bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1593: Synergistic effect of SH003 and Docetaxel by targeting a metabolic pathway in non-small cell lung cancer cells
Authors: Choi Yu-Jeong , Lee Kangwook , Kang Sooyeon , Lee Seo Yeon , Hwang Hyun-Ha , Ko Seong-Gyu 
Published: April 2023

Abstract
The identification of molecular biomarkers that can predict the response of cancer treatment facilitates more clear targeted therapy by lowering the side effect. Therefore, the present study investigated the key regulatory genes that determine the efficacy of SH003, a herbal medicine, combined with docetaxel (DTX) in non-small cell lung cancer cells. We identified that the combination treatment inhibited the process of the de novo biosynthesis of pyrimidine nucleotide via the reduction of the related enzyme expressions, resulting in DNA damage and apoptosis. However, we found that NSCLC cells have different sensitivities to combination treatment. As a result, the difference in sensitivity was determined by the p53 gene expression pattern of lung cancer cells, indicating that the treatment response of combination enhances by activating p53 in p53 wild-type lung cancer. Lung cancer cells harboring p53 mutations were resistant to the metabolic inhibition by the combination, whereas this effect was restored when p53 is expressed normally. In conclusion, this study revealed the genetic characteristics of cancer cells that are susceptible to treatment response when SH003 and DTX are combined, suggesting that p53 will be an important predictor of combination treatment.
Citation Format: Yu-Jeong Choi, Kangwook Lee, Sooyeon Kang, Seo Yeon Lee, Hyun-Ha Hwang, Seong-Gyu Ko. Synergistic effect of SH003 and Docetaxel by targeting a metabolic pathway in non-small cell lung cancer cells [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 1593.
Abstract 1600: Phase I trial of intravenous mistletoe extract in advanced cancer
Authors: Paller Channing J. , Wang Lin , Fu Wei , Kumar Rajedra , Durham Jennifer , Azad Nilofer , Laheru Daniel , Browner Ilene , Kachhap Sushant , Boyapati Kavya , Odeny Thomas , Armstrong Deborah , Meyer Christian , Gaillard Stephanie , Brahmer Julie , Page Ivelisse , Wang Hao , Diaz Luis A. 
Published: April 2023

Abstract
Purpose: Mistletoe extract is widely used in cancer patients to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration.
Patients and Methods: This phase I trial of intravenous Mistletoe (Helixor M) aimed to determine the recommended phase 2 dosing and to evaluate safety. Solid tumor patients progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL.
Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The maximum tolerated dose was 600mg. Treatment-related adverse events (AEs) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in three patients (14.8%). Stable disease was observed in five patients who had 1-6 prior therapies. Reductions in baseline target lesions were observed in three patients who had 2-6 prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by FACT-G increased from 79.7 at week 1 to 93 at week 4.
Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted.
Citation Format: Channing J. Paller, Lin Wang, Wei Fu, Rajedra Kumar, Jennifer Durham, Nilofer Azad, Daniel Laheru, Ilene Browner, Sushant Kachhap, Kavya Boyapati, Thomas Odeny, Deborah Armstrong, Christian Meyer, Stephanie Gaillard, Julie Brahmer, Ivelisse Page, Hao Wang, Luis A. Diaz. Phase I trial of intravenous mistletoe extract in advanced 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 1600.
Abstract 1619: Generation of a novel estrogen receptor degrader
Authors: Liu Yuan , Kennerdell Jason R. , Lin Bo , Larsen Mads B. , Alfaras Irene , Camarco Daniel P. , Tuncer Ferhan , Finkel Toren , Chen Bill B. 
Published: April 2023

Abstract
Fulvestrant is an effective therapy to treat post-menopausal women with estrogen receptor (ER)-positive metastatic breast cancer. The compound works as a selective estrogen receptor degrader (SERD). Structurally similar to estrogen, fulvestrant binds to the ligand binding domain (LBD) of the ER, altering the stability of the protein, leading to its accelerated proteasomal degradation. While effective, fulvestrant must be given intramuscularly, which has limited its clinical adoption. Based on the success of fulvestrant, multiple attempts have been made to generate orally available SERDs. These attempts have focused on compounds that, like fulvestrant, bind within the LBD of the ER. Overall, these intensive efforts have generated limited success. We reasoned that it may be possible to identify potential SERDs that bind to the ER in regions outside the LBD. Such an approach would be useful for tumors bearing wildtype ER, and likely for those bearing a mutant form of the ER, since most mutations cluster in the LBD. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bind outside of the LBD, and in particular to the N-terminal region of the ER. This strategy identified CL-ER-100, a small molecule that directly bound to the N-terminal region of the ER and functioned as a SERD. While CL-ER-100 rapidly induced ER proteasomal-dependent degradation, it had no effect on the protein levels of other, structurally related nuclear receptors. Based on its structure and size (~ MW 300 Da), CL-ER-100 is expected to have excellent bioavailability. Consistent with its binding outside of the LBD, addition of tamoxifen had no effect on the ability of CL-ER-100 to induce ER protein degradation. In cells, CL-ER-100 was able to markedly inhibit the growth of breast cancer cell lines such as MCF7 and T47D (IC50 of ~ 100 nM) while not inhibiting the growth of a wide array of normal and non-breast cancer tumor cell lines. Taken together, these results identify a novel strategy to develop small molecule SERDs that induce ER protein degradation by binding to previously untargeted regions of the estrogen receptor.
Citation Format: Yuan Liu, Jason R. Kennerdell, Bo Lin, Mads B. Larsen, Irene Alfaras, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Generation of a novel estrogen receptor degrader [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 1619.
Abstract 1620: Identification of a molecular degrader targeting the AR-V7 splice variant
Authors: Liu Yuan , Lin Bo , Larsen Mads B. , Alfaras Irene , Kennerdell Jason R. , Camarco Daniel P. , Tuncer Ferhan , Finkel Toren , Chen Bill B. 
Published: April 2023

Abstract
Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bound to AR-V7. One such molecule, CL-AR-100, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. This compound did not affect the expression of other structurally related ligand-activated nuclear receptors. In prostate cancer cell lines expressing AR-FL, CL-AR-100 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, CL-AR-200 inhibited the growth of 22RV1 cells (IC50=0.3uM), a cell line that predominantly expresses AR-V7. In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth. These results thereby identify a small molecule molecular degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer.
Citation Format: Yuan Liu, Bo Lin, Mads B. Larsen, Irene Alfaras, Jason R. Kennerdell, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a molecular degrader targeting the AR-V7 splice variant [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 1620.
Abstract 1645: JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division
Authors: Yang Guiqun , Wang Yanping , Li Haijun , Chen Mingming , Lin Yiwei , Sun Xin 
Published: April 2023

Abstract
Background: Aurora kinase A (AURKA), a crucial mitotic regulator, is frequently dysregulated in a wide range of cancers and contributes to clinical aggressiveness and poor patient survival. Abnormally activated AURKA promotes tumorigenesis through enhancing cancer cell proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal, rendering it an attractive therapeutic target. We have developed JAB-2485, a highly selective small-molecule AURKA inhibitor.
Methods: Biochemical and cell-based assays were performed to determine the IC50 of JAB-2485 on Aurora kinase family members. Fluorescence activated cell sorting (FACS) and caspase 3/7 assay were performed to detect JAB-2485-induced cell cycle arrest and apoptosis, respectively. The CellTiter-Glo assay was performed to evaluate the effect of JAB-2485 in multiple cancer cell lines. Finally, the antitumor effect of JAB-2485 either as a single agent or in combinations was investigated in tumor cell line-derived xenografts.
Results: JAB-2485 is potent and highly selective on AURKA, with IC50 of 0.33nM and around 1700-fold selectivity over AURKB. Following treatment of JAB-2485, the level of AURKA phosphorylation as a pharmacodynamic marker was significantly decreased in a dose-dependent manner. As a single agent, JAB-2485 inhibited in vitro proliferation of small cell lung cancer (SCLC), triple-negative breast cancer (TNBC) and neuroblastoma cell lines along with induced G2/M cell cycle arrest and apoptosis, and significantly inhibited in vivo tumor growth on SCLC and neuroblastoma xenografts. Furthermore, JAB-2485 showed strong synergy with cisplatin and paclitaxel in SCLC and TNBC animal models, respectively.
Conclusions: Taken together, preclinical results provide robust evidence supporting further evaluation of JAB-2485 both as a single agent and in combinations for treatment of various types of cancers. A Phase 1/2a clinical trial of evaluating JAB-2485 in adult patients with advanced solid tumors is enrolling patients in the US (NCT05490472).
Citation Format: Guiqun Yang, Yanping Wang, Haijun Li, Mingming Chen, Yiwei Lin, Xin Sun. JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division [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 1645.
Abstract 1677: ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development
Authors: Wang Guoqian , Tang Yao , Lv Tingduo , Ning Jinying , Hao Feng 
Published: April 2023

Abstract
Introduction: KRAS mutations occur in nearly 30% of human cancers, the most frequent ones being G12C, G12D and G12V. The approval of AMG510 in 2021 broke the curse of KRAS’s non-druggability. AMG510 targets the KRAS-G12C mutation and achieves up to 90% disease control rate, but drug resistance quickly develops. KRAS-G12D, the most prevalent and oncogenic KRAS mutation, still lacks inhibitors. MRTX-1133, the first reported highly selective KRAS-G12D inhibitor, is currently in the preclinical phase. Similarly, drug resistance will inevitably develop to KRAS-G12D inhibitors.
Methods: To explore the resistance mechanisms of KRAS-G12D mutation, our group used ASPC-1 cell line, which naturally expresses KRAS-G12D, to generate the ASPC-1-MRTX-1133R cell line using a dose-escalation method after treating cells with a mutagenic agent. Specifically, ASPC-1 cells were treated by MRTX-1133 with increasing dosage for 4 weeks, the remaining live cells were harvested and designated as ASPC-1-MRTX-1133R. Cell survival assay showed that IC50 of ASPC-1-MRTX-1133R is &gt;2000nM, 100-fold more resistant than the parental ASPC-1 cell line (22nM). We identified the potential resistance mechanisms using whole exome sequencing (WES) and RNA-Seq. The resistance to MRTX-1133 of ASPC-1-MRTX-1133R cell line was highly stable after 20 cell passages.
Conclusion: The ASPC-1-MRTX-1133R cell line can be a useful in vitro model in the development of KRAS-G12D inhibitors.
Citation Format: Guoqian Wang, Yao Tang, Tingduo Lv, Jinying Ning, Feng Hao. ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development [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 1677.
Abstract 1684: Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis
Authors: Kwon Mi Jeong , Chae Ha Yeong , Lee So Young , Kang Shin Ung , Jung Tae Woong , Cho Soo Youn , Han Jinil , Jeong Hyojin , Sung Chang Ohk , Shin Young Kee 
Published: April 2023

Abstract
Resistance to platinum-based chemotherapy is one of major causes of therapy failure and tumor recurrence in ovarian cancer patients. However, the molecular mechanism of platinum resistance is not fully understood. Here, we compared gene expression between cisplatin-sensitive and -resistant ovarian cancer cells using gene expression microarray analysis and found the significantly up-regulated expression of SERPINE1 encoding plasminogen activator inhibitor-1 (PAI-1), a serine protease regulating the fibrinolysis and extracelluar matrix, in cisplatin-resistant ovarian cancer cells. The correlation of high PAI-1 expression with low cisplatin sensitivity was confirmed in ovarian cancer cells. PAI-1 overexpression in ovarian cancer cells significantly decreased the sensitivity to cisplatin, whereas PAI-1 down-regulation by SERPINE1 siRNA or PAI-1 inhibitor increased cisplatin sensitivity. PAI-1 inhibited cisplatin-induced apoptosis in ovarian cancer cells by suppressing reactive oxygen species (ROS) production and DNA damage. PAI-1 also decreased cisplatin-induced ferroptosis through the upregulation of GPX4 levels. Furthermore, Kaplan-Meier survival analysis using TGGA data demonstrated that high PAI-1 expression was significantly associated with shorter platinum-free survival of patients with ovarian cancer. Collectively, these results illustrate that PAI-1 promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis, suggesting that targeting PAI-1 increases the sensitivity to cisplatin in ovarian cancer.
Citation Format: Mi Jeong Kwon, Ha Yeong Chae, So Young Lee, Shin Ung Kang, Tae Woong Jung, Soo Youn Cho, Jinil Han, Hyojin Jeong, Chang Ohk Sung, Young Kee Shin. Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis [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 1684.
Abstract 1740: CCR5/CCL5 axis inhibition reverses cisplatin-chemoresistance phenotye in gastric cancer cells
Authors: Brebi Priscilla , Reyes Maria Elena , Ili Carmen Gloria , Mora Yuselin , Buchegger Kurt , Riquelme Ismael , Zanella Louise , Lobos-Gonzalez Lorena , Burdiles Camila , Mora-lagos Barbara 
Published: April 2023

Abstract
Gastric cancer (GC) is an important public health problem worldwide. Advanced GC treatment is mainly based in chemotherapy with Cisplatin (CDDP). Unfortunately, the high recurrence rate of GC is predominantly attributable to chemoresistance. The CCR5/CCL5 axis, that participates in inflammatory process, has been associated with the development and progression of cancer. However, its role in GC chemoresistance has not been fully elucidated. The objective of this work was to elucidate the role of CCR5/CCL5 axis on GC chemoresistance cells. AGS R-CDDP was established through a method based on stepwise increasing drug doses and characterized by functional assays. RNA-Sequencing (RNA-seq) was performed on Illumina HiSeq 4000. A fold change &gt;2 and P&lt;0.05 were used as cut-off to choose the differentially expressed genes (DEGs). Gene Ontology (GO) and signaling pathways analysis were analyzed by PANTHER. CCL5 candidate gene was validated by qRT-PCR. Signaling pathways such as STAT3, MAPK and PI3K, associated with cytokines, proliferation and survival were evaluated by western blot assays. Cell viability of CCR5/CCL5 axis inhibition was evaluated in AGS R-CDDP exposed to Chemokine receptor antagonist (CRA) alone and in combination with CDDP. Characterization studies have effectively demonstrated that AGS R-CDDP is a reliable CDDP-resistant model. Bioinformatics analyses identified a total of 189 DEGs associated mainly to molecular functions (GO) involved in CDDP-resistance. The most enriched signaling pathway was the inflammation mediated by chemokine and cytokine which could be involved in the development of CDDP resistance in GC. CCL5 was upregulated in AGS R-CDDP cells. The main signaling pathways associated with CCR5/CCL5 axis were not activated in resistant GC cells compared parental GC cells.The cytotoxicity assays showed that CRA/CDDP combination re-sensitized AGS R-CDDP cells, decreasing cell viability. Our results indicate that CCR5/CCL5 axis induce chemoresistance and CRA/CDDP combination sensitize AGS R-CDDP cells revealing its potential as coadjuvant in GC therapy.
Citation Format: Priscilla Brebi, Maria Elena Reyes, Carmen Gloria Ili, Yuselin Mora, Kurt Buchegger, Ismael Riquelme, Louise Zanella, Lorena Lobos-Gonzalez, Camila Burdiles, Barbara Mora-lagos. CCR5/CCL5 axis inhibition reverses cisplatin-chemoresistance phenotye in gastric cancer cells [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 1740.
Abstract 1755: ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal
Authors: Loh Jia Jian , Wong Tin Lok , Lu Shixun , Yan Helen HN , Siu Hoi Cheong , Xi Ren , Chan Dessy , Kam Max JF , Zhou Lei , Tong Man , Copland John A. , Chen Leilei , Yun Jingping , Leung Suet Yi , Ma Stephanie 
Published: April 2023

Abstract
Targetable drivers governing to 5-fluorouracil and cisplatin (5FU+CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Accordingly, we established 5FU+CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 was demonstrated to confer chemoresistance and self-renewal in an RNA editing-dependent manner. WES-seq coupled with RNA-seq identified enrichment of hyperedited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increased binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogated chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveiled a novel actionable target to circumvent chemoresistance.
Citation Format: Jia Jian Loh, Tin Lok Wong, Shixun Lu, Helen HN Yan, Hoi Cheong Siu, Ren Xi, Dessy Chan, Max JF Kam, Lei Zhou, Man Tong, John A. Copland, Leilei Chen, Jingping Yun, Suet Yi Leung, Stephanie Ma. ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal [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 1755.