenograft models (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg BID showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors.
Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.
Citation Format: Alexander Drilon, Jun Zhong, Ying Lu, Yongbo Liu, Hao Wang, Minchun Chen, Xiaohu Chen, John Zhu, Shun Lu, Vivek Subbiah. The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor [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 5363.
Abstract 5387: Investigating the role of p53 in doxorubicin-mediated lysosome membrane permeabilization in breast cancer cells
Authors: Nicoletto Rachel , Ofner Clyde M. 
Published: June 2022

Abstract
Background: Doxorubicin (DOX) is a chemotherapeutic characterized by multiple mechanisms. Wild-type p53 (WTp53) may be activated in the presence of either DNA damage or ROS. Upon activation, WTp53 may upregulate the transcription of pro-apoptotic Bcl-2 family members capable of triggering mitochondrial membrane permeabilization or lysosome membrane permeabilization (LMP), ultimately resulting in apoptosis. We have previously reported of DOX-induced LMP between WTp53 and mutant p53 (MUTp53) breast cancer cells. The goals of this study were to establish (1) the role of p53 in the initiation of DOX-mediated LMP and (2) whether p53 is critical to the onset of cytotoxicity.
Methods: Studies were conducted using DOX at a range of concentrations and durations in both WTp53 (MCF-7 and MDA-MB-361) and MUTp53 (MDA-MB-231 and T47D) breast cancer cells. LMP was demonstrated using fluorescence microscopy as the cytosolic release of a 10 kDa AlexaFluor-488 Dextran conjugate that was preloaded into lysosomes. Viability was determined by MTT. Cytotoxicity was determined by trypan blue. Experiments were conducted in the presence of pifithrin-α p53 inhibitor to establish the importance of p53 towards DOX cytotoxicity.
Results: Significant LMP was determined as early as 0.5 h in both of the WTp53 cell lines at 10 μM. MDA-MB-361 cells demonstrated a greater degree of LMP with 1 μM DOX showing significant LMP by 2 h, an effect that was not observed in MCF-7 cells until 6 h. The earliest onset of notable LMP in MUTp53 MDA-MB-231 cells occurred at 6 h with 10 μM DOX only. T47D cells did not demonstrate notable LMP at this time. By 24 h, both WTp53 cell lines demonstrated LMP across all of the tested concentrations of DOX, while both MUTp53 cell lines only demonstrated notable LMP for 10 μM DOX. At this same time, notable reductions in cell viability for the tested range of concentrations were observed for all cell lines except for T47D cells. Overall, the inhibition of p53 reversed notable LMP in both MCF-7 and MDA-MB-361 cells across all of the tested conditions. Similarly, reduced viability was reversed following the inhibition of p53.
Conclusions: These results indicate a role of p53 in LMP in WTp53 cells. Furthermore, the combination of p53 and LMP seem necessary for the induction of cytotoxicity in WTp53 cells. Under circumstances of MUTp53 expression, cells promote a pro-oncogenic response with a lesser potential for LMP, MMP, and cytotoxicity.
Citation Format: Rachel Nicoletto, Clyde M. Ofner. Investigating the role of p53 in doxorubicin-mediated lysosome membrane permeabilization in breast cancer cells [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 5387.
Abstract 5397: Gene signatures for predicting patients with aggressive type of bladder cancer and shorter survivals
Authors: Sheu Jim Jinn-Chyuan , Lin Bo-Chen , Yang Oscar , Chang Chung 
Published: June 2022

Abstract
Bladder cancer is frequently associated with high recurrence and metastasis. With the success of cancer genome project in bladder cancer, we aimed to discover novel cancer drivers in muscle-invasive bladder cancer (MIBC), the most aggressive type of bladder cancer. A total of 155 genes were filtered out using RNAseq data from the TCGA cohort (n = 367), which are overexpressed (Z scores &gt; 2.0) in more than 5% patients and correlated with poor overall survivals by Cox regression (p-value &lt; 0.05) and FDR correction (q-value &lt; 0.05). Using a unique HD-MAC (high-dimensional analysis of molecular alterations in cancer) algorithm developed by our team, 25 genes were further selected which show statistical significances as independent prognosis biomarkers for shorter overall survivals. Through clinical association study (including tumor stage, lymph node invasion, angiogenesis, and metastasis) by using CGDSR (Cancer Genomics Data Server in R), five most significant genes were further filtered which can be validated by another cohort (GSE13507). Although those genes show no direct gene-gene interactions, gene set enrichment analysis (GSEA) revealed common pathways governed by those driver genes, including cancer-related signaling, glycome alterations for TME remodeling, regulation in cell death, glutamate & neuronal signaling, and ER-Golgi transportation. The above findings can be also confirmed at the protein levels by IHC staining. In this study, how those key genes assist cell survival under nutrition crisis and their impacts on aggressive behaviors of bladder cancer will be discussed.
Citation Format: Jim Jinn-Chyuan Sheu, Bo-Chen Lin, Oscar Yang, Chung Chang. Gene signatures for predicting patients with aggressive type of bladder cancer and shorter survivals [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 5397.
Abstract 5404: Identification prognostic markers for patients with defective mismatch repair in colorectal cancer: MKI67, TPR,TCHH
Authors: Liu Zheng , Lv Jingfang , Zhao Hongmei , Wang Xishan , Wang Dongliang 
Published: June 2022

Abstract
Background: Deficiency in the mismatch repair system (dMMR/MSI-H) is found in approximately 15-20% of colorectal cancer. However, the prognostic evaluation of patients with dMMR CRC in stage II/III is still incomplete and lacks systematic studies.
Methods: In this study, we systematically analyzed the prognostic risk of 32 patients with dMMR CRC in stage II/III based on whole-exome sequencing and clinical characters. Differentially mutated genes (DMGs) were explored by fisher-test. For survival analysis, Kaplan-Meier survival curves were generated and compared using the log-rank test. Univariate and multivariate Cox regression analyses were performed to evaluate association DMGs with progression-free survival (PFS). Furthermore, these genes were verified in TCGA Pan Can Atlas 2018 cohort.
Results: The patients with dMMR CRC in stage II/III have the highest levels of MKI67, TCHH and TPR mutations (53.4%). Across all 73 patients with MSI-H, the mutational frequencies of MKI67, TCHH and TPR were (30%, 24% and 15%, respectively), which were associated with PFS (P=0.029, P=0.00261 and P=0.00298, respectively). That means the patients with MKI67, TCHH and TPR mutations have poor prognosis. Furthermore, MKI67, TCHH and TPR mutations were verified as independent factors for dMMR/MSI-H colorectal cancer both in training cohort and validation cohort.
Conclusions: MKI67, TCHH and TPR were potential prognostic markers for dMMR colorectal cancer. Based on these data and rationale, we suggest that mutations in all exons of these 3 genes should be integrated into predictive biomarker panels for patients with dMMR/MSI-H, aiming to provide more accurate guidance for the selection of personalized diagnosis.
Keywords: MKI67, TPR, TCHH, Defective Mismatch Repair, Colorectal Cancer, Prognostic Markers
Citation Format: Zheng Liu, Jingfang Lv, Hongmei Zhao, Xishan Wang, Dongliang Wang. Identification prognostic markers for patients with defective mismatch repair in colorectal cancer: MKI67, TPR,TCHH [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 5404.
Abstract 5443: BPI-421286: A highly potent small molecule inhibitor targeting KRASG12C mutation
Authors: Zhu Xiaoguan , Lu Yuan , Guo Jing , Yan Dan , Li Boyan , Chen Xiaoping , Chen Haibo , Lan Hong , Wu Hao , Ding Lieming , Wang Jiabing 
Published: June 2022

Abstract
KRAS is a GTP-binding protein that links receptor tyrosine kinase activation to intracellular signaling. Mutation of KRAS favors the GTP-bound active state and constitutive activation of downstream effects. KRASG12C mutation has been identified as an oncogenic driver of tumorigenesis, which is found in approximately 14% of lung cancer, 4% of colorectal (CRC), and 1-3% of other solid tumors. Herein, we report BPI-421286, a highly potent and selective covalent small molecular KRASG12C inhibitor. In vitro, BPI-421286 showed a high Kinact/Ki value (256,000 M-1 s-1), and inhibited KRAS-GTP/GDP exchange with a lower IC50 (55 nM). In cell-based assays, BPI-421286 suppressed proliferation of KRASG12C mutant cell lines with sub-nanomolar potency, but did not affect cell lines with wide type or non-G12C KRAS mutations. BPI-421286 also inhibited phospho-ERK in MIA PaCa-2 cell with a low IC50 value (2.9 nM). In vivo, daily oral administration of 3-100 mg/kg BPI-421286 led to tumor growth suppression or regression in multiple KRASG12C mutant xenograft or PDX models of NSCLC, CRC and PDAC. The in vivo PKPD in MIA PaCa-2 xenograft model showed that durable pERK inhibition can be achieved without continuous drug exposure, featuring BPI-421286 as a covalent, non-reversible KRAS inhibitor. Combining BPI-421286 with several targeted agents, including a SHP2 inhibitor BPI-442096 and a CDK4/6 inhibitor BPI-16350, demonstrated enhanced tumor growth inhibition compared to either agent alone. Notably, for the acquired resistance mutations that are clinically observed after KRASG12C inhibitor treatment, such as G12C/H95D, G12C/H95Q, G12C/R68S and G12C/Y96C, BPI-421286 also exhibited strong inhibitory activities, suggesting that BPI-421286 could overcome the acquired resistance of currently approved KRASG12C inhibitors. Taken together, BPI-421286 is a highly potent and selective KRASG12C inhibitor, with favorable ADME properties and wide therapeutic index in pre-clinical toxicology studies. BPI-421286 is currently in Phase 1 clinical study.
Citation Format: Xiaoguan Zhu, Yuan Lu, Jing Guo, Dan Yan, Boyan Li, Xiaoping Chen, Haibo Chen, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-421286: A highly potent small molecule inhibitor targeting KRASG12C mutation [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 5443.
Abstract 5468: A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate cancer
Authors: Kim Sora Q. , Utturkar Sagar , Atallah Nadia M. , Kim Kee-Hong 
Published: June 2022

Abstract
Prostate cancer (PCa) growth is mediated by androgens via activation of androgen receptor (AR). Accordingly, androgen deprivation therapy (ADT) is the gold standard for the treatment of advanced PCa, but progression to castration-resistant PCa (CRPC) follows. Enzalutamide (ENZ) is an AR antagonist used for the management of CRPC. However, patients acquire resistance to the drug in a short period. Meanwhile, cholesterol is a precursor to androgen and its metabolism is dysregulated in PCa. In addition, cholesteryl ester (CE) accumulation aggravates tumor growth but its association with ENZ treatment has not been studied. Thus, we hypothesized that inhibition of CE formation by blockage of sterol-O-acyltransferase 1 (SOAT1) could enhance the response to ENZ. We found that SOAT1 mRNA is upregulated in clinical prostate tumors compared to normal/benign tissues in TCGA dataset. SOAT1 mRNA level was also highly correlated with AR expression in SU2CF/PCF cohorts and TCGA dataset, suggesting critical role of the cholesterol metabolism in prostate tumor progression and potential association to AR signaling pathway. We treated 22RV1 prostate cancer cells with ENZ in the presence or absence of SOAT1 inhibitor, avasimibe, and found the combination treatment effectively reduced the level of CEs compared to control, which accompanied inhibition of colony formation and cell proliferation. Combination index value was calculated and the relationship between the two drugs showed synergism. Furthermore, genetic knockdown of SOAT1 sensitized cells to ENZ treatment and also reduced the number of colonies formed. In TCGA dataset, patients who had previously undergone ADT were analyzed, and their Kaplan-Meier survival curve showed low SOAT1 expressing patients had a significantly longer progression-free survival rate than their counterpart, indicating that SOAT1 could act as a prognostic biomarker predicting PCa treatment outcome. Gene set enrichment analysis of patients with ADT history showed androgen response gen sets were enriched in high SOAT1 expressing PCa patient group. Inhibition of SOAT1 and the combination treatment did not change AR and ARV7 protein level, but downstream genes such as PSA were down regulated upon the combination treatment. In summary, our in vitro results showed blockage of SOAT1 enzyme sensitized PCa cells to ENZ treatment and analysis of PCa patient data suggested that SOAT1 gene expression has potential as a prognostic marker.
Citation Format: Sora Q. Kim, Sagar Utturkar, Nadia M. Atallah, Kee-Hong Kim. A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate 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 5468.
Abstract 5487: An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer
Authors: Chen Xiaotong , Liu Fangcen , Yu Xiaoxiao , Li Lin , Yan Jiayao , Liu Baorui 
Published: June 2022

Abstract
Gastric cancer is a worldwide health problem. Concurrent chemoradiotherapy (CRT) represents an important strategy to reduce recurrence and prolong survival for gastric cancer. However, non-targeted cytotoxic drugs capable of enhancing radiosensitization remain the main choice to be combined with radiotherapy, which has limited the anti-tumor efficacy of CRT by off-target side effects. Monomethyl auristatin E (MMAE) is a highly potent anti-tubulin agent and has been reported to act as an effective radiosensitizer recently. Kita-Kyushu lung cancer antigen 1 (KK-LC-1) is a cancer/testis antigen highly and exclusively expressed in multiple types of cancers including gastric cancer, representing a promising target for drug delivery. Previously, we identified a KKLC-1-targeting cyclic nonapeptide (1131 peptide) by screening a phage display peptide library. Here, we described a novel peptide-drug conjugate (PDC) 1131-MMAE by connecting the 1131 peptide with MMAE via a protease-sensitive linker for tumor-selective radiosensitization. We demonstrated that 1131-MMAE could be efficiently internalized by gastric cancer cells through KKLC1-mediating endocytosis and exhibited a comparable cytotoxicity profile with free MMAE. 1131-MMAE could arrest the cell cycle at the most radiosensitive G2/M phase in a dose-dependent manner and selectively enhance the radiation response of KK-LC-1 positive gastric cancer cells by increasing DNA double-strand break as indicated by γH2Ax immunofluorescence staining. Furthermore,1131-MMAE was able to inhibit tumor growth as a monotherapy at 2mg/kg with a good safety profile in vivo. Increased tumor control was achieved when 1131-MMAE was combined with radiotherapy at a relatively low dose of 0.3mg/kg. Overall, we proposed an MMAE-based PDC targeting a novel tumor marker KK-LC-1 and demonstrated its tumor-selective radiosensitization in gastric cancer models for the first time. This anti-KKLC1 PDC may help to promote the clinical progress in precision chemoradiotherapy for multiple types of cancer.
Citation Format: Xiaotong Chen, Fangcen Liu, Xiaoxiao Yu, Lin Li, Jiayao Yan, Baorui Liu. An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric 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 5487.