bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1085: PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models
Authors: Zhao Baiteng , Wang Lei , Liu Haidong , Huang Suping , Shang Xiao , Han Tae 
Published: June 2022

Abstract
PRO1184 is an antibody-drug conjugate (ADC) directed toward folate receptor alpha (FOLR1), a glycosyl phosphatidylinositol anchored membrane protein. FOLR1 is overexpressed in many cancers with unmet medical need, including ovarian, lung, and breast cancers, while normal tissue expression is limited. PRO1184 is comprised of a 1) human monoclonal antibody that selectively binds to FOLR1, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. Upon binding to FOLR1 on the surface of malignant cells, PRO1184 is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. The mechanism of action and clinical potential of PRO1184 was tested in a series of studies. PRO1184 bound selectively and specifically to FOLR1 with nM affinity. PRO1184 was efficiently internalized and demonstrated cytotoxicity against multiple cell lines, in vitro. In mouse carcinoma models, PRO1184 demonstrated robust anti-tumor activity across multiple tumor types that represent ovarian, non-small cell lung, and breast cancer. In addition, PRO1184 was more potent with greater tumor growth inhibition than that of a DM4-conjugated ADC. PRO1184 was tolerated at the 60 mg/kg dose level in cynomolgus monkeys and the safety profile was generally more favorable than that for a DXd-based ADC. The pharmacokinetics (PK) of PRO1184 were similar to that of the unconjugated parent antibody in rats. PRO1184 has the potential for a meaningful therapeutic window to provide an appropriate benefit to risk profile for patients with FOLR1-expressing cancers.
Citation Format: Baiteng Zhao, Lei Wang, Haidong Liu, Suping Huang, Xiao Shang, Tae Han. PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models [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 1085.
Abstract 1090: Repurposing an overactive bladder drug to treat chemoresistant lung cancer
Authors: Bassett Joslyn , Bland Tyler 
Published: June 2022

Abstract
Background: Non-small cell lung cancer (NSCLC) is one of the most common types of cancer diagnosis among men and women leads the most cancer-related deaths in the United States. This is largely due to treatment failure which arises from therapy-resistant tumors. The current study investigates the role of muscarinic acetylcholine receptor 3 (CHRM3) in the development and treatment of NSCLC chemotherapy-resistance and the potential of the overactive bladder CHRM3 antagonist darifenacin to treat this lethal form of cancer.
Methods: Human NSCLC cell cultures were used to harvest protein for Western blot analyses of protein expression and activity of intracellular pathways. The chemotherapy drug docetaxel’s (DTX) ability to induce apoptosis was measured with crystal violet survival assay and colony formation assay.
Results: CHRM3 expression was measured in chemonaive NSCLC cells (A549) and chemoresistant cells (A549R), which showed increased expression in A549R cells. Chemoresistant A549R were pretreated with the CHRM3 antagonist darifenacin (Dari, 10 μM, 24 hrs) before treatment with DTX (48 hrs). Crystal violet survival assay and colony formation assays showed a significant reduction in cell survival in the Dari + DTX combination treatment group suggesting that CHRM3 signaling is necessary in a chemoresistant state. Chemonaive A549 cells and CHRM3 overexpressing A549 cells (A549 M3OE) were pretreated with carbachol (10 µM, 24 hrs) to activate CHRM3 before treatment with a set of serial dilutions of DTX (48 hrs). Crystal violet survival assay results showed that carbachol was not able to protect either cell line from DTX-induced cell death, suggesting that CHRM3 signaling alone is not sufficient to induce a chemoresistant state.
Conclusion: CHRM3 overexpression is observed in chemoresistant forms of NSCLC. While activation of CHRM3 does not instill a resistant state in chemonaive cells, its signaling is essential for maintenance of the chemoresistant state. The repurposing of the CHRM3 antagonist darifenacin shows strong potential as a therapeutic to treat lethal chemoresistant forms of NSCLC.The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant #P20GM103408
Citation Format: Joslyn Bassett, Tyler Bland. Repurposing an overactive bladder drug to treat chemoresistant lung 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 1090.
Abstract 1098: Structure-activity relationship of pentacyclic triterpenes against chemoresistance and metastasis on non-small lung adenocarcinoma cells
Authors: Delgado Yamixa , Perez Daraishka , Torres Grace 
Published: June 2022

Abstract
Lung cancer is the second most common and leading cause of cancer-related death worldwide, 85% of these cases being non-small cell lung carcinoma (NSCLC). Although chemotherapy is the first-line treatment for lung cancer, its effectiveness is hampered by the dose-limiting toxic effects, chemoresistance, and metastatic process. Recently, plant-derived cyclic triterpenoids (eg, cholesterol-structure like compounds) have shown a wide spectrum of pharmacological activities, especially their potential against different cancer cells. Herein, we investigated the structure-activity relationship of several pentacyclic triterpenes: oleanolic acid (OleA), ursolic acid (UrA), betulinic acid (BeA), Asiatic acid (AsA), betulin (BeN), lupeol (Lupe), diosgenin (Dio), stigmasterol (Stg) and β-sitosterol (β-Sito) on NSCLC A549 cells. From our studies, the IC50 for OleA, UrA, BeA, AsA, BeN, Lupe, Dio were in the low µM range (from 10-75 µM) after 24h of incubation. β-Sito and Stg did not show any significant cytotoxic pattern in this µM range. In addition, BeA showed the highest cytotoxic pattern in these cells. We performed metabolic activity assays to determine the mechanism of action of these triterpenes. Mitochondrial membrane and caspases activity assays showed that all the cytotoxic triterpenes induced activation of caspase-3 and decline in the mitochondrial potential, except BeA and AsA. Our results also show that all the cytotoxic triterpenes disrupt cell membrane, except for OleA. However, there is no reactive oxygen species production for all of them. Gene expression assays of chemoresistance- and metastasis-related genes (EGFR, VEGF, MMP9, Pgp, TP53, NDRG1, CHD4) using qPCR demonstrated the downregulation of all of these genes after the incubation with the cytotoxic triterpenes. These results demonstrated that even slight structural changes in these triterpenes could influence the cytotoxic and metabolic pathways responses. This study opens promising perspectives for further research on the role of phytochemical triterpenes, which ultimately will contribute to a more rational application in lung cancer therapy.
Citation Format: Yamixa Delgado, Daraishka Perez, Grace Torres. Structure-activity relationship of pentacyclic triterpenes against chemoresistance and metastasis on non-small lung adenocarcinoma 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 1098.
Abstract 112: Epac signaling facilitates malignant transformation of melanocytes
Authors: Singh Mithalesh Kumar , Altameemi Sarah , Lares Marcos , Sadangi Shreyans , Setaluri Vijayasaradhi 
Published: June 2022

Abstract
Cyclic AMP (cAMP) signaling plays a critical role in melanocyte proliferation and differentiation. However, the role of cAMP signaling in malignant transformation of human melanocytes and initiation of melanoma is not fully understood. Previously, we demonstrated that cAMP signaling plays opposite roles in primary and metastatic melanoma cells, i.e., pro- and anti-proliferative roles, respectively. This switch in cAMP action is mediated by the alternative cAMP signaling axis involving EPAC-RAP1 (exchange protein directly activated by cyclic AMP-Ras-related protein 1). In this study, we tested the hypothesis that activation of EPAC signaling is an early event in malignant transformation of melanocytes and is required for survival and proliferation of malignant melanocytes. Here, we show that shRNA-mediated knockdown of PTEN alone or PTEN-KD with lentiviral transduction with BRAF(V600E) results in upregulation of EPAC expression and activation of RAP1 (i.e., RAP1-GTP) in human primary melanocytes. Interestingly, activation of phosphoinositide 3-kinase (PI3K) signaling alone is sufficient for stimulation of maximal EPAC expression as well as proliferation suggesting that EPAC activation is an early event associated with loss of PTEN and melanoma tumor initiation. Inhibition of EPAC activity by either EPAC 1/2 or EPAC2-selective inhibitors suppressed the growth of transformed melanocytes by inhibiting cell cycle progression as evident by downregulation of cyclins E, -A2 and -B1. Inhibition of EPAC signaling also increased cells expressing senescence-associate beta galactosidase activity suggesting that EPAC may contribute to the senescence escape mechanisms in BRAF(V600E) melanocytes. Our data suggest that activation of PI3K pathway alone or in combination with mitogen-activated protein kinase pathway activates EPAC signaling in melanocytes. Since primary but not metastatic melanoma cells remain dependent on EPAC signaling, understanding the mechanisms of action EPAC can open new avenues to prevent melanomagenesis and inhibit melanoma tumor progression.
Citation Format: Mithalesh Kumar Singh, Sarah Altameemi, Marcos Lares, Shreyans Sadangi, Vijayasaradhi Setaluri. Epac signaling facilitates malignant transformation of melanocytes [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 112.
Abstract 1143: ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent in vivo efficacy in gastric cancer patient-derived xenografts
Authors: Chen Peng , Liu Yun , Deng Min , Tian Linjie , Lynch Kevin , Shan Bo , Mei Jay , Hou Bing 
Published: June 2022

Abstract
Background: Antibody-drug conjugates (ADCs) have become promising antitumor agents in recent years. ADCs are comprised of a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells, cross-linked to small molecule payloads with cytotoxic activity. Human Claudin 18.2 (CLDN18.2) is overexpressed in a large proportion of gastric and pancreatic cancers, with restricted normal tissue expression. The monoclonal antibody targeting CLDN18.2 (IMAB362) has demonstrated promising clinical benefit in combination with chemotherapies for gastric cancer patients. However, the same antibody shows suboptimal efficacy in patients with low CLDN18.2 expression. Here we report the potent in vivo efficacy of ATG-022, a CLDN18.2 ADC, in multiple gastric cancer patient-derived xenograft (PDX) models, including those with low CLDN18.2 expression.
Methods: The binding affinity of ATG-022 with CLDN18.2 was detected by SPR and FACs analysis. The in vitro 50% inhibition concentration (IC50) of ATG-022 was determined in CLDN18.2 positive cell lines using CellTiter-Glo luminescent cell viability assay. In vivo efficacy of ATG-022 was evaluated in a series of gastric cancer PDX models with different expression level of CLDN18.2 The expression level of CLDN18.2 was determined using IHC staining. ATG-022 was dosed twice at 1 mg/kg, 3 mg/kg or 10 mg/kg every two weeks.
Results: ATG-022 binds to CLDN18.2 protein with sub-nM affinity. It induced potent in vitro cytotoxicity in CHOK1 cells overexpressing CLDN18.2, with an IC50 of 5-7nM. Bystander killing by ATG-022 was observed. ATG-022 demonstrated potent in vivo antitumor efficacy in a gastric cancer PDX model with high CLDN18.2 expression. Intravenous dosing of 1 mg/kg, 3 mg/kg, and 10 mg/kg ATG-022 induced 35.41%, 71.56% tumor growth inhibition (%TGI) and tumor regression respectively. In a PDX model with low CLDN18.2 expression, 3 mg/kg ATG-022 or 10 mg/kg clinical benchmark CLDN18.2-ADC did not inhibit tumor growth, while 10 mg/kg ATG-022 induced tumor regression.
Conclusions: ATG-022 demonstrated potent in vitro and in vivo antitumor effects, with in vivo efficacy observed in CLDN18.2-low expression PDX models, suggesting a promising therapeutic strategy for gastric cancer patients with a broad range of CLDN18.2 expression levels.
Citation Format: Peng Chen, Yun Liu, Min Deng, Linjie Tian, Kevin Lynch, Bo Shan, Jay Mei, Bing Hou. ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent in vivo efficacy in gastric cancer patient-derived xenografts [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 1143.
Abstract 1157: Uncovering transcriptional changes related to cisplatin treatment and mixing of TNBC subclones using single-cell RNA sequencing
Authors: Nicholas Shadae , Mukashyaka Patience , Kumar Pooja , Chuang Jeffrey , Liu Edison 
Published: June 2022

Abstract
Triple negative breast cancer (TNBC) has long been characterized by having a high degree of intratumoral heterogeneity. While significant contributions have been made in understanding the components of TNBC tumors, examining the dynamics of interaction between subclones in TNBC is relatively unexplored. By using single-cell RNA sequencing (scRNA-seq) technology, this study aims to focus on understanding changes in gene expression of two TNBC subclones: the cisplatin-resistant subclone (A50) and cisplatin-sensitive subclone (B), when cocultured in 3D organoids in the presence and absence of cisplatin. We hypothesized that there will be significant differentially expressed genes (DEGs) due to various concentrations of cisplatin and mixing effect. We found DEGs (ACTB, FOS, EIF5, BRD2, MAFG, SF3B4, ID1, MGMT, DDIT4 and LPP) due to treatment with cisplatin in both subclones, with the largest clear effect present at a high concentration of cisplatin. Additionally, the network analysis showed that cisplatin was an upstream regulator for 11 DEGs. Even though, gene expression changes due to mixing are much more subtle than effects due to treatment, we saw some DEGs caused by the mixing effect like MT1X which is related to cisplatin resistance. Taken together, the findings of this project will help in future studies when deducing which genes to target in TNBC chemotherapy treatments based on predictive molecular biomarkers.
Citation Format: Shadae Nicholas, Patience Mukashyaka, Pooja Kumar, Jeffrey Chuang, Edison Liu. Uncovering transcriptional changes related to cisplatin treatment and mixing of TNBC subclones using single-cell RNA sequencing [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 1157.
Abstract 1162: A systematic analysis of RET mutations and their sensitivity to different RET inhibitors
Authors: Rotkopf Shay , Haham DIkla , Fillipov-Levy Natalie , Birnbaum Lea , Dehan Elinor , Kifer Ilona , Barbash Zohar , Tarcic Gabi 
Published: June 2022

Abstract
The RET oncogene is a receptor tyrosine kinase, mainly expressed in neural crest-derived tissues, that plays a role in cell growth and differentiation. Since the first identification of inherited mutations in RET as the cause of Multiple endocrine neoplasia type 2 (MEN2), somatic RET alterations have been identified as actionable drivers in subtypes of lung and thyroid, among other cancer types. This enabled the development of several RET targeted treatments, such as pralsetinib and selpercatinib, showing meaningful clinical benefit. To understand the full scope of RET alteration frequency and heterogeneity we used the AACR-GENIE database. We found that the frequency of RET alterations pan-cancer is 3%, of which two-thirds are missense mutations. The major cancer types with RET alterations are medullary thyroid, papillary thyroid and NSCLC, as expected, but also breast, colorectal and melanoma. An important distinction between NSCLC and thyroid cancer compared to colorectal, breast and melanoma is the fraction of missense vs. fusion events, with 30%-40% of samples in the former group containing RET fusions. This is in contrast with &gt;80% of samples in the latter group containing RET missense mutations. Moreover, the heterogeneity of RET alterations is large, with over 1,000 unique types of missense mutations identified. The vast majority of mutations are classified as variants of uncertain significance (VUS). To better understand the potential activity of these mutations, we assayed over 200 different missense mutations and fusions using a high-throughput cell-based functional assay. Results were analyzed using a novel machine learning model consisting of a multi-scale deep convolutional neural net, followed by a tree-based regressor. Our results show that the assay correctly predicted the activity of both known activating alterations as well as of loss of function mutations. Interestingly, only ~3% of over 150 VUS tested were found to be activating. Furthermore, we show that the active alterations are sensitive to the FDA-approved targeted agents pralsetinib and selpercatinib, with varying IC50 values. Taken together, these results uncover the full extent of actionable RET alterations, differentiating between active and non-active variants, as well as the effectiveness of RET inhibitors.
Citation Format: Shay Rotkopf, DIkla Haham, Natalie Fillipov-Levy, Lea Birnbaum, Elinor Dehan, Ilona Kifer, Zohar Barbash, Gabi Tarcic. A systematic analysis of RET mutations and their sensitivity to different RET inhibitors [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 1162.
Abstract 1165: Therapeutic targeting of glucocorticoid receptor in ETS rearranged cancer
Authors: Sekar Arunachalam , Nataraj Nishanth Belugali , Yarden Yosef 
Published: June 2022

Abstract
The Nuclear receptor Glucocorticoid receptor (GR) acts as a ubiquitous hormone-dependent transcription factor, which regulates many cellular functions. Here, we discovered that some ETS (E-twenty-six) family transcription factors form physical complexes with GR. Two members of the family, FLI1 and ERG exhibited stronger binding with the ligand-activated GR. GR-FLI1 interaction enhance the transcriptional activity of DNA-bound GR. Antagonizing GR or lowering cortisol levels in Ewing sarcoma (ES) animal models, a pediatric bone malignancy driven by EWS-FLI1 fusion, robustly retarded tumor growth, as well as inhibited bone to lung metastasis. These findings prompted us to identify prognostic, GR-regulated gene signature in ES. Because the genomic binding sites of GR in ES are still unknown, using chromatin immunoprecipitation followed by high-throughput DNA sequencing in A673 cells we found previously known and new target genes of GR. By utilizing the protein-fragment complementation assay (PCA), we discovered that GR physically interacts with additional ETS factors. Disruption of this complex is enabled by clinically approved GR antagonist RU486 or newly developed selective GR modulators (i.e., SGRMs without AR or PR cross-reactivity). ETS proteins has been strongly associated with tumor progression and metastasis in several cancers. Taken together, we hypothesised that these mechanisms are also relevant for other ETS rearranged cancers. Results of co-immunoprecipitation analysis confirm the interaction of GR and ERG/ETV4 in ETS-positive prostate cancer cells. In addition, migration and proliferation were reduced when we knocked-down or antagonized GR. It is important noting that the pharmacology of GR is very well developed and some GR-targeting drugs are among the most prescribed medicines. These discoveries will open the way to clinical tests and eventual application of anti- hormone therapy in the discipline of pediatric sarcomas and ETS-rearranged cancers.
Citation Format: Arunachalam Sekar, Nishanth Belugali Nataraj, Yosef Yarden. Therapeutic targeting of glucocorticoid receptor in ETS rearranged 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 1165.
Abstract 1197: Refining the drug-gene interaction database for precision medicine pipelines
Authors: Cannon Matthew , Stevenson James , Kuzma Kori , O'Sullivan Colin , Miller Katherine , Grischow Olivia , Coffman Adam , Kiwala Susanna , McMichael Joshua F. , Morrissey Dorian , Cotto Kelsy , Griffith Obi , Griffith Malachi , Wagner Alex 
Published: June 2022

Abstract
The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a publicly accessible resource that aggregates 102,426 gene records and 57,498 drug records from 40 drug-gene interaction data sources to aid both researchers and clinicians in identifying associations between genes of interest and available drugs and therapeutics. By using peer-reviewed data sources and publications, DGIdb represents a stand-alone resource with over 100,000 drug-gene interaction claims across 30 interaction types to drive hypothesis generation in precision medicine and interpretation pipelines. The background process that normalizes drugs to a harmonized ontological concept has been upgraded. These improvements have increased concept normalization for drugs by 20% and are now available as a stand-alone service for use (https://normalize.cancervariants.org/therapy/). Leveraging our platform’s ability to find relationships between disease-critical genes and available therapeutics, DGIdb has been used in clinical interpretation pipelines to find drugs for specific diseases with an emphasis on regulatory approval status. DGIdb now uses annotations from Drugs@FDA as an additional source to provide more accurate descriptors for market and maturity status of drugs, when available. Lastly, to enhance the annotation potential for DGIdb in precision medicine pipelines, we have updated our druggable gene category sources with an additional curated list of 2,217 genes. Used alone or in combination with existing categories-such as the heavily-utilized ‘clinically actionable’ category-this additional source will give precision medicine and interpretation pipelines the power to find concise, actionable annotations for specific diseases including pediatric cancers and epilepsy. These lists are managed and maintained as a publicly-available resource to provide up-to-date annotations on disease-associated genes as they become available.
Citation Format: Matthew Cannon, James Stevenson, Kori Kuzma, Colin O'Sullivan, Katherine Miller, Olivia Grischow, Adam Coffman, Susanna Kiwala, Joshua F. McMichael, Dorian Morrissey, Kelsy Cotto, Obi Griffith, Malachi Griffith, Alex Wagner. Refining the drug-gene interaction database for precision medicine pipelines [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 1197.