bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A136: Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles
Authors: Zhang Weijie , Maeser Danielle , Lee Adam , Huang Yingbo , Gruener Robert F , Jena Sampreeti , Patel Anand G , Huang R. Stephanie 
Published: December 2023

Abstract
Single-cell sequencing techniques have greatly advanced our current understanding of intratumoral heterogeneity through identifying tumor subpopulations with distinct biologies and therapeutic responses. However, translating biological differences into treatment strategies is challenging, as we still lack tools to facilitate efficient drug discovery that tackles heterogeneous tumors. One key step in development of such approaches centers around accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we present a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual-cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening datasets. Our method detects shared expression patterns between the two data sources and utilizes such information to project cellular drug response. This method achieves high accuracy, with predicted sensitivities easily able to separate cells into their true cellular drug resistance status as measured by effect size (Cohen's d &gt; 1.0); this holds when using single-cell RNA-seq from both cell line and in vivo models. More importantly, we examine our method’s utility with three distinct prospective tests, and in each our predicted results are accurate and mirrored biological expectations. In the first two tests, we investigated predicting drugs for cell subpopulations that are resistant to standard-of-care (SOC) therapies due to intrinsic resistance or effects of tumor microenvironments. In both, our results showed high consistency with results from the original studies. In the third test, we generated SOC therapy resistant cell lines, used scIDUC to identify drugs predicted effective on the resistant line, and validated the predictions with in vitro experiments. Together, scIDUC quickly and directly translates scRNA-seq data into meaningful cellular drug response for individual cells, displaying the potential to be used by researchers as a first-line tool for nuanced and heterogeneity-aware drug discovery.
Citation Format: Weijie Zhang, Danielle Maeser, Adam Lee, Yingbo Huang, Robert F Gruener, Sampreeti Jena, Anand G Patel, R. Stephanie Huang. Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A136.
Abstract A138: Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody
Authors: Yokoyama Miki , Oitate Masataka , Sakurai Ken , Iguchi Takuma , Damme Katja , Nanai Kayoko , Fukuchi Keisuke 
Published: December 2023

Abstract
Background: CD147 is a member of the immunoglobulin superfamily that is highly expressed in various cancers and is involved in growth, metastasis, and activation of inflammatory signals in cancer cells. DS-1471a is a novel humanized anti-human CD147 monoclonal antibody under development as an anticancer agent. In this study, pharmacokinetic (PK)-pharmacodynamic (PD) analysis of DS-1471a was conducted to set the dose and dosing regimen for first-in-human (FIH) study. The safety profile of DS-1471a was also assessed in cynomolgus monkeys.
Methods: Preclinical pharmacological study was conducted in xenograft model mice transplanted with MIA PaCa-2 cells by intravenous (IV) administration of DS-1471a, and receptor occupancy (RO) of CD147 in tumor was measured. Monkey PK and RO in blood were measured after the IV administration of DS-1471a. The expression levels of CD147 in hepatocytes and erythrocytes in monkeys and humans were measured to estimate the species differences. Using monkey PK, RO, and CD147 expression data, a minimal physiologically based pharmacokinetic (PBPK) model was constructed. Subsequently, PK and RO profiles in humans were predicted by replacing physiological parameters and CD147 expression levels with human values. For the safety assessment, DS-1471a was intravenously administered to monkeys every 2 weeks for 1 month.
Results: In xenograft model mice, DS-1471a exhibited partial and potent antitumor activity at 1 and 3 mg/kg, respectively. At those doses, RO in tumor the day after dosing was 18% (1 mg/kg) and 89% (3 mg/kg). In monkeys, non-linear PK was observed, owing to high expression of CD147 in erythrocytes, resulting in target-mediated drug disposition. Compared to the findings in monkeys, the human expression level of CD147 was lower in erythrocytes and higher in hepatocytes. PBPK modeling, incorporating species differences in CD147 expression levels, projected that RO in tumor after the IV administration of DS-1471a to humans would reach 20%, 50%, and 90% at 2 day after injection at 0.3, 1, and 3 mg/kg, respectively. In the monkey toxicity study, DS-1471a was well tolerated at up to 158.4 mg/kg (human equivalent dose of 51 mg/kg).
Conclusions: Based on preclinical PK-PD analysis and safety study of DS-1471a, the starting dose in FIH study was set to 1 mg/kg as a safe and efficacious dose.
Citation Format: Miki Yokoyama, Masataka Oitate, Ken Sakurai, Takuma Iguchi, Katja Damme, Kayoko Nanai, Keisuke Fukuchi. Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A138.
Abstract A153: ALK proximitome reveal SLC3A2, part of the polyamine transporter, as a membrane interaction partner with growth promoting ability
Authors: Hallberg Bengt , Lai Wei-Yun , Chuang Tzu-Po , Palmer Ruth 
Published: December 2023

Abstract
Solute Carrier Family 3, Member 2 (SLC3A2 or 4F2hc) was identified as a potential ALK interacting partner in a BioID-proximity labeling screen in neuroblastoma cells. SLC3A2 is a multifunctional glycoprotein that mediates integrin-dependent signaling, acts as a trafficking chaperone for amino acid transporters, and regulates polyamine transportation. However, the functional consequences of an interaction between SLC3A2 and ALK are unclear. In this work we confirm that endogenous SLC3A2 and ALK interact in NB cells. This SLC3A2:ALK interaction is abrogated upon treatment with the ALK inhibitor lorlatinib. In agreement, stimulation of ALK with ALKAL2 ligand, resulted in SLC3A2 protein levels, which was decreased upon lorlatinib treatment. We show here that loss of ALK activity leads to suppressed SLC3A2 expression and reduced SLC3A2 protein stability in a panel of neuroblastoma cells. Solute Carrier Family 7 Member 3 (SLC7A5, also known as LAT1) is an amino acid transporter that forms a stable complex with SLC3A2 for localization at the plasma membrane, where they function. This complex is lost upon knockdown of SLC3A2, with concomitant inhibition of NB cell growth. To investigate the therapeutic potential of SLC3A2/SLC7A5 complex targeting, we performed monotreatment of NB cells with AMXT-1501 (a polyamine transport inhibitor) only showed a moderate effect in NB cells. In contrast, a combined lorlatinib/AMXT-1501 treatment resulted in synergistic inhibition of cell growth in ALK-driven primary-cultured mouse neuroblastoma cell lines. Taken together, our results show that SLC3A2 protein stability and its interaction with ALK depend on ALK signaling in ALK-driven neuroblastoma. The synergistic effect of combined ALK and polyamine transport inhibitors suggests a potential therapeutic option for ALK-driven neuroblastoma.
Citation Format: Bengt Hallberg, Wei-Yun Lai, Tzu-Po Chuang, Ruth Palmer. ALK proximitome reveal SLC3A2, part of the polyamine transporter, as a membrane interaction partner with growth promoting ability [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A153.
Abstract A154: PDLIM2 is required for regulating inflammation and cellular redox levels in mouse colorectal epithelial model
Authors: Ward Stephanie , Melgar Silvia , Cox Orla T , Morelli Raffaella , O'Connor Rosemary 
Published: December 2023

Abstract
PDLIM2 is a cytoskeletal and nuclear protein present in hematopoietic and epithelial cells that regulates cell differentiation and the protein stability of transcription factors including NF-κB, STATs, and β-catenin (1). PDLIM2 expression is repressed in certain cancers, but is highly expressed in cancer cells that exhibit a metastatic phenotype (2). PDLIM2 is also highly expressed in the tumour microenvironment of breast cancer, particularly in the pro-wound healing M2 macrophage population. In line with this, bone-marrow derived macrophages from PDIM2 knockout (KO) mice have impaired differentiation towards the M2 macrophage phenotype (3). Here we investigated the effects of PDLIM2 loss in epithelial and immune cells in a colitis-associated cancer model using PDLIM2 wild type (WT) and KO mice exposed to dextran sodium sulphate (DSS) and azoxymethane (AOM). We observed that PDLIM2 KO mice exhibited a strong response to DSS alone. Colon tissue from DSS-treated mice exhibited impaired epithelium repair, sustained inflammation, and low levels of wound-healing M2 macrophages compared to WT tissues. To address the molecular mechanisms associated with PDLIM2 KO in colon epithelial cells, we suppressed or knocked out PDLIM2 in the Caco2 cell line. Caco-2 cells lacking PDLIM2 displayed dysregulated adhesion signalling, which was accompanied by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction and increased dependence on glycolysis. Overall, we conclude that PDLIM2 is required for the resolution of inflammation and to promote intestinal epithelial repair through regulating cell adhesion signalling and cellular redox balance. 1. Guo ZS, Qu Z. PDLIM2: Signaling pathways and functions in cancer suppression and host immunity. Biochim Biophys Acta Rev Cancer. 2021 Dec;1876(2):188630. doi: 10.1016/j.bbcan.2021.188630. 2. Cox OT, Edmunds SJ, Simon-Keller K, Li B, Moran B, Buckley NE, Bustamante-Garrido M, Healy N, O'Flanagan CH, Gallagher WM, Kennedy RD, Bernards R, Caldas C, Chin SF, Marx A, O'Connor R. PDLIM2 Is a Marker of Adhesion and β-Catenin Activity in Triple-Negative Breast Cancer. Cancer Res. 2019 May 15;79(10):2619-2633. doi: 10.1158/0008-5472.CAN-18-2787. 3. Cox OT, O'Sullivan N, Tresse E, Ward S, Buckley N, O'Connor R. PDLIM2 is highly expressed in Breast Cancer tumour-associated macrophages and is required for M2 macrophage polarization. Front Oncol. 2022 Nov 30;12:1028959. doi: 10.3389/fonc.2022.1028959.
Citation Format: Stephanie Ward, Silvia Melgar, Orla T Cox, Raffaella Morelli, Rosemary O'Connor. PDLIM2 is required for regulating inflammation and cellular redox levels in mouse colorectal epithelial model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A154.
Abstract A155: The TGF-β/BMP signaling cascades induce opposing fates in breast cancer and medulloblastoma through chromatin and cell cycle modulation
Authors: Ali Mohamad Moustafa , Ohata Yae , Heldin Carl-Henrik , Moustakas Aristidis 
Published: December 2023

Abstract
The transforming growth factor β (TGF-β) superfamily comprises more than 30 structurally-related proteins, including TGF-β1, TGF-β2, TGF-β3 and bone morphogenesis proteins (BMPs). TGF-β/BMP ligands bind to their respective kinase receptors culminating paradoxically in either tumor-promoting or suppressing outcomes. The former fate is attributed mainly to the induction of the epithelial-mesenchymal transition and microenvironmental remodeling by TGF-β/BMP, whereas the latter outcome is a consequence of various antiproliferative mechanisms. To gain a broader perspective, we studied the fates of different cancer models, including breast cancer and medulloblastoma, either challenged with TGF-β/BMP ligands or depleted of essential transcription factors. In 3D cultures, TGF-β stimulation enhances the genome-wide chromatin accessibility of normal-like and transformed breast epithelial models. Concomitantly, we observed a dramatic increase in accessible regions mapped to transcription start sites and, to less extent, at annotated enhancers. The corresponding transcriptome-wide analyses indicated positive modulation of DNA replication and repair associated with resistance to cyclin-dependent kinase inhibition in breast cancer organoids. Nevertheless, such TGF-β-induced remodeling was partly dependent on the activity of the transcription factor SOX4. Further implementation of whole transcriptome spatial profiling in medulloblastoma PDX tissues identified several cell cycle-related pathways and chromatin remodeling terms that negatively associate with activated BMP signaling. In this context, the stem cell capacity of medulloblastoma spheroids was significantly inhibited by BMP stimulation in vitro. Moreover, we uncovered a regulatory network that maintains the transcriptional activation of BMP receptor type I (ACVR1) through the LHX2 transcription factor that maintains an active chromatin landscape at the ACVR1 proximal promoter. The depletion of LHX2 resulted in reduced tumor formation capacity of medulloblastoma in vivo. Taken together, our extensive studies across multiple model systems suggest that the TGF-β superfamily remodels the chromatin state to alter the cell cycle progression and, subsequently, affect cancer stemness and cell fate.
Citation Format: Mohamad Moustafa Ali, Yae Ohata, Carl-Henrik Heldin, Aristidis Moustakas. The TGF-β/BMP signaling cascades induce opposing fates in breast cancer and medulloblastoma through chromatin and cell cycle modulation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A155.
Abstract A158: Rational development of synergistic therapies alongside BMI1 Inhibition for group 3 medulloblastoma
Authors: Bakhshinyan David , Custers Stefan , Adile Ashley , Brown Kevin , Qazi Maleeha , Chokshi Chirayu , Escudero Laura , Suk Yujin , Venugopal Chitra , Moffat Jason , Singh Sheila 
Published: December 2023

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of its four distinct molecular subgroups, Group 3 MBs are associated with increased risk of recurrence, metastasis and overall poor patient outcome. In recent years, small molecule inhibitors that decrease BMI1 expression have shown to be efficacious against several types of malignant tumors including pediatric MB. Although in vivo studies provide a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB, mice that receive treatment eventually succumb to their disease. These results suggest that additional mechanisms may underlie the maintenance of MB and underscore the main obstacle in treating a constantly evolving tumor. After initial preclinical validation of BMI1 inhibitor PTC-596, DNA barcoding clonal tracking technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC-596. Comparison of clonal composition of tumors extracted from brains and spines post-treatment revealed the persistence of a small number of clones with the ability to escape therapy and drive subsequent tumor expansion. In order to better understand molecular susceptibilities of MB cells post-BMI1 inhibition, we undertook an in vitro genome-wide CRISPR/Cas9 screening to identify context-specific MB regulatory pathways that could be synergistically targeted along with BMI1. By comparing the results of the in vitro genome wide CRISPR/Cas9 screen to the essential genes in human neural stem cells (hNSCs), we identified several context specific regulators of mTOR, AKT and PLK1 pathways. Combination treatment alongside PTC-596 has demonstrated synergistic efficacy against MB cells with minimal toxicity to hNSCs in vitro and in preclinical in vivo studies. This study provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB.
Citation Format: David Bakhshinyan, Stefan Custers, Ashley Adile, Kevin Brown, Maleeha Qazi, Chirayu Chokshi, Laura Escudero, Yujin Suk, Chitra Venugopal, Jason Moffat, Sheila Singh. Rational development of synergistic therapies alongside BMI1 Inhibition for group 3 medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A158.
Abstract A166: CRISPR-Cas9 genome editing in iPSCs for functional genetic screening
Authors: Isachenko Nadja , Hu Dongfang , Chenchik Alex , Diehl Paul , Tedesco Donato 
Published: December 2023

Abstract
Induced pluripotent stem cells (iPSCs) are widely used for disease modeling, drug discovery, and cell therapy development. However, iPSCs are difficult to engineer with an efficient CRISPR/Cas9 system for functional genetic screens. We used WTC11 human iPS cells to generate functionally validated, lentiviral-transduced Cas9 lines, characterized by high gene-editing activity and sustained potential to differentiate. Flow cytometry was used to check for the expression of pluripotency markers Oct3/4, TRA1-60, and SSEA-4 in the iPS-Cas9 cells, and their actual pluripotency was then confirmed by testing the ability to differentiate into the three germ layers: ectoderm, mesoderm, and endoderm. Furthermore, genome-wide transcriptome analysis was performed to confirm the expression of germ layer-specific markers in the differentiated cells. Sustained Cas9 activity was confirmed in the differentiated cells. This study provides proof-of-principle that patient-derived iPSCs can be used to enable CRISPR/Cas9 functional genetic screening technology in reconstituted patient-specific tissues or disease models.
Citation Format: Nadja Isachenko, Dongfang Hu, Alex Chenchik, Paul Diehl, Donato Tedesco. CRISPR-Cas9 genome editing in iPSCs for functional genetic screening [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A166.
Abstract B051: PARG inhibition leads to the formation of toxic nuclear PARP1 aggregates
Authors: Paradkar Sateja , Cui Annie , Purcell Julia , Friedman Sam , Jensen Ryan , Bindra Ranjit 
Published: December 2023

Abstract
Mutations in DNA repair genes, such as BRCA1/2 mutations, occur in 50-70% of breast cancers among others. PARP inhibitors (PARPis) have shown remarkable efficacy against these tumors, however, emerging clinical evidence has revealed that PARPi resistance represents a major concern in these cancers with up to 90% of initial responders eventually developing resistance to the therapy. To overcome the limitations of PARPis, researchers have been working towards developing PARG inhibitors (PARGis) for the treatment of DNA repair-deficient cancers. In response to DNA damage, PARP1 synthesizes poly(ADP-ribose) (PAR) chains at break sites, which are crucial for the proper release of PARP1 and the recruitment of downstream repair proteins to the break site. PAR glycohydrolase (PARG) is the primary enzyme responsible for the resolution of PAR chains following repair. Owing to their central role in PARP-dependent processes, PARG inhibitors are currently being developed for cancer therapy, however, their precise mechanism of action has yet to be determined. Here we report that PARG loss or inhibition leads to cytotoxic effects through the formation of toxic PARP1 aggregates in response to DNA damage. Using live cell imaging assays, we determined that PARP1 aggregates form at sites distant from the original site of damage, causing a mislocalization of DNA repair factors from the damage site. We also find that these aggregates are formed by and composed of long, branched PAR chains, which are likely sequestering ATP and NAD+ reserves in the nucleus. Finally, we show that these aggregates are associated with increased cell death in BRCA-deficient cell lines suggesting that these aggregates are critical for PARGi mechanism of toxicity. Overall, this work elucidates the mechanism of action of PARG inhibitors, which will help identify patient populations in which these drugs could be used.
Citation Format: Sateja Paradkar, Annie Cui, Julia Purcell, Sam Friedman, Ryan Jensen, Ranjit Bindra. PARG inhibition leads to the formation of toxic nuclear PARP1 aggregates [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B051.
Abstract B053: Applying a new drug discovery platform for the discovery and development of inhibitors of DDR proteins APE1 and Pol eta
Authors: Das Debanu , Duncton Matthew , Deacon Ashley , III David Wilson 
Published: December 2023

Abstract
Quickly generating reliable hits from library screening and rapidly converting them into lead compounds, which can be verified in functional assays, is critical in early preclinical drug discovery. The expedited validation of “druggability” of targets and identification of modulators to advance to preclinical studies can significantly increase the success of drug discovery and development. Our SaXPy (“SAR by X-ray Poses Quickly”) platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or “undruggable” targets, allows (i) hit generation; (ii) mapping of protein-ligand interactions; (iii) assessment of target ligandability; (iv) discovery of novel and potential allosteric binding sites; and (v) hit-to-lead progression. These advances inform chemical tractability, downstream biology, and intellectual property. We describe here the application of SaXPy in the discovery and development of DNA Damage Response (DDR) inhibitors against DNA polymerase eta (Pol 𝝶 or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our studies resulted in the first crystal structures of these targets bound to small molecules and the discovery of novel, multiple binding sites, which we could quickly progress from hit-to-lead development and demonstrate functional activity in bioassays.
Citation Format: Debanu Das, Matthew Duncton, Ashley Deacon, David Wilson III. Applying a new drug discovery platform for the discovery and development of inhibitors of DDR proteins APE1 and Pol eta [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B053.