bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4899: Inhibition of murine tumor growth by decitabine is correlated with enhanced expression of the mouse mammary tumor virus
Authors: Zhang Jieyu , Higgins Savannah , Smith Riley , Reginald Tania , Qi Andrew , Li Jiayi , King Anna , Liu Yingguang 
Published: April 2023

Abstract
The purpose of this study is to clarify the mechanisms of the antineoplastic effect of decitabine (DAC), a DNA methyltransferase inhibitor. We previously reported that DAC inhibited the proliferation of the 4T1 mammary cancer cell line in vitro while inhibiting MMTV env and pol expression in the same cells. Here we present findings in vivo using two murine tumor models. We inoculated 4T1 cells into BALB/c mice from which the cell line was derived. In addition, we inoculated the murine colon carcinoma cell line, MC38, into C57BL/6 mice, the mouse strain of its origin. We treated the mice with DAC when tumors became palpable. DAC inhibited tumor growth in both tumor models and inhibited metastasis of 4T1 cells into the lungs. Quantitative PCR detected elevated expression of MMTV genes in the tumor tissues of DAC-treated mice in both models. The levels of MMTV env RNA in tumor tissues were negatively correlated with tumor mass in both models, so were the levels of the MMTV Env protein in 4T1 tumors. DAC also significantly mitigated tumor-induced splenomegaly. Hepatotoxicity of DAC was observed in C57BL/6 mice. Our data suggest the possibility that decitabine inhibits tumor growth in vivo and in vitro via different mechanisms. The findings also support the current understanding of decitabine upregulating endogenous retroviruses (ERVs) which subsequently activate an interferon response. The negative correlation between tumor mass and MMTV Env protein expression suggests a possible role of ERV proteins serving as tumor-associated antigens and decitabine enhancing adaptive immunity against cancer by stimulating ERV expression on tumor cells. Further studies of the interaction between decitabine and MMTV using immunodeficient mice may help us understand the possible involvement of adaptive immunity in the pharmacodynamics of decitabine as well as the role of ERVs in tumor development.
Citation Format: Jieyu Zhang, Savannah Higgins, Riley Smith, Tania Reginald, Andrew Qi, Jiayi Li, Anna King, Yingguang Liu. Inhibition of murine tumor growth by decitabine is correlated with enhanced expression of the mouse mammary tumor virus. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4899.
Abstract 4918: Natural compounds ursolic acid and digoxin exhibit anti-cancer effects through nuclear receptor RORγ-dependent and -independent mechanisms
Authors: Zou Hongye , Yang Yatian , Cai Demin , Chen Hong-Wu 
Published: April 2023

Abstract
Natural compounds such as ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have also been at several clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) in tumor cells severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target in castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC). Previous studies implicated UA and digoxin as potential RORγ antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA down-regulates RORγ-stimulated AR expression and AR signaling, whereas digoxin up-regulates AR signaling pathway. UA also showed potent anti-growth effects in AR-positive prostate cancer cells compared to AR-negative prostate cancer cells. In TNBC cells, UA but not digoxin alters RORγ-regulated cell proliferation and apoptosis gene programs. Together, our study shows for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in prostate cancer and TNBC cells. Our finding that RORγ is a direct target of UA in specific type of cancer will help select patients with tumors that likely respond to UA treatment.
Citation Format: Hongye Zou, Yatian Yang, Demin Cai, Hong-Wu Chen. Natural compounds ursolic acid and digoxin exhibit anti-cancer effects through nuclear receptor RORγ-dependent and -independent mechanisms. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4918.
Abstract 4983: Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a targetable vulnerability
Authors: Sugarman Adam J. , Huynh Luong Do , Cristofano Antonio Di 
Published: April 2023

Abstract
Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we have analyzed gene expression profiles from a genetically engineered ATC mouse model and from two human patient datasets, and have found consistent and coordinated upregulation of several genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate nucleotides, glutathione and glycine. We have used a combination of cell line and in vivo approaches to assess the role of this pathway in the progression and maintenance of ATC and the effect of its inhibition on tumor behavior. Genetic and pharmacological inhibition of both MTHFD2 and SHMT2, key enzymes of the mitochondrial arm of the one-carbon pathway, rendered mouse and human ATC cells auxotroph for glycine and led to significant inhibition of tumor cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool leading to arrest in S phase. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic blockage of the one-carbon pathway dramatically impaired tumor growth in vivo, both in immunocompetent allograft models and in immunocompromised xenograft models of ATC. Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes.
Citation Format: Adam J. Sugarman, Luong Do Huynh, Antonio Di Cristofano. Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a targetable vulnerability. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4983.
Abstract 4995: Targeting PLK1 effectively suppresses growth of small cell lung cancer
Authors: Schmitz John C. , Zhang Guojing , Ivanov Andrey A. , Pannucci Abbe , Ridinger Maya , Owonikoko Taofeek K. 
Published: April 2023

Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid disease progression and poor patient survival. Key transcription factors implicated as drivers of unique biological phenotypes of SCLC include ASCL1, NEUROD1, YAP1, and POU2F3. Strategies to exploit these phenotypes for innovative precision medicine approaches will be impactful. Using an unbiased agnostic preclinical drug screen to uncover therapeutic opportunities in SCLC, we identified a strong signal with PLK1 inhibitors (PLK1i) with low nanomolar IC50. We extended the in vitro findings by testing the efficacy of PLK1i in vivo using traditional xenograft of SCLC H526 cell line and patient derived xenografts (PDX). Volasertib achieved significant tumor growth inhibition relative to control in H526 xenografts. Also, onvansertib significantly inhibited growth of platinum-resistant and platinum-sensitive PDXs. The combination of PLK1i with standard chemotherapeutic agents identified promising synergy of the combination of onvansertib and paclitaxel. We further interrogated for predictive biomarkers of PLK1i sensitivity using gene expression profile comparing highly sensitive to less sensitive cell lines. High expression of C-MYC but not PLK1, TP53 or RB was associated with resistance to PLK1i. Conversely, while TP53 expression level did not correlate, TP53 gene mutation status (inactivating disruptive mutations) correlated with cell sensitivity to PLK1i. We queried the publicly available CCLE and the Cancer Therapeutics Response Portal to evaluate whether any of the SCLC subtypes have therapeutic vulnerability to PLK1i. In general, high expression of YAP1 in SCLC cell lines correlated with greater sensitivity to PLK1i. A YAP1 positive cell line, SW1271, with strong TP53 expression was particularly resistant to PLK1i. CRISPR knockout of YAP1 in this cell line enhanced SW1271 sensitivity to PLK1i suggesting that YAP1 expression as a marker of vulnerability to PLK1i could be context dependent especially when co-occurring with TP53 mutations. The mechanism of this interaction will be discussed.
Citation Format: John C. Schmitz, Guojing Zhang, Andrey A. Ivanov, Abbe Pannucci, Maya Ridinger, Taofeek K. Owonikoko. Targeting PLK1 effectively suppresses growth of small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4995.
Abstract 5006: Discovery of novel heterobifunctional degraders of mutant EGFR proteins for NSCLCs harboring various EGFR mutations
Authors: Ki Dong Hyuk , Joo Min Sung , Nam Joonwoo , Choi Hunmi , Seo Kyoungwan , Kim Eun-Jung , Kim Jiyeon , Kim Chulwon , Jin Jimmy Taiguang , Han Wooseok 
Published: April 2023

Abstract
Abnormal expression and activation of Epidermal Growth Factor Receptor (EGFR) contribute to malignancy development, especially in non-small cell lung cancers (NSCLCs). Although the first- to third-generation EGFR small molecule inhibitors have made significant progress in the treatment of EGFR mutant NSCLC patients, acquired mutations have been developed rapidly, resulting in drug resistance. Targeted protein degradation (TPD) technologies including PROteolysis Targeting Chimeras (PROTACs) have recently emerged as a promising alternative modality to address the confronting issues of small molecule inhibitors such as drug resistance. Recently, we have developed a series of heterobifunctional degraders of EGFR mutant proteins, which showed strong degradation ability against a variety of mutant EGFRs including triple mutants with C797S. DC50 (half-maximal degradation concentrations) values of the degraders were obtained using HiBiT assay in NCI-H1975 (EGFR L858R/T790M), HCC827 (EGFR Del19), and H1299 (EGFR WT) cells. Our lead compounds demonstrated excellent EGFR degradation potency with high selectivity against EGFR wild type. Moreover, C-09045, C-09066, and C-13951 strongly inhibited the cell growth of Ba/F3 cells harboring one of the EGFR mutations including L858R/C797S, Del19/C797S, L858R/T790M/C797S, Del19/T790M/C797S, and Exon20 NPH insertion. By contrast, these compounds showed much weaker potency in normal lung fibroblast (HFL-1) and Ba/F3 cells harboring EGFR wild-type. In PK analysis, C-09066 showed good oral bioavailability in mice (F%=41.4) with desirable pharmacokinetic parameters and robust tumor growth inhibition efficacy in the NCI-H1975 EGFR L858R/T790M/C797S xenograft and the Ba/F3 Del19/C797S allograft mouse models. In summary, we have identified selective, potent, and orally bioavailable degraders of various EGFR mutant proteins with broad spectrum anti-tumor efficacy both in vitro and in vivo.
Citation Format: Dong Hyuk Ki, Min Sung Joo, Joonwoo Nam, Hunmi Choi, Kyoungwan Seo, Eun-Jung Kim, Jiyeon Kim, Chulwon Kim, Jimmy Taiguang Jin, Wooseok Han. Discovery of novel heterobifunctional degraders of mutant EGFR proteins for NSCLCs harboring various EGFR mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5006.
Abstract 5051: Assessment of boron delivery peptides with angiopep-2 for boron neutron capture therapy
Authors: Liu Qi , Xiang Jing , Ma Lin , Ren Qiushi 
Published: April 2023

Abstract
Boron neutron capture therapy (BNCT) induces intracellular nuclear reactions that release heavy charged particles to destroy cancer cells during thermal neutron radiation. In order to selectively eliminate cancer cells but avoid harmful effects to normal tissues, targeted delivery of boron-10 in cancer cells is required, whereas the conventional boron delivery agent phenylalanine (BPA) is unsatisfactory. Angiopep-2 is a cell-penetrating peptide that can trigger transcytosis and traverse the blood-brain barrier by recognizing low density lipoprotein-related protein 1. In this study, we developed angiopep-2 for boron delivery in BNCT. Angiopep-2 was labeled with boron-10 using solid-phase peptide synthesis with 4-carboxyphenylboronic acid and fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids, namely ANG-B. Molecular mass of the synthesized ANG-B were validated by mass spectrometry. In a cell proliferation assay, little toxicity of ANG-B was detected. Boron concentrations in 6 cell lines from different cancer types and an intracranial glioblastoma mouse model after treatment with ANG-B or BPA were analyzed by ICP-AES. The in vivo distribution of ANG-B showed that the ratio of boron content of tumor tissue to that of blood (T/B ratio) was 9.42±2.47 at 4h post treatment, while the ratio of boron content of tumor tissue to that of normal brain tissue (T/N ratio) was 5.61±1.0, demonstrated an optimal tumor targeting ability of ANG-B. We further measured the effects of ANG-B in BNCT by clonogenic cell survival assay in vitro or by PET/CT imaging on a glioblastoma mouse model in vivo. Radiation for BNCT was given with neutron flux at 3.0±0.4 × 1011 n/cm2. BNCT with 5 mM ANG-B resulted in 86.5%±5.3% clonogenic cell death, while the number was 72.9%±5.1% for BPA. The effect of ANG-B based BNCT in vivo was also better than BPA. The glioblastoma tumors in ANG-B treated group at 31 days after BNCT were shrank by 62.9% in average, while the BPA treated tumors shrank by only 23.0% (P&lt;0.05). Therefore, we concluded that ANG-B is an efficient boron delivery agent, which may improve BNCT performance in clinical trials.
Citation Format: Qi Liu, Jing Xiang, Lin Ma, Qiushi Ren. Assessment of boron delivery peptides with angiopep-2 for boron neutron capture therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5051.
Abstract 5059: High-throughput monitoring of proteoforms and pathways through multiplexed and customizable mass spectrometry assay panels
Authors: Müller Sebastian , Laforte Véronique , Savickas Simonas , Müller Maik , Feng Yuehan , Reiter Lukas 
Published: April 2023

Abstract
Proteins represent a key class of analytes in pharmacodynamic (PD) analysis, an essential component in preclinical and clinical studies which inform about a biological system’s response to drug treatment. Pharmacodynamic signatures typically comprise target engagement marker and downstream pathway markers. With recent development in targeted therapies and novel therapeutic modalities such as protein degraders, the scope of PD has widened to cover predictive and stratification biomarkers which can inform patient selection and contribute to further understanding of potential drug resistance.
Using peptides as surrogate for proteins of interest, mass spectrometry (MS)-based approach alleviates the barriers of reagent specificity of antibody-based methods which can be affected by species and matrices used in preclinical drug development. Moreover, the use of stable-isotope labeled standard (SIS) reference peptides grants targeted MS assays unraveled specificity and the ability to determine absolute quantity of a given analyte.
Harnessing the power of targeted MS, we present an oncology-focused assay repository which contains 804 peptides corresponding to 582 proteins. All 804 peptide surrogates were chosen under strict selection criteria such as uniqueness/proteotypicity and stability. Off-the-shelf availability (PQ500 kit) of SIS reference peptides for all 582 proteins facilitates the deployment of any of these assays in a plug-and-play manner. The collection of 582 protein targets cover &gt; 180 cellular pathways (Reactome pathways e.g. cytokine signaling, cell-cell communication, activation of matrix metalloproteinases) together with 49 FDA-approved drug targets. To further evaluate the performance of these assays, we carried out a case control study comprising plasma samples from 5 patient groups (lung, colorectal, pancreatic, breast and prostate cancer) and age and gender-matched healthy subjects. In total, we measured absolute quantities of 582 proteins across 180 plasma samples while validating the expression profiles of well-characterized biomarkers in patient plasma.
To conclude, we’ve demonstrated the application of targeted MS approach for the routine analysis of pharmacodynamic biomarkers. Its multiplexing capability, together with the adaptability to various species allow this method to maneuver through preclinical and clinical scenarios.
Citation Format: Sebastian Müller, Véronique Laforte, Simonas Savickas, Maik Müller, Yuehan Feng, Lukas Reiter. High-throughput monitoring of proteoforms and pathways through multiplexed and customizable mass spectrometry assay panels. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5059.
Abstract 5230: Comprehensive genetic analysis using clinical specimens of gastric adenocarcinoma and proximal polyposis of stomach
Authors: Matsumoto Chihiro , Iwatsuki Masaaki , Mimori Koshi , Baba Hideo 
Published: April 2023

Abstract
Background and Purpose: Gastric adenocarcinoma and proximal polyposis (GAPPS) is an autosomal dominant genetic disorder that causes gastric carcinoma from fundus gland polyposis. Although germline mutation of APC promoter 1B was reported as a pathogenic variant in 2016, there are still many unknowns about the carcinogenesis. In this study, we performed a comprehensive Next generation sequencing (NGS) analysis of GAPPS clinical specimens to investigate the molecular profile characteristic of carcinogenesis.
Patients and Methods: Seven cases from three GAPPS families experienced in our department were included in this study. In each case, tissues were collected from normal mucosa, polyps, and carcinoma,
and FFPE and fresh-frozen samples were prepared. After pathological diagnosis was performed on each sample, RNA and DNA were extracted and analyzed based on data obtained by next generation sequence (NGS).
Results: In the RNA sequence, gene expression analysis was performed on 45 pathologically diagnosed samples, which were classified into four clusters by K-means clustering. Gene Set Enrichment Analysis (GSEA) of the four clusters showed that cancer-related genes such as p53 and KRAS were significantly enriched in the cluster of cancer, and genes related to immune response were significantly enriched in the cluster of cancer compared to the and clusters of polyp and normal. Gene mutation analysis using whole-exome sequence (read depth/coverage&gt;20) confirmed mutation of APC promoter 1B in all samples. On the other hand, in tumor samples (N=10), the percentage of mutation of genes previously suggested to be associated with GAPPS (TP53, FBXW7, GNAS, and KRAS) were 50%, 0%, 30%, and 60%, respectively.
Conclusion: Comprehensive gene expression analysis by RNA sequence and whole-exome sequence was performed using clinical samples of GAPPS. In the future, we plan to identify specific gene-pathways involved in carcinogenesis.
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Citation Format: Chihiro Matsumoto, Masaaki Iwatsuki, Koshi Mimori, Hideo Baba. Comprehensive genetic analysis using clinical specimens of gastric adenocarcinoma and proximal polyposis of stomach. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5230.
Abstract 5320: The RenMice™ HiTS (Hyperimmune target specific) Platform facilitates identification of novel therapeutic antibodies for challenging targets
Authors: Zhang Xiaoqian , Fu Shufang , Zhang Shujin , Ji Xin , Hui Li , Jin James , Zhang Jing 
Published: April 2023

Abstract
In recent years, an increasing number of therapeutic antibodies have shown to be effective for the treatment of cancer and other diseases. However, limitations in the traditional discovery process, including immune tolerance of highly homologous genes, challenges with antibody sequence humanization, clone selection, and model selection for drug efficacy and safety evaluation, often hinder the process of identifying new therapeutic antibodies. The RenMice™ HiTS (Hyperimmune Target Specific) Platform is a library of chromosome engineered mice with fully human immunoglobulin variable domains replacing the mouse loci, each with a specific drug target gene knocked out. These mice are designed to establish robust immune responses and generate antibodies that bind to more epitopes of the target protein, including conserved domains. The platform is ideal for challenging targets, such as proteins with high homology across species, or multi-pass transmembrane proteins (e.g. GPCRs/ion channels). Here, we show that the platform can be used to generate antibodies that cross-react with multiple species, like human, monkey, dog, and mouse targets, by immunizing with both human and mouse or dog antigen. We provide examples for newer campaigns, including species cross-reactivity and internalization of novel antibodies targeting NECTIN-4, and high-throughput in vivo efficacy screening of novel anti-PD-1 antibodies in wild-type mice. In the future, we will evaluate the preliminary toxicity of these cross-reactive antibodies in preclinical animal models. Thus, selection of the best antibody candidate based on in vivo efficacy and safety allows for a streamlined and successful preclinical phase. In conclusion, the RenMice™ HiTS platform facilitates the generation of developable antibodies that recognize novel epitopes and challenging targets.
Citation Format: Xiaoqian Zhang, Shufang Fu, Shujin Zhang, Xin Ji, Li Hui, James Jin, Jing Zhang. The RenMice™ HiTS (Hyperimmune target specific) Platform facilitates identification of novel therapeutic antibodies for challenging targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5320.