bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1826: New inhibitors of oncology targets discovered using the affinity-mediated selection of DNA-encoded chemical libraries followed by machine-learning
Authors: Keefe Anthony D. , AbouZleikha Mohamed , Baghaie AJ , Clark Matthew A. , Guie Marie-Aude , Guilinger John P. , Walsh Ryan , Zhang Ying 
Published: March 2024

Abstract
X-Chem’s DNA-Encoded Chemical Library platform generates a large amount of binding data for each target it is screened against. Here, we report the application of machine learning to these large datasets with case studies that include the identification of novel inhibitors of two oncology targets. One, ERα, is an estrogen-activated receptor that controls transcription and stimulates breast cell proliferation including in breast cancer. The second, DCAF1, is the substrate-recognition component of an E3 ligase complex that is associated with the proliferation of colon cancer cells. Over 100 billion DNA-Encoded compounds were synthesized and screened for their affinity to each target. The selection output data was then featurized and used to train multiple machine-learned models. Models with demonstrated predictive power were then used to score virtual catalogue compounds which were subsequently acquired and tested. A range of successful data-science strategies will be described including those that lead to double-digit nM inhibitors of each of DCAF1 and ERα.
Citation Format: Anthony D. Keefe, Mohamed AbouZleikha, AJ Baghaie, Matthew A. Clark, Marie-Aude Guie, John P. Guilinger, Ryan Walsh, Ying Zhang. New inhibitors of oncology targets discovered using the affinity-mediated selection of DNA-encoded chemical libraries followed by machine-learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1826.
Abstract 1838: Advancing cancer research with Next-Generation Protein Sequencing™ on Platinum™ by Quantum-Si
Authors: Nguyen Khanh Dinh 
Published: March 2024

Abstract
Protein sequencing has the potential of playing a crucial role in advancing cancer research by providing insights into the specific proteins involved in cancer pathways. New discoveries from protein sequencing advance our understanding of cancer and potential targeted therapies. Here, we demonstrate the power of next-generation protein sequencing™ using the insight-generating Platinum™ platform. Individual peptides are digested from proteins and immobilized on a semiconductor chip and probed by dye-labeled N-terminal amino acid (NAA) recognizers, followed by subsequent aminopeptidase cleavage to expose each NAA in the peptide for recognition. By recording and analyzing fluorescent intensity, lifetime, and binding kinetics of each NAA binding event, we can decipher single amino acid substitutions and modifications.
To demonstrate the versatility of this methodology across proteins associated with cellular biology, we sequenced a series of interleukins: IL4, IL6, IL7, IL13, IL20, and IL34. Interleukins, a group of cytokines that play a vital role in cancer by modulating immune responses, promoting inflammation, and influencing tumor microenvironment, impacting tumor growth and the efficacy of treatments. We have successfully sequenced all the mentioned interleukins individually or within protein mixtures. Furthermore, we were able to sequence IL6 that was enriched through immunoprecipitation from human serum. Finally, we demonstrated the unique potential of Platinum in detecting post-translational modifications (PTMs) relevant to cancer, as exemplified by the successful identification of arginine citrullination in vimentin, an onco-protein that promotes cancer cell mobility and invasion into surround tissues.
These results demonstrate the transformative potential of next-generation protein sequencing using Platinum™ in enabling the identification of proteins in complex mixtures and biofluids, as well as the detection of critical PTMs implicated in human pathophysiology, offering valuable insights into cancer research.
Citation Format: Khanh Dinh Nguyen. Advancing cancer research with Next-Generation Protein Sequencing™ on Platinum™ by Quantum-Si    [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1838.
Abstract 1859: Diverse CD28-binding IgG and heavy chain-only antibodies for T-cell engager development
Authors: Lam Katherine , Zhi Shirley , Kraft Lucas , Vigano Elena , Wei  , Faralla Cristina , Odekunle Esther , Bullock Kelly , Marshall Erin , Cid Melissa , Leung Grace , DeVorkin Lindsay , Duncan Sherie 
Published: March 2024

Abstract
Engagement of the CD28 co-receptor by T-cell engager (TCE) molecules can enhance activation, proliferation, and anti-tumor activities, particularly in immunosuppressive tumor microenvironments. In this study, we present data on a diverse panel of CD28-binding IgG and heavy chain-only (HCAb) antibodies for T-cell co-stimulation. Our diverse panel of CD28-binding antibodies add co-stimulatory building blocks to our TCE repertoire. Using single B cell-screening, we identified fully human IgG and HCAb binders to human and non-human primate CD28 with a high degree of sequence diversity. We selected a subset of antibodies for expression and assessed binding to both human and cynomolgus CD28-expressing cells. These antibodies displayed a wide range of binding avidities in the sub-nanomolar to micromolar range, and epitope binning analysis identified seven epitope communities. Co-stimulatory activity for a subset of molecules was assessed in vitro. Antibodies displayed a wide range of crosslinked T-cell activation with the majority showing no activation independent of crosslinking. Data presented here describe a diverse set of CD28-binding antibodies ready for engineering into co-stimulatory TCEs. Combining these molecules with our TCE platform or other T-cell activating strategies will enable development of novel TCE modalities with co-stimulatory function for diverse tumor targets.
Citation Format: Katherine Lam, Shirley Zhi, Lucas Kraft, Elena Vigano, Wei, Cristina Faralla, Esther Odekunle, Kelly Bullock, Erin Marshall, Melissa Cid, Grace Leung, Lindsay DeVorkin, Sherie Duncan. Diverse CD28-binding IgG and heavy chain-only antibodies for T-cell engager development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1859.
Abstract 194: Single-cell mechanical analysis reveals that astrocytes and glioblastoma cells have similar viscoelastic properties
Authors: Najera Julian , Onwudiwe Killian , Holen Luke , Burchett Alice A. , Rodriguez Dorielis , Zarodniuk Maksym , Siri Saeed , Datta Meenal 
Published: March 2024

Abstract
Despite recent advances in treatment, the survival rate of glioblastoma (GBM) patients remains low due to the cancer’s resistance to current treatment modalities. Solid tumors like GBM are known to harbor physical abnormalities at the tissue and cell level. An understanding of GBM cell mechanics may therefore lead to the identification of novel disease mechanisms, biomarkers, and therapeutic strategies to improve treatment outcomes. In this study, we aimed to compare the mechanics of human GBM cells and their normal counterpart, immortalized human astrocytes (IHAs). To accomplish this, we used a parallel-plate flow system to expose single cells to physiological fluid shear stress and recorded the resulting deformation using a camera-coupled microscope. We then utilized digital image correlation analysis to create strain-time profiles of individual cells and fit the profiles with a three-parameter generalized Maxwell model to characterize their nuclear and cytoplasmic viscoelastic properties. We also used fluorescence microscopy and atomic force microscopy to quantify actin density and alignment and adhesion energy in both cell types, respectively. Our results showed that, contrary to extracranial cancer cells, the viscoelastic properties of GBM cells are similar to their normal counterpart. This may explain why metastasis in GBM patients is rare and conventional treatment options are unsuccessful. We also found that actin organization and localization and adhesion energy is different between GBM cells and IHAs. Thus, future research which links the genetic and microenvironmental factors that modulate these unique mechanical features may lead to the development of rational and novel clinical strategies against GBM.
Citation Format: Julian Najera, Killian Onwudiwe, Luke Holen, Alice A. Burchett, Dorielis Rodriguez, Maksym Zarodniuk, Saeed Siri, Meenal Datta. Single-cell mechanical analysis reveals that astrocytes and glioblastoma cells have similar viscoelastic properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 194.
Abstract 1947: Studies on pMEK inhibitors for the treatment of RAS-mutant cancers as a single agent or combinations
Authors: Lv Xiaobing , Xu Min , Hu Yong , Zhao Lanjiao , Chen Xiuquan , Chen Youqin , Yang Chen , Li Jizhi , Chen Chen 
Published: March 2024

Abstract
RAS mutations are the most common oncogene in human cancers and KRAS has the highest frequency in non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC). KRAS G12C inhibitors have been approved to treat NSCLC patients. However, drug-resistance is eventually developed for these treatments. Preclinical studies suggested MAPK pathway reactivation is one possible mechanism. Among many MEK inhibitors in clinical development, CH5126766 binds to MEK1 inactive conformation and blocks its phosphorylation and activation. We believe this compound should prevent MAPK “paradoxical activation” commonly observed in most RAF and MEK inhibitors such as vemurafenib and cobimetinib. We studied this compound in various in vitro assays and found its potential in combating the paradoxical activation, which might be the cause of drug-resistance for MAPK signal pathway inhibitors, including RAS-, RAF- MEK- and ERK-inhibitors, as a single agent or in combination with above-mentioned inhibitors. In addition, we are developing a series of compounds based on CH5126766, by improving the inhibition of MEK1/2 kinase activity in addition to its activation. In summary, studies on the pMEK inhibitor demonstrated that this class of compounds might mitigate the MAPK pathway reactivation and prolong drug efficacies in clinical. Detailed research results will be discussed.
Citation Format: Xiaobing Lv, Min Xu, Yong Hu, Lanjiao Zhao, Xiuquan Chen, Youqin Chen, Chen Yang, Jizhi Li, Chen Chen. Studies on pMEK inhibitors for the treatment of RAS-mutant cancers as a single agent or combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1947.
Abstract 1952: Co-alterations in PIK3CA and ARID1A lead to enhanced sensitivity to PI3K inhibition
Authors: Udgata Shirsa , Stoecker Jordan N. , Lippert Anna L. , Pasch Cheri A. , Deming Dustin A. 
Published: March 2024

Abstract
Background: There is increasing interest in developing precision medicine strategies for cancers with PIK3CA mutations. Co-alterations in PIK3CA and ARID1A (AD) occur in ~1% of all cancers. Previously, patients with co-alterations in PIK3CA and AD have shown both an improved objective response rate and improved progression free survival following copanlisib (cop) treatment compared to cancers with PIK3CA mutations and wild-type AD. Here we evaluate potential mechanisms for this enhanced clinical benefit.
Methods: AD was knocked out in SW48 and SW48PIK3CA-H1047R (SW48PK) human 2D colorectal cancer cell lines using CRISPR (SW48AD; SW48PKAD). Knockouts were confirmed using PCR genotyping, amplicon sequencing, and western blot (WB). A cell proliferation assay (WST-1) was performed at increasing doses of cop for 48hrs to determine cell viability. WBs were performed at 6hrs and 24hrs after cop treatment to determine levels of phosphorylation of AKT, S6, and 4EBP1 and levels of apoptosis-related proteins (MCL-1, BCL-xL, BCL-2, PARP). Athymic nude mice were flank injected with SW48PK and SW48PKAD and treated with cop (10mg/kg in PEG400/acidified water (0.1N HCl, pH 3.5; 20/80, v/v) or vehicle for 25 days or until moribund.
Results: WST-1 assay showed highest sensitivity to cop in SW48PKAD cells compared to SW48, SW48PK and SW48AD. At 10nM (p=0.01), there was a significant difference in cell viability between SW48PK and SW48PKAD. No significant difference was seen in the phosphorylation (p) of AKT, S6, or 4EBP1 between SW48PK and SW48PKAD. Expression of MCL-1 protein decreased in SW48PKAD compared to SW48PK. No difference was seen in levels of BCL-xL and BCL-2. On treatment with cop, there was a greater reduction in pS6 in SW48PKAD at 24 hours compared to SW48PK, but no significant difference in pAKT and p4EBP1. There was a gradual increase in MCL-1, BCL-xL, and cleaved PARP in SW48PKAD overtime following cop treatment compared to SW48PK. In vivo, untreated SW48PKAD tumors grew more quickly than the SW48PK tumors (8-fold increase in tumor size in SW48PKAD compared to 5-fold increase in SW48PK by day 25, p=0.06). SW48PKAD mice had significant tumor reduction (p=0.002) on cop treatment by day 25; however, SW48PK mice did not.
Conclusions: ARID1A loss along with PIK3CA mutation leads to greater PI3K inhibition response most likely due to enhanced induction of apoptosis. Further confirmation of this enhanced sensitivity is required with better in vitro models such as patient-derived cancer organoids.
Citation Format: Shirsa Udgata, Jordan N. Stoecker, Anna L. Lippert, Cheri A. Pasch, Dustin A. Deming. Co-alterations in PIK3CA and ARID1A lead to enhanced sensitivity to PI3K inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1952.
Abstract 1992: A novel RB1 E3 ligase TRIM37 contributes to palbociclib resistance in breast cancer
Authors: You Chanping , Tsoi Ho , Man Pui Sum , Chow Larry Ka Yue , Dai Wei , Khoo Ui Soon 
Published: March 2024

Abstract
The tripartite motif-containing 37 (TRIM37) is a RING finger E3 ubiquitin ligase and is a poor prognostic factor in breast cancer patients. The gene is located in chromosome 17q23, a region amplified in up to 40% of breast cancers. We observed that activation of androgen receptor (AR) could induce resistance to the CDK4/6 inhibitor Palbociclib, the mechanism yet to be clarified. ChIP-sequencing data suggested that AR binds to the TRIM37 promoter, with AR activation resulting in TRIM37 expression. We hypothesized that TRIM37 might be involved in Palbociclib resistance. Using an ER+ve cell line MCF7 and a TNBC cell line MDA-MB 453, we found that overexpression of TRIM37 could induce Palbociclib resistance. TRIM37 overexpression resulted in RB1 protein downregulation, which is the primary downstream target of CDK4/6, while TRIM37 knockdown enhanced RB1 protein expression. Ubiquitination assay demonstrated TRIM37 overexpression increased the level of RB1 protein ubiquitination. The co-immunoprecipitation (Co-IP) assay confirmed that TRIM37 protein could interact with the RB1 protein. These results suggest that TRIM37 could be the E3 ligase that regulates RB1 degradation. Various deletion mutants of TRIM37 were cloned for Co-IP experiments between these mutants and RB1. Results show that the MATH and c-terminal domains of TRIM37 was the essential region for the interaction. Overexpression of the mutant with the TRIM37 MATH and c-terminal domains (TRIM37-MATH/C) could enhance RB1 protein level. This might be due to competition of TRIM37-MATH/C with wild-type TRIM37 for RB1 binding. Our findings suggest TRIM37 is a novel RB1 E3 ligase, and it binds to the RB1 protein via the MATH and C-terminal domains to regulate protein degradation. Our study also suggests that high expression of TRIM37 mediated by AR activation could deplete RB1, which is the target of Palbociclib, eventually leading to resistance. These findings are supportive of the contribution of AR activation to Palbociclib resistance.
Citation Format: Chanping You, Ho Tsoi, Pui Sum Man, Larry Ka Yue Chow, Wei Dai, Ui Soon Khoo. A novel RB1 E3 ligase TRIM37 contributes to palbociclib resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1992.
Abstract 2082: Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape
Authors: Cook Ashley L. , Sur ojit , Dobbyn Laura , Watson Evangeline , Cohen Joshua D. , Ptak Blair , Lee Bum Seok , Paul Suman , Hsiue Emily , Popoli Maria , Vogelstein Bert , Papadopoulos Nickolas , Bettegowda Chetan , Gabrielson Kathy , Zhou Shibin , Kinzler Kenneth , Wyhs Nicolas 
Published: March 2024

Abstract
Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen revealed disruption of kinase SMG1’s phosphorylation of UPF1 as a potent disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.
Citation Format: Ashley L. Cook, ojit Sur, Laura Dobbyn, Evangeline Watson, Joshua D. Cohen, Blair Ptak, Bum Seok Lee, Suman Paul, Emily Hsiue, Maria Popoli, Bert Vogelstein, Nickolas Papadopoulos, Chetan Bettegowda, Kathy Gabrielson, Shibin Zhou, Kenneth Kinzler, Nicolas Wyhs. Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2082.
Abstract 2092: Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure
Authors: Cianci Francesca , Rey Guido , Krex Dietmar , Ceresa Davide , Malatesta Paolo , Mazzanti Michele 
Published: March 2024

Abstract
Glioblastoma (GB) is the most aggressive type of brain tumor, and current treatments are generally ineffective in preventing recurrence. Tumor Treating Fields (TTFields) are an innovative treatment that has been shown to improve patients' life expectancy in the last two decades. TTFields therapy has an antitumoral effect that involves different mechanisms and is an optional add-on to standard maintenance temozolomide. Although TTFields therapy initially slows tumor progression, it does not prevent tumor relapse in most patients. In the present investigation, we run a genomic and proteomic analysis of surgical material from 10 patients treated with TTFields. GB tissues were obtained from the primary tumor mass and from a second surgery after tumor relapse. All the patients, in addition to brain tumor standard therapies, were treated with TTFields for eighteen hours a day, the time span of treatment application was dependent on GB recurrence. Control samples were obtained from primary and secondary surgeries of 5 patients treated with standard therapy alone. The GB tissue extracts were analyzed with an RNAseq routine, and the results from the secondary surgery were compared with the data obtained from tumor specimens of the primary surgery. A common feature of transcripts among all the patients was the alterations of several pathways promoting the increase of intracellular oxidation and cell cycle regulation. In parallel with the analysis of patient specimens, we developed an in vitro GB cell relapse model. This was instrumental in investigating the beneficial contribution of TTFields action during tumor relapse, but also in uncovering the limitation of this therapeutic procedure. GB primary cultures obtained from patients' surgery were exposed for up to 12 days with 200 kHz TTFields stimulation using the inovitro™ system. After 12 days of continuous TTFields application, GB cells showed an average depolarization of the resting membrane potential, increasing oxidation, and acidification of the cytoplasm. Genomic analysis of treated cells compared with wild-type primary culture, denoted an increase of tumor stem cell markers, activation of several metabolic pathways, and upregulation of different ion channel protein transcripts. Our final goal is to identify specific molecular features enhanced by TTFields treatment to be used as a parallel therapy to fight GB recurrence.
Citation Format: Francesca Cianci, Guido Rey, Dietmar Krex, Davide Ceresa, Paolo Malatesta, Michele Mazzanti. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2092.