tbuckley/cabot-search huggingface dataset:
Abstract 4519: Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving complete tumor regression
Authors: Haibin Zhou, Dimin Wu, Longchuan Bai, Ranjan K. Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Shaomeng Wang
Journal: Cancer Research (2024)

Abstract STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic targets for cancer and other human diseases. We have previously reported the discovery of SD-36 and SD-91 as potent, selective and highly efficacious STAT3 degraders. In the present study, we report the discovery and extensive evaluation of highly potent, selective and efficacious new STAT3 degraders designed using novel cereblon ligands and novel STAT3 ligands. Our most potent STAT3 degraders are &amp;gt;10-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates &amp;gt;100-fold degradation selectivity over other STAT members. They achieve nanomolar IC50 values in leukemia and lymphoma cancer cell lines with activated STAT3. A single intravenous dose of these STAT3 degraders reduces the STAT3 protein for &amp;gt;48 hrs in xenograft tumor and native tissues, without reducing another other STAT members. Weekly administration of these STAT3 degraders is capable of achieving complete tumor regression in xenograft tumor models without any signs of toxicity. Taken together, these STAT3 degraders are promising lead compounds for extensive evaluation for the treatment of the treatment of human cancers and other human diseases in which STAT3 plays a key role. Citation Format: Haibin Zhou, Dimin Wu, Longchuan Bai, Ranjan K. Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving complete tumor regression [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 4519.
Abstract 4376: The pseudokinase PTK7 is a negative regulator of EPHA2 in colorectal cancer
Authors: Jean-Paul Borg, Charlotte Dessaux, Luc Camoin, Stéphane Audebert, Emilie Baudelet, Avais Daulat
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) remains a major public health issue. Identification of biomarkers predicting high risk of recurrence and discovery of novel targets for therapy are urgently needed1. The cell surface receptor PTK7 is a poorly described evolutionary conserved member of the receptor tyrosine kinase superfamily that was first identified in human colon carcinoma and melanoma2-3. Accumulated data highlighted the implication of PTK7 in diverse cancer-related signaling pathways4-6 and, despite the lack of kinase activity, anti-PTK7 inhibitors are currently in development at preclinical and clinical stages7-9. The dual aim of this project is to increase the basic knowledge about PTK7 and to evaluate its role in CRC in order to propose in the future novel therapeutics directed against PTK7. With the aim to discover novel PTK7 associated pathways, we used a proximity biotinylation strategy coupled to mass spectrometry in CRC cells. Among the partners identified, we found that the pseudokinase PTK7 interacts with the active receptor tyrosine kinase EphrinA2 (EPHA2). Similarly to PTK7, EPHA2 expression correlates with poor prognosis in CRC10. In this work, we also demonstrate that PTK7 acts as a negative regulator of EPHA2 activation through the promotion of distinct oligomeric protein complexes and the modulation of EPHA2 phosphorylation. We also shed in light on the role of PTK7 in EPHA2 K63-linked ubiquitination and its subsequent endosomal sorting and lysosomal degradation. References 1 Punt CJ et al, Nat. Rev. Clin. Oncol., 2016; 2 Lhoumeau AC et al, Cell Cycle, 2011; 3 Lhoumeau AC et al, PLoS One, 2015; 4 Puppo F et al, EMBO reports, 2011; 5 Martinez S et al, J. Biol. Chem., 2015; 6 Daulat AM and Borg JP, Trends in Cancer, 2017; 7 Damelin M et al, Sci. Transl. Med., 2017; 8 Jie Y et al, Front. Immunol., 2021; 9 Maitland ML et al, Clin. Cancer. Res., 2021; 10 Dunne P et al, Clin. Cancer. Res., 2016; 11 Cioce M and Fazio VM, Cancers, 2021. Citation Format: Jean-Paul Borg, Charlotte Dessaux, Luc Camoin, Stéphane Audebert, Emilie Baudelet, Avais Daulat. The pseudokinase PTK7 is a negative regulator of EPHA2 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 4376.
Abstract 6380: Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database
Authors: Junyi Shen, Anqi Lin, Quan Cheng, Jian Zhang, Peng Luo
Journal: Cancer Research (2024)

Abstract Background: With the widespread use of immune checkpoint inhibitors (ICIs) in the treatment of childhood cancers, their associated ICIs-related adverse events (irAEs) have become an important challenge. Our study was conducted to explore the pediatric high-risk ICIs-related AEs (pediatric irAEs) and explore the underlying mechanisms of pediatric irAEs. Methods: We analyzed ICIs-related adverse reaction reports in VigiBase from 1967 to 2023 and the FDA Adverse Event Reporting System (FAERS) database from 2013 to 2022. Using three methods, the reporting odds ratio (ROR), the proportional reporting ratio (PRR), and the information component (IC), we conducted a disproportionality analysis between pediatric and adult cancer patients using ICIs to discover pediatric irAEs. Furthermore, we explored the impact of clinical factors on the occurrence of pediatric irAEs and their subsequent prognosis through univariate and multivariate logistic regression analyses. Finally, combining these data with pan-cancer transcriptome data from the Gene Expression Omnibus (GEO) database, we explored the potential biological mechanisms related to pediatric irAEs. Results: We identified 4 categories of pediatric irAEs in the VigiBase and FAERS databases, including cytokine release syndrome (RORVigiBase = 17.05; RORFAERS = 14.17), acute respiratory distress syndrome (RORVigiBase = 10.26; RORFAERS = 12.39), seizure (RORVigiBase = 7.18; RORFAERS = 10.63) and febrile neutropenia (FN) (RORVigiBase = 3.01; RORFAERS = 4.84). The occurrence of pediatric irAEs may be related to mechanisms such as activation of immune cells, imbalance of inflammatory factors, activation of pathogen recognition, downregulation of inhibitory synapses, excitation/inhibition imbalance and central nervous system dysfunction. Conclusion: This study systematically analyzed the high-risk irAEs that may occur after using ICIs in pediatric cancer patients. Next, we explored the possible biological mechanisms of these pediatric irAEs to provide certain theoretical guidance for the prevention and treatment of adverse reactions in pediatric cancer patients after treatment with ICIs. Citation Format: Junyi Shen, Anqi Lin, Quan Cheng, Jian Zhang, Peng Luo. Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database [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 6380.
Abstract 4009: Discovery of inhibitory CAR target DSG1 for damping NECTIN4 on-target off-tumor toxicity in iPSC-derived CAR-T cell therapy
Authors: Matthew S. Hall, Christopher M. Dower, Michael Miller, John Wheeler, Jill Carton, Ohad Manor, Hyam Levitsky
Journal: Cancer Research (2024)

Abstract Century Therapeutics is developing NECTIN4 targeted induced Pluripotent Stem Cell (iPSC) derived Chimeric Antigen Receptor (CAR) T cell therapy. NECTIN4 targeted antibody drug conjugate enfortumab vedotin, while generally well tolerated, causes severe skin adverse events in some patients, thought to be driven by on-target off-tumor toxicity against NECTIN4 displaying skin keratinocytes. We include a safety switch in our first clinical-stage iPSC-derived CAR-NK cell therapy, CNTY-101, which provides an antibody target for elimination of the engineered cells should that be necessary. An additional method for reducing the incidence and severity of this type of adverse event is through the incorporation of an inhibitory CAR, also known as a NOT-gate, directed against antigen expressed on normal skin keratinocytes, but the optimal surface protein to target with such an inhibitory CAR for a NECTIN4 targeted therapy is unknown. Here, we identify DSG1 (Desmoglein-1) as a top inhibitory CAR target for NECTIN4 targeted CAR-T cell therapy by conducting a multi-omics analysis of public single-cell RNAseq, bulk RNAseq, and protein microarray immunohistochemistry datasets. We find that DSG1 is constitutively and uniformly displayed on the surface of skin keratinocytes in the layers of epidermis where they display NECTIN4, and DSG1 gene expression in normal skin is uniformly high across individuals. Conversely, DSG1 mRNA and protein are rarely expressed in NECTIN4 expressing cancer indications including bladder, breast, non-small cell lung, ovarian, and pancreatic. Further, autoimmune antibodies specific to DSG1 have been described, suggesting that DSG1 is targetable by a CAR in situ. Finally, DSG1 is not expressed by our iPSC-derived CAR-T cells. While NECTIN4 expression is greatest in skin keratinocytes, epithelial cells in other tissues express NECTIN4 at lower levels. In this study, we compare the expression levels of NECTIN4 to targets associated with tissue and cell-type specific on-target off-tumor toxicity in primary CAR-T cell clinical trials. Our findings support the strategy of DSG1-directed inhibitory CAR incorporation into NECTIN4 specific CAR-T cell therapeutic candidates. Citation Format: Matthew S. Hall, Christopher M. Dower, Michael Miller, John Wheeler, Jill Carton, Ohad Manor, Hyam Levitsky. Discovery of inhibitory CAR target DSG1 for damping NECTIN4 on-target off-tumor toxicity in iPSC-derived CAR-T cell 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 4009.
Abstract 3262: Elucidating the mechanism of resistance to tyrosine kinase inhibitors in <i>ROS1-</i>and <i>ALK-</i>fusion non-small cell lung cancer: The role of CD74
Authors: Vivian Ho, Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, Susumu S. Kobayashi
Journal: Cancer Research (2024)

Abstract The therapeutic landscape in treating advanced oncogene-mutated non-small cell lung cancer (NSCLC) was revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Despite the efficacious breakthrough and improved patient outcomes, disease progresses once more due to the seemingly inevitable development of drug resistance in tumor cells. This poses a considerable predicament in the clinical management of oncogene-mutated NSCLC and signifies the importance of elucidating the mechanism of resistance in tumor cells that harbor these genomic alterations which give rise to oncogenic drivers. Recent evidence suggests that drug-tolerant persister (DTP) cells, which are tolerant to initial exposure to TKIs give rise to acquired drug-resistant cells. Currently, the mechanism by which tumor cells undergo a drug-tolerant state is not well understood in NSCLCs driven by ALK or ROS1 fusion. Previously, we identified CD74 as a gene that may play a role in a drug-tolerant state in EGFR-mutated lung cancer via single-cell RNA-sequencing (scRNA-seq). Here, we sought to determine whether the CD74 signaling also leads to resistance to TKIs in NSCLCs with ALK or ROS1 fusion. We showed that CD74 expression increased at both the mRNA and protein levels after treatment with respective TKIs in ALK and ROS1 fusion cells lines. Notably, the ALK and ROS1 fusion cell lines also exhibited an increase in mRNA expression levels of upstream and downstream genes of CD74. Additionally, we generated CD74 knock-out and overexpression models in two cells lines, HCC78 (SLC34A2-ROS1 fusion) and H2228 (EML4–ALK fusion), to further examine the role of CD74 expression in DTP cells. We demonstrated that resistance to TKIs were dependent on CD74 expression. Furthermore, it was determined that anti-CD74 antibody-drug conjugates, in combination with TKIs, synergistically induced apoptosis in these cell lines. In conclusion, our data suggest that CD74 can be a therapeutic target in NSCLC with ALK or ROS1 fusion. Citation Format: Vivian Ho, Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, Susumu S. Kobayashi. Elucidating the mechanism of resistance to tyrosine kinase inhibitors in ROS1-and ALK-fusion non-small cell lung cancer: The role of CD74 [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 3262.
Abstract 6768: Matched XPDX™derivative models as a platform for continuity across preclinical drug development
Authors: Melissa Millard, Aaron Carlson, Danielle Y. Nadeau, Kimberly J. Burgess, Alyssa Simonson, Armando Diaz, Michael Wick, Teresa DesRochers
Journal: Cancer Research (2024)

Abstract Drug discovery is a reductive process in which druglike entities are carried through increasingly complex assay formats to tease out the compounds best suited for human studies. In vivo efficacy remains the benchmark for successful preclinical drug development. Cell-based models are a mainstay in early stages but translatability of different models across platforms remains a challenge. In oncology, patient-derived xenografts (PDX) are the gold standard for animal studies because they recapitulate key features of human tumors including the cellular heterogeneity, growth patterns, and drug response of the original patient tumor. Ex vivo, PDX derivatives have the potential to harness these same traits thereby extending the utility of PDX models to earlier stages of preclinical drug development. The KIYA-Predict™ platform is a clinically validated tool for the assessment of ex vivo drug responses across a broad range of drug classes that when applied to XPDX models shows good correlation to in vivo drug responses and excellent intra-sample reproducibility over time. Working with the well-characterized XenoSTART™ XPDX model repository, Kiyatec has derived 2D cell lines and organotypic 3D-expansion cultures to complement the ex vivo predictive value of our KIYA-PREDICT™ XPDX drug response profiling (DRP) platform. The development of syngeneic models applicable to simpler, high-throughput library screening (2D formats) and lower-throughput more complex mechanistic studies (3D organotypic models) could alleviate the burden and pitfalls of extrapolating data across unrelated models. Matched sets of 2D cell lines (2D-XPDX™) and 3D organotypic (XPDXO™) cultures were established from single cell suspensions of digested, mouse-cell depleted XPDX™ tissue samples. Drug response profiling of the XPDX™ in their various ex vivo culture formats showed relative similarities across platforms. Genomic profiling of the derivates confirmed shared tissue origin and retention of genomic and phenotypic signatures to varying degrees across models. Mechanistic evaluation of 3D organotypic culture demonstrated that disease-relevant biomarkers and processes are maintained. Together these results demonstrate the feasibility of this novel drug discovery platform that avoids ambiguity imparted by discordant models. Citation Format: Melissa Millard, Aaron Carlson, Danielle Y. Nadeau, Kimberly J. Burgess, Alyssa Simonson, Armando Diaz, Michael Wick, Teresa DesRochers. Matched XPDX™derivative models as a platform for continuity across preclinical drug 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 6768.
Abstract 677: Discovery of a first-in-class allosteric inhibitor of the small GTPase Rac1
Authors: Robert Silverman, Alan Cooper, Ronodip Kar, Mayuri V. Raman, Ramu Ravirala, Mubarak Hasan Shah, Sandeep Mahankali, Erik T. Goka
Journal: Cancer Research (2024)

Abstract The Rac1 signaling pathway is known to be hyperactivated in numerous solid tumors. We developed a Rac1 AlphaLISA assay that is amenable to high-throughput screening (HTS) to screen large libraries of small molecules. Based on molecular modeling of a putative allosteric binding site for several of the hits, we optimized a series of compounds that lead to RP-102124. RP-102124 engages with Rac1 in both biochemical and cellular target engagement assays. RP-102124 has greater potency than previously reported Rac1 inhibitors in biochemical assays, with potent inhibition of phenotypic characteristics of Rac signaling such as cell migration and cytoskeletal rearrangements. RP-102124 is a Racmulti inhibitor with activity against oncogenic Rac1b. RP-102124 is orally bioavailable and shows dose dependent inhibition of tumor growth in xenograft models at doses that are well-tolerated. RP-102124 is a first-in-class allosteric Racmulti inhibitor that shows promising therapeutic potential. Citation Format: Robert Silverman, Alan Cooper, Ronodip Kar, Mayuri V. Raman, Ramu Ravirala, Mubarak Hasan Shah, Sandeep Mahankali, Erik T. Goka. Discovery of a first-in-class allosteric inhibitor of the small GTPase Rac1 [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 677.
Abstract 7499: Circulating tumor cell enumeration and protein expression by CapioCyte and Allegro Plus imaging
Authors: Ju-heon Lim, Chassidy Johnson, Tal Kaplan, Michael J. Poellmann, Yuval Harari, Elad Kfir, Andrew Z. Wang, Seungpyo Hong
Journal: Cancer Research (2024)

Abstract Radiation or chemoradiation followed by surgical resection is the current standard of therapy for many diseases. These treatments are increasingly supplemented with monoclonal antibodies, such as epidermal growth factor receptor (EGFR)-targeting and programmed death ligand 1 (PD-L1) checkpoint-blocking antibodies. The use of these therapies is typically dependent on solid tissue biopsy to confirm elevated expression of these markers in the solid tumor, which carries complications and may only be sampled at diagnosis. In contrast, a liquid biopsy may detect these markers with minimal invasiveness and at multiple points throughout treatment and recovery. Here, we describe the development of an automated and integrated workflow for circulating tumor cell (CTC) analysis. We previously demonstrated that the CapioCyte method is a highly sensitive approach for enrichment of CTCs using a combination of biomimetic rolling on recombinant E-selectin and antibody-mediated capture on a nanostructured polymer surface within a flow chamber for capture. Here we report a fully automated CapioCyte instrument for CTC purification and immunofluorescence staining using epithelial, white blood cell and nuclear makers to identify and distinguish CTCs from WBCs while also quantifying EGFR or PD-L1 presence on respective CTCs. The immunostaining conditions were developed and validated for high analytical sensitivity and specificity using cell lines and health donor white blood cells with known biomarker status. The final assay conditions were transferred to the CapioCyte for automated immunostaining. CapioCyte enriched and stained CTC samples are paired with the BioView Allegro Plus platform, an imaging and analysis solution using machine learning and customized algorithms for automated imaging and CTC candidate identification based on high-resolution Z-stack images. The reported comprehensive and automated workflow was used to enumerate CTCs in patients with non-small cell lung carcinoma (NSCLC) in a feasibility cohort. Median CTC counts from NSCLC patients was 7.5 CTC/ml (n=26, mean 51.7, range 0.3 - 406.2). Studies are on-going to expand the cohort including testing blood from head and neck cancer patients and respective EGFR and PD-L1 status. The combined and automated CapioCyte-Allegro Plus workflow shows great potential for routine quantification of CTCs and EGFR and PD-L1 status. Citation Format: Ju-heon Lim, Chassidy Johnson, Tal Kaplan, Michael J. Poellmann, Yuval Harari, Elad Kfir, Andrew Z. Wang, Seungpyo Hong. Circulating tumor cell enumeration and protein expression by CapioCyte and Allegro Plus 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 7499.
Abstract 6996: A role for the cell adhesion molecule NCAM1 in regulating activity of the receptor tyrosine kinase RET in cancer
Authors: Montdher H. Hussain, Brandy D. Hyndman, Frederick S. Vizeacoumar, Mathieu J. Crupi, Franco J. Vizeacoumar, Lois M. Mulligan
Journal: Cancer Research (2024)

Abstract RET (REarranged during Transfection) is a receptor tyrosine kinase with essential roles in early development; however, genetic alterations lead to aberrant RET activity that contributes to oncogenic processes in several cancers. While some of the mechanisms by which RET mediates these processes are known, the network of proteins facilitating its activity remains largely undiscovered. To address this, we performed a genome-wide synthetic dosage lethal screen which identified NCAM1 (Neural Cell Adhesion Molecule 1) as one potential candidate modulating RET activity. Using an NCAM1 knockdown (KD) in SH-SY5Y neuroblastoma cells, we show that loss of NCAM1 reduces total protein levels of RET with no effect on RET transcription. Despite reduced abundance of RET, we show that the mature form of RET has a prolonged half-life in the absence of NCAM1. Assessing the functional outcomes of reduced RET protein levels, we observe reduced activation of RET by its extracellular ligand GDNF (Glial cell line-derived neurotrophic factor) and a subsequent reduction in activation of proliferative signaling pathways downstream of RET. As a result, RET-mediated proliferation is diminished in the absence of NCAM1, with reduced viability of NCAM1 KD SH-SY5Y observed in response to GDNF. Together, our data suggest that the synthetic lethal relationship between RET and NCAM1 may arise from a role for NCAM1 in regulating total RET protein available for activation, thereby reducing RET-mediated cell viability and proliferation. Our work has uncovered a role for NCAM1 in modulating RET activity in cancer and validates the use of our synthetic dosage lethal approach in uncovering proteins facilitating oncogenic RET activity. Citation Format: Montdher H. Hussain, Brandy D. Hyndman, Frederick S. Vizeacoumar, Mathieu J. Crupi, Franco J. Vizeacoumar, Lois M. Mulligan. A role for the cell adhesion molecule NCAM1 in regulating activity of the receptor tyrosine kinase RET in 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 6996.