tbuckley/cabot-search huggingface dataset:
Abstract 3091: Discovery of highly selective ligands with unique binding modes for challenging oncology targets using DNA-encoded chemical libraries
Authors: Ying Zhang, Anthony Keefe, Matthew A. Clark
Journal: Cancer Research (2024)

Abstract DNA-encoded chemical library (DEL) technology enables the efficient screening of large collections of encoded compounds and has emerged as a powerful tool for hit identification in recent years. The technology allows for the multiplexed interrogation of target-ligand binding interactions and results in DEL hits with unusual binding modes and desirable selectivity. This screening methodology is particularly effective for oncology targets. Examples of discovery of highly selective ligands for challenging oncology targets, including kinases, protein-protein interactions, and receptors, will be presented. We will illustrate how DEL campaign strategies directly aim at novel binding modes, and provide molecular details around the uniqueness of these interactions. Furthermore, we will show how these novel binding modes lead to unique pharmacology with direct benefit to patients. Lastly, we will demonstrate how X-Chem’s high-quality encoded libraries enhance the tractability and novelty of chemical equity discovered with the platform. Citation Format: Ying Zhang, Anthony Keefe, Matthew A. Clark. Discovery of highly selective ligands with unique binding modes for challenging oncology targets using DNA-encoded chemical libraries [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 3091.
Abstract 4161: Identification of pancreatic adenocarcinoma using urokinase plasminogen activator probe detected using optoacoustic imaging
Authors: Vung Kim, Phillip Chuong, Ryan Bynum, William Grizzle, Lacey R. McNally
Journal: Cancer Research (2024)

Abstract Purpose: Diagnosing and treating pancreatic cancer remains a challenge. The hypovascularized nature of pancreatic cancer renders modern chemotherapeutics and cancer detection contrast agents ineffective. A promising approach to the challenges is the adoption of a novel imaging technique known as Multispectral Tomography (MSOT). We hypothesize that a urokinase plasminogen activator (UPA) probe will enhance the detection of orthotopic pancreatic cancer xenografts. Methods: Pancreatic tumor cell lines (Panc1, MiaPaca-2, S2VP10, and S2C9) were assessed for UPA-receptor expression using western blot analysis. UPA peptide was synthesized and to the HiLyte-750 NIR dye. Flow cytometry and immunofluorescence were utilized to examine the specificity and activity of this UPA-750. The UPA-750 binding efficiency was assessed through a competitive inhibition assay with a UPAR-blocking antibody using fluorescence microscopy. Then SCID mice (5 mice/group) received orthotopic implantation of S2C9 (1.5 x 105) or MiaPaCa2 (2.0 × 106) pancreatic tumor cells. UPA-750 or 750 dye alone was IV injected into mice after the tumors reached 3mm. Biodistribution and accumulation of UPA-750 were observed through MSOT images taken at 2-hour intervals over 8 hours and at 24 hours. UPA-750 in the tumor, liver, and kidney was confirmed through ex vivo fluorescent imaging. Results: UPAR expression was observed in every pancreatic cancer cell line, with the greatest relative abundance in S2P9 cells (3.0X), followed by S2VP10 (2.5X), Panc1 (1.77X), and MiaPaca-2 (1.3X). Application of the UPAR blocking antibody on S2CP9, S2VP10, MiaPaCa2, and SKOV3p1 (positive control) cell lines resulted in the inhibition of cellular binding of the UPA-750, as evidenced by fluorescence microscopy. UPA-probe was successfully observed in pancreas tumor slices with peak intensity at 4-hrs of imaging by MSOT. Ex vivo NIR fluorescence imaging confirmed UPA-750 signal in pancreatic tumors but not in liver or kidney. Conclusion: UPA-probe exhibits potential as a marker for pancreatic cancer. Citation Format: Vung Kim, Phillip Chuong, Ryan Bynum, William Grizzle, Lacey R. McNally. Identification of pancreatic adenocarcinoma using urokinase plasminogen activator probe detected using optoacoustic imaging [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 4161.
Abstract 1675: Investigating the role of SRC-family kinases in MPNST tumorigenesis
Authors: Elamine Zereg, Laure Voisin, Karl Grenier, Mathieu Courcelles, Sungmi Jung, Pierre Thibault, Sylvain Meloche
Journal: Cancer Research (2024)

Abstract Purpose: Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, is the leading cause of mortality in patients with neurofibromatosis type 1. Over the past two decades, significant advancement has been made in understanding the pathogenesis of MPNST. Still, this progress has not improved overall survival of patients. Therefore, ongoing efforts to identify alterations contributing to the transformation, progression, and metastasis of MPNST are essential for pinpointing targetable oncogenic signaling pathways for this cancer. Previous studies have revealed an increase in YAP/TAZ activity through both LATS1/2-dependent and LATS1/2-independent mechanisms, suggesting that YAP/TAZ hyperactivity may act as a convergence point for MPNST pathogenesis. YES and SRC, two members of the SRC-family kinases (SFKs), were shown to phosphorylate LATS1/2 and YAP/TAZ, and stimulate the transcriptional activity of YAP/TAZ by promoting their nuclear accumulation in hepatocellular carcinoma and colorectal cancer cells. Thus, we have investigated whether YES and SRC are involved in the pathogenesis of MPNSTs. Experimental Design: To assess whether the SFK-YAP/TAZ signaling axis is implicated in the development of MPNST, we have used genetic and pharmacological approaches to investigate the roles of YES and SRC in the proliferation of a subset of human MPNST cell lines, and in the growth of xenografted MPNST tumors in ectopic and orthotopic mouse models. We also performed a phosphoproteome and a transcriptome analysis of YES and SRC-depleted MPNST cells to assess their oncogenic signaling network. Lastly, we evaluated the clinical significance of phospho-SFK and YAP in human MPNST TMAs. Results: Our findings reveal that YES and SRC activity play an essential and redundant role in sustaining the proliferation of human MPNST cell lines. Further, the simultaneous depletion of both kinases impedes tumor growth in xenograft MPNST mouse models. Transcriptomic analyses identified YAP and TAZ as potential effectors of SFKs, as well as other family of transcription factors. Finally, TMA data suggested a correlation between the expressions of YAP, YAP/TAZ, and phospho-SFK and the progression of MPNST. Citation Format: Elamine Zereg, Laure Voisin, Karl Grenier, Mathieu Courcelles, Sungmi Jung, Pierre Thibault, Sylvain Meloche. Investigating the role of SRC-family kinases in MPNST tumorigenesis [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 1675.
Abstract 4153: PET/CT imaging of pancreatic ductal adenocarcinoma with a claudin-4 binding peptide in preclinical mouse model
Authors: Jai Woong Seo, James Wang, Aris J. Kare, Spencer K. Tumbale, Bo Wu, Marina N. Raie, Mallesh Pandrala, Katherine W. Ferrara
Journal: Cancer Research (2024)

Abstract There is a critical need to develop new imaging and therapeutic strategies for pancreatic cancer. Current positron emission tomography (PET) imaging assessments of pancreatic ductal adenocarcinoma (PDAC) rely on 18F-FDG as a radiopharmaceutical. To increase the sensitivity of PDAC detection, we identified Claudin-4 (CLDN4), a tight junction transmembrane protein, as a PDAC biomarker through spatial transcriptomic and proteomic analyses. CLDN4 expression has previously been reported to be enhanced in 99% of primary and 100% of metastatic pancreatic cancer tissue samples and in 10 of 11 precancerous pancreatic intraepithelial neoplasia (PanIN) specimens. A small fragment of naturally occurring Clostridium perfringens enterotoxin (CPE) was previously reported to bind to the extracellular loop domain of CLDN4 protein (PDB:7kp4) with nanomolar (nM) affinity (Kd). A CLDN4 binding peptide (C4BP) was developed as a radioligand by modifying the n-terminus of C4BP which does not impact receptor binding. Here, we designed and synthesized a DOTA-PEG1-C4BP ligand on a rink amide resin using a microwave-assisted peptide synthesizer. Radiolabeling of DOTA-PEG1-C4BP (2 nmol) with 64CuCl2 (70 MBq) conferred 64Cu-C4BP (28 MBq/nmol) with 80% non-decay corrected yield and &amp;gt;99% radiochemical purity. PET/CT imaging of 64Cu-C4BP (~0.1 μg/mouse) performed in an inducible PDAC (KrasLSL-G12D/+;Rosa26LSL-tdTomato/LSL-tdTomato(KT);Ptf1aCreER;Trp53fl/fl) model at 84 day after tamoxifen injection resulted in ~25% injected activity per cubic centimeter (IA/cc) accumulation in metastases and at ~18% IA/cc retention in pancreatic tumors within 30 minutes of tail vein injection with minimal background accumulation. Ex vivo PET imaging confirmed the localized accumulation of 64Cu-C4BP in transgenic mice within the colon, pancreas, and liver. Blocking of 64Cu-C4BP accumulation with the cold compound in a xenograft model (NOD/SCID) bearing Capan-1 PDAC tumors demonstrated the specificity of 64Cu-C4BP binding. Here we report that CLDN4 is a promising target and 64Cu-C4BP is a promising ligand for the detection of pancreatic cancer. Citation Format: Jai Woong Seo, James Wang, Aris J. Kare, Spencer K. Tumbale, Bo Wu, Marina N. Raie, Mallesh Pandrala, Katherine W. Ferrara. PET/CT imaging of pancreatic ductal adenocarcinoma with a claudin-4 binding peptide in preclinical mouse model [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 4153.
Abstract 4588: Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic cancer
Authors: Kristina Drizyte-Miller, Wen-Hsuan Chang, Andrew M. Waters, Clint A. Stalnecker, Junning Wang, Andrew J. Aguirre, Adrienne D. Cox, Channing J. Der
Journal: Cancer Research (2024)

Abstract KRAS is mutationally activated in 95% of pancreatic ductal adenocarcinoma (PDAC) patients. Direct KRAS inhibitors are under intense preclinical and clinical development, with two KRASG12C mutant-selective inhibitors (G12Ci) now approved. However, treatment-associated resistance to KRAS inhibitors has been reported in the clinic highlighting an urgent need to identify both additional therapeutic targets and novel combination treatment strategies with KRAS inhibitors. To that end, we performed a CRISPR/Cas9 loss-of-function screen using a library targeting ~2,500 druggable genes in KRASG12C/D-mutant PDAC cell lines. We identified multiple genes that were essential for PDAC cell growth and selected PRMT5, a protein arginine methyltransferase, to assess as a novel therapeutic target for pancreatic cancer. We found that suppression of PRMT5 activity using two distinct first-generation clinical candidate small molecule inhibitors (JNJ-64619178 and GSK3326595) demonstrated single agent activity and reduced PDAC cell growth. We further assessed a mechanistically distinct MTA-cooperative clinical candidate PRMT5 inhibitor, MRTX1719, that is selective for MTAP-deleted tumors, which occur in ~25% of PDAC patients. We determined that MRTX1719 exhibited low nanomolar GI50 activities in MTAP-deficient but not MTAP wild-type KRAS-mutant cell lines. Unexpectedly, PDAC cells treated with MRTX1719 exhibited a paradoxical activation of ERK, suggesting that combined inhibition of PRMT5 and KRAS might be therapeutically advantageous. In support of our hypothesis, we demonstrated that combination treatment with MRTX1719 and mutant selective KRAS inhibitors (G12Ci/MRTX849 and G12Di/MRTX1133) further sensitized KRASG12C/D-mutant PDAC cells to KRAS inhibition in short- and long-term growth assays as well as in vivo xenograft studies. Our ongoing studies are evaluating the consequences of co-targeting PRMT5 and KRAS on gene expression changes using RNA-Seq and cancer cell signaling pathways using RPPA analyses. In summary, our data support concurrent inhibition of PRMT5 and KRAS as a promising therapeutic strategy for MTAP-deficient KRAS-mutant pancreatic cancer. Citation Format: Kristina Drizyte-Miller, Wen-Hsuan Chang, Andrew M. Waters, Clint A. Stalnecker, Junning Wang, Andrew J. Aguirre, Adrienne D. Cox, Channing J. Der. Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic 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 4588.
Abstract 4597: RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer
Authors: Xiaoting Zhang, Na Qin, Fenfen Ji, Hao Su, Hongyan Chen, Haiyun Shang, Huarong Chen
Journal: Cancer Research (2024)

Abstract The widespread presence of N1-methyladenosine (m1A) modifications controls RNA metabolism and is pivotal to fundamental biological processes. However, the understanding of RNA m1A involved in cancer is still minimal. Here we reported the oncogenic role and the therapeutic targeting of RNA m1A methyltransferase TRMT61A in colorectal cancer (CRC). We observed consistent elevation of TRMT61A expression and RNA m1A levels in primary CRC tissues, which was significantly associated with poor patient survival in two independent cohorts (both P&amp;lt;.001). CRISPR/Cas9 screenings revealed that TRMT61A is the most essential gene among m1A regulators. TRMT61A facilitates the growth and metastasis of CRC cells by increasing the stability of mRNA of crucial targets, such as ONECUT2, which leads to the activation of MAPK/ERK signaling in an m1A-dependent manner. Notably, depletion of ONECUT2 or inhibition of MAPK/ERK could abrogate the tumor-promoting role of TRMT61A, implying that TRMT61A induces ONECUT2-MAPK/ERK axis to facilitate CRC. Inhibiting TRMT61A with nanoparticle-encapsulated siTRMT61A or our recently identified small molecule compound PGG shows promising anti-CRC effects in vitro and in vivo. Together, our study reveals the promoting role of TRMT61A-induced m1A modification in MAPK/ERK signaling and highlights the potential of targeting TRMT61A as a promising therapeutic approach in CRC treatment. Citation Format: Xiaoting Zhang, Na Qin, Fenfen Ji, Hao Su, Hongyan Chen, Haiyun Shang, Huarong Chen. RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal 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 4597.
Abstract 1325: CD19 CAR-expressing iPSC-derived NK cells effectively enhance migration and cytotoxicity into glioblastoma by targeting to the pericytes in tumor microenvironment
Authors: Dasom Kong, Daekee Kwon, Bokyung Moon, Da-Hyun Kim, Kyung-Sun Kang
Journal: Cancer Research (2024)

Abstract In cancer immunotherapy, targeting specific antigens with chimeric antigen receptors (CARs) has emerged as a potent tool for cell-based therapy. After being accessed by CARs, the selective anticancer lysis by CAR-natural killer (NK) cells through ‘missing-self’ and ‘induced-self’ mechanisms can mitigate off-tumor toxicity, a contrast to CAR-T cells. This specificity can be advantageous in the heterogeneous milieu of solid tumors. In the tumor microenvironment of glioblastoma (GBM), pericytes not only support tumor growth but also contribute to immune evasion, underscoring their potential as therapeutic targets in GBM treatment. Indeed, we examined and observed the presence of CD19-positive pericytes derived from GBM in patient samples, particularly within the perivascular niche, highlighting CD19 as a possible therapeutic target. Given this context, our study aimed to target the GBM tumor microenvironment, with a special focus on pericytes expressing CD19, to evaluate the potential effectiveness of CD19 CAR-iNK cells against GBM. In this study, we generated induced pluripotent stem cell-derived NK (iNK) cells with CD19 CAR. To determine whether CD19 CAR targets the tumor microenvironment pericytes in GBM, we developed GBM-blood vessel assembloids (GBVA) by fusing GBM spheroids with blood vessel organoids. When co-cultured with GBVA, CD19 CAR-iNK cells migrated towards the pericytes surrounding the GBM, inducing tumor lysis through NKp44 upregulation. Using a microfluidic chip, we observed that post-infused CD19 CAR-iNK cells targeted pericytes in a perfusion-like setting, facilitating an examination of CD19 CAR-driven migration and their tumor-specific cytotoxicity on the GBM. Therefore, we conclude that CD19 CAR-iNK cells may effectively target the pericytes in the GBM tumor microenvironment, suggesting their potential therapeutic value for GBM treatment. Citation Format: Dasom Kong, Daekee Kwon, Bokyung Moon, Da-Hyun Kim, Kyung-Sun Kang. CD19 CAR-expressing iPSC-derived NK cells effectively enhance migration and cytotoxicity into glioblastoma by targeting to the pericytes in tumor microenvironment [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 1325.
Abstract 1677: The emerging role of the Plasminogen-Apple-Nematode (PAN) domain in cancer therapy
Authors: Kuntal De, Debjani Pal, Wellington Muchero
Journal: Cancer Research (2024)

Abstract The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in more than 28,000 proteins across 959 genera. However, its role in protein function still needs to be elucidated. Numerous proteins initially characterized the PAN domain, including a well-known master regulator for cancer cell proliferation, HGF (Hepatocyte growth factor). Abnormal regulation of HGF-mediated signaling results in multiple deadly cancers. The binding of HGF to its cell surface receptor, c-MET, triggers signaling pathways, which leads to cancer. Here, we show that mutating four core cysteine residues in the HGF PAN domain reduces c-MET interaction, subsequent c-MET autophosphorylation, and phosphorylation of its downstream targets, perinuclear localization, cellular internalization of HGF and its receptor, c-MET, and c-MET ubiquitination. Furthermore, transcriptional activation of HGF/c-MET signaling-related genes involved in cancer progression, invasion, metastasis, and cell survival was impaired. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway. Additionally, we found this domain in the tumor suppressor gene, MST1 (macrophage stimulating 1), and mutating the domain altered the protein function through protein stability and ubiquitination. In another study, we show that cysteine residues in the vestigial plasminogen-apple-nematode (PAN) domain of NRP1 are necessary for SARS-CoV-2 spike protein internalization. Mutating novel cysteine residues in the PAN altered NRP1 stability and downstream activation of the extracellular signal-regulated kinase (ERK) signaling pathway, impairing its interaction with the spike protein. These results show the diverse critical role of the PAN domain beyond cancer therapy. Citation Format: Kuntal De, Debjani Pal, Wellington Muchero. The emerging role of the Plasminogen-Apple-Nematode (PAN) domain in cancer therapy [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 1677.
Abstract 4540: SY-7021, a novel DNA-PK inhibitor, exhibits significant anti-tumor activity <i>in vitro</i> and <i>in vivo</i>
Authors: Kai Zhang, Zhihua Liu, Yuhao Gao, Chang Lu, Shikang Cheng, Xijie Liu, Hong Luo, Yinghui Sun
Journal: Cancer Research (2024)

Abstract Cancer therapies such as ionizing radiation or topoisomerase II inhibitors (for example, doxorubicin) induce DNA double-strand breaks (DSBs), which can subsequently be repaired by homologous recombination or non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine protein kinase complex, is a pivotal component of the NHEJ process that maintain genome integrity. The critical role of DNA-PK in DNA damage response (DDR) and the dysregulated DNA-PK expression in cancer make it an intriguing therapeutic target for cancer, especially when combined with DSBs agents. Here, we identified a highly potent and selective DNA-PK inhibitor, SY-7021, with an IC50 value of 0.242 nM on DNA-PK kinase and high selectivity on ATM and ATR (greater than 400-fold) in biochemical assays. In a reporter assay for NHEJ repair, SY-7021 was able to dose-dependently reduce cellular NHEJ efficiency. Functionally, SY-7021 inhibited cell proliferation in multiple cancer cell lines alone or combined with doxorubicin. Basically, combination of SY-7021 and doxorubicin induced significant G2/M phase arrest and cell apoptosis, as well as enhanced the phosphorylation on Ser139 of γH2AX, Tyrosine 68 of CHK2 and Serine15 of p53 in MDA-MB-468 cells. In a subcutaneous NCI-H1703 xenograft tumor model, SY-7021 administered orally twice daily achieved dose-dependent tumor growth inhibition in vivo, with a tumor growth inhibition (TGI) of 105.6% at 60 mg/kg and no significant weight loss was observed. In addition, SY-7021 demonstrates good PK properties and acceptable safety profiles in in vivo studies. Collectively, SY-7021, a potent and selective DNA-PK inhibitor, shows significant inhibition on tumor growth in in vitro and in vivo studies, providing a rationale treatment for multiple tumors in monotherapy or in combination with other agents. Citation Format: Kai Zhang, Zhihua Liu, Yuhao Gao, Chang Lu, Shikang Cheng, Xijie Liu, Hong Luo, Yinghui Sun. SY-7021, a novel DNA-PK inhibitor, exhibits significant anti-tumor activity in vitro and in vivo [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 4540.