tbuckley/cabot-search huggingface dataset:
Abstract 3919: Identifying dual inhibitions of kinases to treat pancreatic ductal adenocarcinoma
Authors: Masahiro Sonoshita
Journal: Cancer Research (2025)

Abstract Significant advancements have been achieved in elucidating the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) through the development and application of mammalian models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, we established a Drosophila model recapitulating the genetic signature of PDAC, characterized by alterations in KRAS, TP53, CDKN2A, and SMAD4, which are associated with the poorest patient prognosis. The ‘4-hit’ flies manifested tumorigenic phenotypes, such as epithelial transformation and reduced animal viability. Comprehensive kinome-wide genetic screening using this model identified potential therapeutic targets, including MEK, AURKB, and GSK3β. Notably, combined inhibition of these targets effectively suppressed the growth of human PDAC xenografts in mice. Moreover, the activity of these kinases correlated with adverse outcomes in PDAC patients. This Drosophila-based platform offers a robust whole-body assay to complement existing methodologies to determine therapeutic targets in PDAC. Citation Format: Masahiro Sonoshita. Identifying dual inhibitions of kinases to treat pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3919.
Abstract 5168: Mouse models accelerating cancer research at The Jackson Laboratory
Authors: Jason Beckwith, Jen Merriam, Darcy Pomerleau, Crystal Davis, Jennifer Kelmenson, Hiroaki Onda
Journal: Cancer Research (2025)

Abstract The Jackson Laboratory (JAX) provides genetically defined mutant and transgenic mice to support the scientific research community. Available are mouse models for specific cancers, xenograft recipients, immunodeficient platforms for PDX studies and multi-purpose tool strains having CRISPR utility, conditional/inducible expression (Cre-lox, FLP-frt, Tet-On/-Off), optogenetic function and calcium-sensing technologies. This poster will highlight newly developed models designed for cancer research. The portfolio of strains useful for transplantation and humanized mouse research continues to expand and complement the NSG (NOD scid IL2rγc-/-) model as premier tools for engraftment with a wide range of malignant or non-malignant human or mouse tissues. Novel fluorescent strains include Gene Editing Reporters for visualizing homology-directed repair (HDR) and non-homologous end joining (NHEJ) repair events, as well as several CRISPR Editing, Bxb1 Integrase Editing, Base Editor, Prime Editor and DNA repair pathway tools. Furthermore, new strains enable researchers to achieve extensive barcode diversity within targeted cell populations. Models utilizing the auxin-inducible degron system allow degradation of tagged proteins following administration of 5-Ph-IAA. In addition to cryopreserving each strain, JAX employs a genetic quality control program that confirms mutation identity and genetic background, and screens for unwanted alleles (such as stray GFP, Cre, neo, etc.). Cancer researchers can query the collection of innovative mouse models using the JAX Mouse Search site (mice.jax.org). This resource includes models created by many generous donating institutions. Researchers are encouraged to donate their mouse lines via a very short Strain Submission form (jax.org/donate-a-mouse). Please also visit the JAX Oncology webpage for cancer research related strains and resources (jax.org/jax-mice-and-services/solutions-by-therapeutic-area/oncology). JAX is supported by the NIH, The Howard Hughes Medical Institute and other private charitable foundations. Citation Format: Jason Beckwith, Jen Merriam, Darcy Pomerleau, Crystal Davis, Jennifer Kelmenson, Hiroaki Onda. Mouse models accelerating cancer research at The Jackson Laboratory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5168.
Abstract 3918: Development and validation of a systemic human multiple myeloma model utilizing luciferase expressing H929 tumor cells
Authors: Bincy John, David Harris, Shu-Chuan Chou, Tyler Rowe, Nicole Westrick, Nick Nightenhelser, Andrew Wong, Elizabeth Rainbolt, Zachary Ward, Jessica Neil
Journal: Cancer Research (2025)

Abstract Multiple Myeloma (MM) is the second most common hematological malignancy of clonal plasma cells that originates in the bone marrow (BM). Despite significant advancements in the treatment of MM, this disease remains incurable with a poor prognosis in relapsed/refractory patients. MM has complex disease dynamics due to the genetically diverse clonal population of myeloma cells. Thus, pre-clinical models are needed to translate tumor heterogeneity for appropriate risk assessment and the development of safe and effective treatment regimens. We established a Multiple Myeloma in vivo model by systemic implantation of the luciferase-expressing tumor cell line H929 (H929-luc) into immunodeficient NCG mice. First, we generated a H929-luc monoclonal cell line from a polyclonal pool of stable luciferase-expressing cells by limiting dilution cloning. Single cells from the stable pool were expanded in selection medium and based on in vitro growth properties and bioluminescence intensity H929-luc monoclonal lines were selected for in vivo evaluation. The in vivo tumor growth profile was determined by testing the monoclonal lines at two different cell inoculums, and disease progression was monitored by in vivo serial bioimaging. For validation of the H929-luc in vivo model, we determined the efficacy and survival benefit in response to various clinically relevant standard of care agents including dexamethasone, daratumumab, cyclophosphamide, and vincristine. The quantification of tumor burden by bioluminescent imaging showed reduced tumor burden and prolonged survival with cyclophosphamide and vincristine. Taken together, we have developed a well characterized and robust systemic H929-luc model that recapitulates the disease dissemination and invasiveness of multiple myeloma for evaluating novel therapeutic approaches to treatment. Citation Format: Bincy John, David Harris, Shu-Chuan Chou, Tyler Rowe, Nicole Westrick, Nick Nightenhelser, Andrew Wong, Elizabeth Rainbolt, Zachary Ward, Jessica Neil. Development and validation of a systemic human multiple myeloma model utilizing luciferase expressing H929 tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3918.
Abstract 3051: DiaXCIP3M: A new small drug molecules conjugate displaying a strong antiproliferative in vitro and in vivo activity against human small cell lung cancer
Authors: Gregoire Pierre Prevost, Gwenaël Forcher, Anne-Caroline Chany, Laurent Fontaine
Journal: Cancer Research (2025)

Abstract The high medical need for new, original therapeutic molecules remains clear for all those fighting small cell lung cancer (SCLC). DiaXCIP3M based on patented technology belongs to a new class of small drug molecules conjugates (SDMCs). Traditional chemotherapy mostly relies on the use of a cocktail of several anticancer drugs. However, two different drugs display two different pharmacokinetics and two different tissue biodistributions meaning that it is very challenging to anticipate the ratio of these two drugs in the tumor or normal cells. Small molecule drug conjugates (SMDCs) are a promising strategy to reduce these limits by coupling two distinct cytotoxic molecules in one new drug therefore inducing only one pharmacokinetic and one biodistribution. The inter-variability of the drug exposure between patients is thus expected to be reduced compared to the cocktail approach. Reduction of the variability allows a better definition of the recommended dose to actively and safely treat the cancer patients. Preclinical studies performed today indicate that DiaXCIP3M has a strong product profile for further development with 1/ a patented chemical structure, 2/ an original mechanism of action that involves simultaneously inhibition of two validated anticancer targets, resulting in activity in a large range of cancer subtypes, 3/ a powerful in vitro antitumor activity at low nM against human SCLCs, 4/ a suitable in vivo plasma stability assessed by iv route in mouse superior to 2 hrs, and 5/ an induction of in vivo tumor reduction at safe dose in human SCLC xenografted model in mice.DiaXCIP3M has the potential to become an integral part of the therapeutic landscape for ES-SCLC, particularly as a second-line alternative to the currently validated chemotherapy, topotecan, or as a third-line treatment after topotecan failure. Citation Format: Gregoire Pierre Prevost, Gwenaël Forcher, Anne-Caroline Chany, Laurent Fontaine. DiaXCIP3M: A new small drug molecules conjugate displaying a strong antiproliferative in vitro and in vivo activity against human small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3051.
Abstract 5635: In vivo assessment of a potent TEAD inhibitor in a panel of malignant mesothelioma PDX model
Authors: Loreley Calvet, Odette Dos-Santos, Emmanuel Spanakis, Anne Caron, Laurence Noblet, Isabelle Sanchez, Yvette Ruffin, Laurent Dassencourt, Philipe Prigent, David Machnik, Olivier Venier, Laurent Debussche, Iris Valtingojer, Valeria Fantin, Sukhvinder Sidhu
Journal: Cancer Research (2025)

Abstract There has been a growing interest in understanding the involvement of the HIPPO tumor suppressor pathway and its downstream effector, Yes1-associated transcriptional regulator (YAP1), in the context of cancer. The YAP1-TEAD complex plays a pivotal role in controlling transcription, influencing cell proliferation, survival, adaptability, and cell migration. Abnormal activation of YAP1 has been documented in various cancer types, including Malignant Mesothelioma (MM). To assess the proportion of MM cases in which YAP1/TEAD-dependent transcription contributes to tumor initiation and progression and to evaluate the pharmacodynamic effects of a new TEAD inhibitor (Compound A), we previously established a gene expression signature associated with YAP1 activity. This signature was employed to monitor the level of YAP1 inhibition in three Cell Line Derived Xenografts (CDX) and eight Patient Derived Xenografts (PDX) of malignant mesothelioma, and it was used to further assess the effectiveness of compound A in vivo. Here we present, for the first time, the potent in vivo antitumor properties of the novel TEAD inhibitor, compound A, in all of these models and we confirm the reliability of the YAP1-transcription signature as a biomarker for patient selection and for assessing the pharmacodynamic effects of YAP1-TEAD inhibition. Citation Format: Loreley Calvet, Odette Dos-Santos, Emmanuel Spanakis, Anne Caron, Laurence Noblet, Isabelle Sanchez, Yvette Ruffin, Laurent Dassencourt, Philipe Prigent, David Machnik, Olivier Venier, Laurent Debussche, Iris Valtingojer, Valeria Fantin, Sukhvinder Sidhu. In vivo assessment of a potent TEAD inhibitor in a panel of malignant mesothelioma PDX model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5635.
Abstract 4864: The dysregulated YY1-EZH2-RKIP axis in cancer and immune evasion
Authors: Benjamin Bonavida, Talia Festekdjian
Journal: Cancer Research (2025)

Background: The current treatment strategies for cancer have evolved with novel effective approaches, particularly immunotherapy. These have resulted in significant tumor regression and prolongation of survival in a subset of cancer patients. However, there is a subset that is initially unresponsive and a responsive subset that becomes subsequently unresponsive leading to tumor progressions and deaths. Rationale: To develop a new immune-therapeutic approach to reverse resistance. Hypothesis: We hypothesized that the unresponsive cancers have in common pivotal gene factors that regulate the resistance and, therefore, are amenable for targeting. These gene factors are the over-expressed Yin Yang1 (YY1) and EZH2 tumor promoters and the under-expressed Raf kinase inhibitor protein (RKIP) tumor suppressor. Altogether, they constitute the dysregulated YY1-EZH2-RKIP axis in cancers and immune evasion. Findings: Analyses of the regulation of expressions of these three gene products revealed that they exhibit cross-talk signaling pathways ( eg the Raf/MEK/ERK, NF-kB, PI3K/Akt). YY1 and EZH2 activate pathways involved in immune resistance and evasion (e.g., inhibition of T cell effector functions, upregulation of T-cell inhibitory receptors and ligands on cancer cells, infiltration of MDSCs, etc.). In contrast, RKIP reverses YY1 and EZH2 immune inhibitory signaling pathways and enhances the anti-cancer immune response. Conclusion: The findings revealed that the dysregulated YY1-EZH2 -RKIP axis in cancer is involved in the resistance of cancer to various immuno-therapeutics and induces an immune-suppressive TME and immune evasion. Various approaches are presented targeting each of the three gene products, individually or in combination, to reverse immune resistance and restore the effectiveness of anti-cancer immunotherapy. We suggest that further investigations are necessary to validate the targeting strategies, preclinically and then clinically. However, there remain challenges to develop agents that specifically target the cancer cells in vivo with minimal side effects. Citation Format: Benjamin Bonavida, Talia Festekdjian. The dysregulated YY1-EZH2-RKIP axis in cancer and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4864.
Abstract 3055: Developing the cyclic peptide AD05 as a novel Hsp90 inhibitor for triple-negative breast cancer therapy
Authors: Ilham Zarguan, Sumin Lu, None vamsi Krishna Kommalapati, Alisha Hussain, Dhruvi Paladiya, Wayne Fang, Lamiae Belayachi, Abdelaziz Benjouad, Abdessamad Debbab, Ahmed Chadli
Journal: Cancer Research (2025)

Abstract The Heat-shock protein 90 (Hsp90), emerged as an exciting molecular target in the late 90s after being recognized as the driving force behind the Ansamycin antibiotic geldanamycin's antitumoral activity. Since then, extensive research has been conducted to develop Hsp90 inhibitors for clinical applications in cancer therapy. Specifically in triple-negative breast cancer (TNBC), studies have shown that using Hsp90 inhibitors as single agents, or in combination with immunotherapy can offer new leads to better therapeutic efficacy. However, traditional inhibitors targeting the N-terminal domain of Hsp90 often trigger a heat shock response (HSR) or are pan-inhibitors which results in detrimental side effects in clinical trials. Considering this, this study aims to identify and characterize small molecules that can inhibit Hsp90 and degrade its oncogenic client proteins, without inducing the HSR. Using a high-throughput progesterone reconstitution screening assay, a cyclic peptide, AD05, was identified from medicinal plant extracts and their symbiotic microorganisms. This compound is intriguing because it inhibits Hsp90 in a distinct manner from the classical N-terminal Hsp90 inhibitor tested in Phase III clinical trials; 17-N-allylamino-demethoxygeldanamycin (17-AAG) and does not induce the HSR. The binding of AD05 to Hsp90 was further characterized in purified and cell-based systems using IP linked to LC-MS, molecular docking analysis, cellular thermal shift assay (CETSA), and Western blot that showed an efficient degradation of oncogenic client proteins. AD05 exhibited significant cytotoxicity against cancer cells evaluated in MTT assays compared to normal cells, immunohistochemistry (IHC), immunofluorescence, electron microscopy, and Seahorse metabolic analyses. Our findings suggest that bioactive natural products are effective and promising inhibitors against the Hsp90 machine for cancer research and therapy. Citation Format: Ilham Zarguan, Sumin Lu, vamsi Krishna Kommalapati, Alisha Hussain, Dhruvi Paladiya, Wayne Fang, Lamiae Belayachi, Abdelaziz Benjouad, Abdessamad Debbab, Ahmed Chadli. Developing the cyclic peptide AD05 as a novel Hsp90 inhibitor for triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3055.
Abstract 7448: Developing virtual staining algorithm of colon cancer organoids using holotomography and deep learning
Authors: Juyeon Park, Geon Kim, YongKeun Park
Journal: Cancer Research (2025)

Abstract Colon cancer organoids hold great potential for studying the development of colon cancer. To assess their physiological and developmental status, both morphological parameters (e.g., cell shape and volume) and functional parameters (e.g., presence of proliferating cells or pluripotent stem cells) are crucial. However, current fluorescence labeling methods are invasive, potentially damaging or altering the organoids, making them disposable. To overcome this limitation, it is essential to develop a non-invasive method for monitoring organoids for long-term. We propose a solution that integrates holotomography and deep learning. Holotomography is a label-free imaging technique that measures the 3D refractive index distribution of samples without requiring any exogenous labeling. While this technique operates within a label-free framework, the resulting images provide only structural information and lack functional information. This limitation makes it challenging for researchers to distinguish cellular and subcellular structures with specific function. We address this challenge by leveraging deep learning to provide both structural and functional information through virtual staining of label-free images. Specifically, we construct a paired dataset using correlative holotomography, which captures both label-free images and their corresponding fluorescence images. Using supervised learning, we train a neural network to map label-free images to their corresponding fluorescence counterparts. Once trained, the neural network can automatically predict virtual fluorescence images from label-free inputs without exposing the organoids to any exogenous chemicals. To validate the accuracy of the trained neural network, we first acquire label-free images of the organoids and input them into the network. After obtaining the network-generated virtual fluorescence images, we chemically stain the same organoids. Finally, we compare the chemically stained images with the virtual images produced by the neural network to evaluate its performance. By combining the safety of label-free imaging with the precision of artificial intelligence, our technology eliminates critical barriers to organoid research and translation. This breakthrough accelerates the development of scalable and safe organoid therapies, bringing us closer to a future where lab-grown organoids revolutionize regenerative medicine and save lives. Citation Format: Juyeon Park, Geon Kim, YongKeun Park. Developing virtual staining algorithm of colon cancer organoids using holotomography and deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7448.
Abstract 6475: Characterizing peri-tumoral tertiary lymphoid structures in non-muscle invasive bladder cancer using a spatial whole transcriptomics approach
Authors: Kartik Sachdeva
Journal: Cancer Research (2025)

Abstract Background: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard for high-risk NMIBC, however over half of patients experience early recurrence or disease progression, highlighting the need for reliable predictive biomarkers. Our previous research identified that B cell dominant peri-tumoral tertiary lymphoid structures (TLSs) evolve during chronic carcinogenesis in a subset of patients who experience early recurrence or progression. TLSs generally correlate with favorable outcomes following treatment with immune checkpoint inhibitors, chemotherapy or oncolytic viruses. In contrast, their abundance in peri-tumoral regions in BCG-naïve NMIBC tumors associates with poor prognosis. This highlights the importance of their in-depth characterization and further exploring their biomarker potential in NMIBC. Methods: Peri-tumoral TLSs and tumor epithelial regions were profiled using the NanoString GeoMx Digital Spatial Profiler based whole transcriptome analysis. Multiplex Immunofluorescence was performed to infer spatial profiles of B, T and myeloid cell functional states as well as immune checkpoint proteins. Results: Spatial whole transcriptome analysis displayed increased expression of genes associated with antigen presentation, complement activation, B cell recruiting chemokines, and immunoglobulins in the TLSs regions. Tumor epithelial regions located adjacent to TLSs showed elevated expression of genes reflective of a luminal subtype. Increased PD-1+ cells in the peri-tumoral regions and enrichment of luminal subtype genes in the epithelial compartment indicated cancer cell intrinsic aggressive features associated with immune exclusion. Conclusion: The novel findings from this study will help establish peri-tumoral TLSs as biomarkers for predicting BCG therapy response, enabling early identification of patients who may benefit from alternative immunomodulatory treatments like oncolytic viruses, gemcitabine-docetaxel chemotherapy, or immune checkpoint inhibitors. Citation Format: Kartik Sachdeva. Characterizing peri-tumoral tertiary lymphoid structures in non-muscle invasive bladder cancer using a spatial whole transcriptomics approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6475.