tbuckley/cabot-search huggingface dataset:
Abstract 5714: EP102: pharmacological inhibition of METTL3 in tumor growth inhibition and comparative efficacy in combination with anti-PD1 or PARP inhibitors
Authors: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Killian Oukoloff, Guillaume Dutheuil
Journal: Cancer Research (2025)

Abstract METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant epigenetic modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of numerous hematological and solid tumor cancers. EPICS has previously presented tumor growth inhibition with its small molecule inhibitors of METTL3 (“M3i”) in various models including in SKOV3 (ovarian) in NSG mice. The aim of the current study is to evaluate whether the efficacy of M3i combines favorably with anti-PD1 inhibitors in comparison to PARP inhibitors. M3i compound potency was evaluated in vitro by measuring the anti-proliferative effects in cell viability assays following a 72h treatment of A20 (B-cell lymphoma, IC50 = 310 nM), SKOV3 (ovarian, IC50 = 9 nM) and MDA-MB-231 (TNBC, IC50 = 24 nM) cells. Compound M3i-A (30 mg/kg, IP, QD) effectively elicited tumor growth inhibition (“TGI”) in SKOV3 (orthotopic implant, NSG mice) but not in A20 (syngeneic mice) either as a standalone therapy nor in combination with anti-PD1. In CD34+ humanized mice, compound M3i-B (20 mg/kg, PO, QD) elicited TGI &amp;gt;60% in the SKOV3 model (SC implant) and &amp;gt;40% TGI in the MDA-MB-231 model (orthotopic implant), but in the latter model with no additional benefit in combination with anti-PD1. SKOV3 is an HR-proficient tumor known to be less sensitive to PARP inhibitors; in a final study, M3i-B effectively prolonged survival in the SKOV3 model in NSG mice (orthotopic implant) and further demonstrated heightened efficacy when tested in combination with Olaparib (50 mg/kg, PO, QD) in data complemented by the resolution of various downstream biomarkers. The current results extend the application of METTL3 inhibitors as a single-agent in the treatment of selected tumors and further suggest that METTL3 inhibitors may be ideally combined with cancer therapies targeting DNA damage response mechanisms, such as PARP inhibitors, as a refined strategy for treatment of solid tumors. Citation Format: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Killian Oukoloff, Guillaume Dutheuil. EP102: pharmacological inhibition of METTL3 in tumor growth inhibition and comparative efficacy in combination with anti-PD1 or PARP inhibitors [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 5714.
Abstract 2130: Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling
Authors: Oleg Demin, Galina Kolesova, Dmitry Shchelokov
Journal: Cancer Research (2025)

Abstract Tarlatamab is a DLL3/CD3 bispecific T-cell engager (TCE) recently approved by the FDA for the treatment of extensive-stage small cell lung cancer (ES-SCLC). The dosing follows a step-up regimen for the first cycle, with 1 mg given on day 1, and 10 mg given on days 8 and 15. A similar step-up dosing regimen, but with 100 mg instead of 10 mg, was also tested in a pivotal phase 2 trial (Ahn et al. N Engl J Med. 2023 Nov 30;389(22):2063-2075). The alternative step-up dose or step-up regimen were not investigated in the study. The aim of our work was to explore the alternative step-up regimens of tarlatamab, predicting trimer (complex of TCE with target receptors) kinetics in the tumor using quantitative systems pharmacology (QSP) modeling. The QSP model integrated pharmacokinetics of tarlatamab, its distribution into the tumor of patients with ES-SCLC, binding with CD3 expressed by T-cells and DLL3 expressed by cancer cells, formation of trimer in the immunological synapse between T-cell and cancer cell, turnover of free and bound receptors, trimer internalization. Predicted peak trimer levels in the tumor are associated with cytokine release syndrome (CRS) incidence following tarlatamab administration. Higher peak levels of trimer are predicted for the doses and regimens causing more frequent CRS events. The model showed that 1 mg is the optimal step-up dose for the regimens tested in clinical trials since lower doses led to a higher peak trimer level after second dose (10 mg given on day 8). However, split dosing of the 1st or 2nd doses and a longer step-up schedule decreased the peak trimer levels following tarlatamab administration. Splitting the first dose in the approved regimen resulted in a reduction of peak trimer by 30-40%, thus mitigating CRS incidence. Administration of the 0.5 mg on day 1 and 0.5 mg on day 4 also caused a minor decrease of peak trimer level after administration of 10 mg on day 8. A substantial reduction of the maximal level of the trimer after the second dose was predicted for the step-up regimen with 100 mg if the second dose given on day 8 is 3 mg instead of 100 mg. This dose optimization might lower the probability of CRS grade 3 events observed in patients treated with 100 mg. Split-dose regimens and regimens with more than one step-up dose allow for minimizing CRS incidence without compromising the efficacy of TCEs. QSP modeling is a useful tool to investigate various doses and regimens of bispecific and multispecific antibodies. Citation Format: Oleg Demin Jr, Galina Kolesova, Dmitry Shchelokov. Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling [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 2130.
Abstract 3164: Micro-TagTM cell target engagement platform - From discovery to optimization
Authors: Ivan Babic, Elmar Nurmemmedov
Journal: Cancer Research (2025)

Abstract Smartly designed drug discovery programs can amplify the success rate and accelerate the progress from hit discovery to optimization. Drug discovery for challenging or “undruggable” drug targets such as transcription factors necessitates the proteomic complexities of the cellular milieu for proper folding and function. Therefore, conventional drug discovery methods are not sufficient for most of these proteins. The incorporation of recent cell target engagement methodologies has helped improve drug discovery efforts. However, currently available high throughput cell target engagement methods are limited to measurement of end-point signal, poor utility across multiple challenging target families and insufficient resolution for kinetic and mechanistic readouts. Here we present MICRO-TAGTM cell target engagement platform for challenging drug targets. We provide data demonstrating utility of MICRO-TAG platform for rapid discovery of novel interacting drug molecules to several challenging drug targets. The platform enables cross experimentation with the same cell reporter system for comprehensive hit identification, validation, lead identification and optimization employing several experimental strategies. Citation Format: Ivan Babic, Elmar Nurmemmedov. Micro-TagTM cell target engagement platform - From discovery to optimization [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 3164.
Abstract 1848: Layered zirconium phosphate nanoparticles as anticancer drug carrier
Authors: Aleannette Lopez-Cubero, Getsemary Cabrera, Armando Santiago, Yairisis Rivera, Maria M. Rivera, Alianys Rosario, Magaly Martinez-Ferrer, Jorge L. Colon
Journal: Cancer Research (2025)

Abstract Layered zirconium phosphate nanoparticles (ZrP), inorganic structures with a layered composition of zirconium atoms linked by phosphate groups, exhibit no cytotoxic effects on healthy or cancer cells, indicating a strong safety profile. We are investigating ZrP as a carrier for mitoxantrone (MTX), an anticancer drug that inhibits topoisomerase II and disrupts DNA synthesis but lacks selectivity between healthy and cancer cells. MTX shows prolonged retention in the body, with potential systemic toxicity affecting thyroid, hepatic, and cardiac tissues. This study aims to reduce systemic toxicity and protect healthy tissues from MTX by intercalating MTX into ZrP (MTX-ZrP) via ion exchange, determining the conditions that affect MTX’s release, and evaluating the cytotoxicity of MTX-ZrP on prostate cancer cells. MTX was intercalated with ZrP nanoparticles, forming MTX-ZrP, which was then characterized by Fourier Transformed infrared spectroscopy, scanning electron microscopy/energy dispersive X-ray spectroscopy, and X-ray powder diffraction at different molar ratios. A drug release study to determine conditions affecting MTX liberation from ZrP at different pHs using simulated body fluid and lysosomal fluid showed that ZrP nanoparticles maintain stable and intercalated MTX at biological pH 7.4. However, at pH 4.5, which simulates the extracellular environment of the tumor, MTX is released, implying that this process is pH-regulated. Cell viability studies with androgen receptor-negative prostate cancer cell line PC3 showed that MTX-ZrP produced a cytotoxic effect. These findings represent the initial phase of a possible drug delivery method that may greatly minimize adverse effects and harm to healthy tissues, offering promise for a more bearable cancer treatment. In the future, we expect to further improve the drug carrier system’s efficacy by modifying the surface of MTX-ZrP, which could significantly enhance its selectivity and specificity. Citation Format: Aleannette Lopez-Cubero, Getsemary Cabrera, Armando Santiago, Yairisis Rivera, Maria M. Rivera, Alianys Rosario, Magaly Martinez-Ferrer, Jorge L. Colon. Layered zirconium phosphate nanoparticles as anticancer drug carrier [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 1848.
Abstract 5658: Overcoming resistance in mCRPC: drug discovery using PDX models and high-throughput drug screening
Authors: Irene Marín-Goñi, Huanyao Gao, Joachim L. Petit, Shreya Indulkar, Adam M. Kase, Cassandra N. Moore, Krishna R. Kalari, Michael T. Barrett, Richard Weinshilboum, Winston Tan, John A. Copland, Liewei Wang
Journal: Cancer Research (2025)

Abstract Background: Second generation androgen receptor signaling inhibitors (ARSIs), such as abiraterone, have demonstrated improved survival in metastatic castration-resistant prostate cancer (mCRPC) patients, however, acquired resistance to these agents often arises. Novel and alternative therapies are needed to combat the ARSI resistant tumor. In the last two decades patient-derived xenograft (PDX) and PDX organoids have become pivotal models in anticancer drug development and biomarker discovery due to their ability to faithfully recapitulate the complex and heterogeneous tumor biology. Methods: We analyzed RNAseq data from mCRPC patients and corresponding PDX models (PROMOTE study, NCT #01953640) and employed L1000 Chem Perturbation down/up signatures database to find candidate drugs to overcome abiraterone resistance by reverse signature search. We then performed proliferation assay using 49 compounds in three PROMOTE-PDX organoid models (2 abiraterone-resistant and 1 abiraterone-sensitive) using our semi high-throughput drug screening platform. Results: Overall, we identified a total of 32 compounds with IC50&amp;lt;10µM in at least one of the models, among which, 5 agents are active in all three models and 5 in at least two of the models. (Table 1). Within active compounds we find selective kinase inhibitors (BRAF, JAK2, AKT, FLT3) and histone deacetylase inhibitors (belinostat and pracinostat). Particularly interesting are two drugs that are only active in the abiraterone resistant setting but not the sensitive PDX. Conclusions: In summary, we leveraged RNAseq data from mCRPC patients and PDX models and performed a high-throughput drug screen in PDX-derived organoid models to identify potential drugs that could overcome abiraterone-resistance in lethal advanced prostate cancer. These data highlight potential drug combinations or subsequent therapeutic strategies for these patients. Citation Format: Irene Marín-Goñi, Huanyao Gao, Joachim L. Petit, Shreya Indulkar, Adam M. Kase, Cassandra N. Moore, Krishna R. Kalari, Michael T. Barrett, Richard Weinshilboum, Winston Tan, John A. Copland, Liewei Wang. Overcoming resistance in mCRPC: drug discovery using PDX models and high-throughput drug screening [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 5658.
Abstract 5661: A 45-color panel for comprehensive immunophenotyping of human leukocyte
Authors: Xiaoyu Zhang, Ming Lei, Peifang Ye, Xiaohuan Wang, Yan Lu, Garret Guenther, Nancy Li
Journal: Cancer Research (2025)

Abstract Multicolor flow cytometry has advanced significantly with instruments capturing more lasers and detectors. Spectral flow cytometry, which records full emission spectra rather than peak emissions, allows fluorochromes with distinct spectral fingerprints to expand panels beyond the 40+ color limit of traditional methods. Agilent’s NovoCyte Opteon spectral flow cytometer, with its five-laser configuration (349nm, 405nm, 488nm, 561nm, 637nm) and 70 fluorescence detection channels, exemplifies this advancement. Using the OMIP-069 panel as a foundation, we expanded it to detect more biomarkers by adding dyes that either fill spectral gaps or possess unique spectral fingerprints despite similar emission maxima. The original OMIP-069 panel allowed characterization of PBMC subsets (e.g., CD4+, CD8+ T cells, B cells, NK cells, monocytes) and included activation/differentiation markers. Our modified 45-color panel introduced five biomarkers: CD31, CD45RO, CD69, CD33, and LAG-3. CD31 and CD45RO identify recent thymic emigrants (RTEs) among CD4+ T cells, CD69 tracks early activated T cells, LAG-3 assesses exhausted T cells alongside PD-1, and CD33 excludes residual monocytes. The results demonstrate that despite incorporating highly overlapping fluorochromes, immune subsets were accurately resolved, preserving dimensionality reduction and clustering outcomes. This highlights the NovoCyte Opteon’s excellent performance, enabling high-dimensional panel design and robust biomarker resolution. Citation Format: Xiaoyu Zhang, Ming Lei, Peifang Ye, Xiaohuan Wang, Yan Lu, Garret Guenther, Nancy Li. A 45-color panel for comprehensive immunophenotyping of human leukocyte [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 5661.
Abstract 3170: DMSO 2.0 - An advanced DMSO product for 2D and 3D cell culture of PROTACs and hydrophobic drugs
Authors: Ketan Patel
Journal: Cancer Research (2025)

Abstract Dimethyl sulfoxide (DMSO) is the most commonly used aprotic solvent for solubilizing poorly water-soluble molecules in cell culture assays. It is an inert, biocompatible solvent with high solubilization capacity. In the last decade, there has been a big parade shift in cancer drug discovery with the development of next-generation cancer therapeutics, especially oncogenic protein-specific small molecules and targeted protein degraders, also known as Proteolysis Targeting Chimera (PROTACs). Such novel drugs are efficiently degrading/inhibiting the key oncoproteins that remained “undruggable” for many years before 2010 e.g., KRAS, PARP, BRAF, etc. Though very efficient, the majority of them fall in beyond Lipinski rule 5 space (bRo5) due to extreme hydrophobicity. Due to poor solubility and rapid precipitation tendency, such molecules pose great challenges during in vitro cell culture and preclinical testing. In our lab, we have observed that stock solution of anticancer molecules (BRD4 PROTAC, EGFR PROTAC, BRD4/MDM2 PROTAC, Sorafenib, Adagrasib, Trametinib, Vemurafenib, Lenvatinib) prepared in DMSO showed immediate to sustained precipitation of drug in DMEM/RPMI media with 5-10% serum. It resulted in significant variation and inaccuracy in cytotoxicity assays. Precipitation of the molecule within the tip (while mixing it from stock solution to media) led to inaccuracy in concentration. Thus, designing and developing an advanced DMSO formulation for testing such novel anticancer molecules is imperative. After screening over 15 hydrophilic adjuvants and their combinations, DMSO 2.0 was developed and tested using the above anticancer molecules. 50 mM stock solution of molecules was prepared in DMSO and DMSO 2.0, followed by addition into cell culture media. Precipitation was monitored by microscopy and high-performance liquid chromatography (HPLC) method. DMSO 2.0 led to the easy mixing of stock solutions with the media by preventing the precipitation of molecules within the tip. Most importantly, DMSO 2.0 led to marked inhibition/slowing down the precipitation of molecules in media compared to DMSO. Precipitation was inhibited at as high as 50 µM and all the subsequent dilutions. DMSO 2.0 showed no apparent cytotoxicity at a concentration below 0.5% v/v in lung cancer cells. Overall, DMSO 2.0 could be a promising solvent for cancer drug discovery, and its drug-specific composition will provide crucial insight into early formulation development strategy for preclinical testing. Citation Format: Ketan Patel. DMSO 2.0 - An advanced DMSO product for 2D and 3D cell culture of PROTACs and hydrophobic drugs [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 3170.
Abstract 4463: A novel method for constructing diverse cyclic peptide libraries for efficient screening of PPI inhibitors
Authors: Zhenyu Wu, Xiaoli Hou, Hongbo Zhang
Journal: Cancer Research (2025)

Abstract Cyclic peptides drug design and discovery has experienced a resurgence of interest due to their target specificity and metabolic stability. In this study, we developed a novel methodology for generating extensive, structurally diverse, and synthesizable virtual libraries of cyclic peptides. Such libraries are essential for the identification of hit compounds against a spectrum of therapeutic targets through screening assays. We introduce an innovative strategy for the creation of diverse cyclic peptide libraries leveraging a “hierarchical generation” approach combined with artificial intelligence (AI)-driven sampling. Our approach begins with the generation of a library of representative linear peptides which are subsequently subjected to cyclization via an array of cyclization reactions. The generation of linear peptides is executed via a hierarchical generation method wherein amino acids are initially categorized according to their physicochemical properties. Next, a sequence of these properties is formulated, and the similarity of these property sequences is calculated through sequence alignment algorithm. Low-similarity property sequences are then processed by AI models to generated multiple sequences of amino acids, while high-similarity sequences are judiciously excluded. The iteration of this process yields a set of representative linear peptides, which are then cyclized to produce the desired cyclic peptides. Employing this novel methodology, we have successfully generated a virtual cyclic peptide library encompassing nearly 6 million molecular cyclic peptides (covering approximately 4 thousand trillion peptides) within a single week. Over 1000 representative cyclic peptides were selected for synthesis via the solid-phase peptide synthesis (SPPS) technique, and a cyclic peptide library with high structural diversity was obtained. In conclusion, the structural diversity of our library, combined with the successful screening results, highlights the robustness of our method in designing diverse cyclic peptides, particularly for hit identification against traditionally undruggable targets. Our findings underscore the utility of this cyclic peptide library in discovering potential PPI inhibitors. Citation Format: Zhenyu Wu, Xiaoli Hou, Hongbo Zhang. A novel method for constructing diverse cyclic peptide libraries for efficient screening of PPI inhibitors [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 4463.
Abstract 3159: The 5-base genome, a simultaneous detection of genomic and methylation signatures using a concise, integrated multiomic library prep
Authors: Evgenii Chekalin, William Jordan, Oscar Murillo, Danielle Goldberg, James Baye, Joshua Beytebiere, Eric Brustad, Kayla Busby, Bridget Dorsey, Sophie Fertel, Stephen Gross, Rebekah Karadeema, Huy Lam, Valerie Montel, June Pais, Suzanne Rohrback, Angelica Schalembier, David Tse, Kat Tzeng, Ali Crawford, Lisa Watson, Allison Yunghans, Fiona Kaper
Journal: Cancer Research (2025)

Abstract Multiomic (multiple omic) approaches provide an integrated tool set to power biological discovery due to their ability to generate comprehensive information about the molecular underpinnings of distinct phenotypes. Such integrated analyses have shown broad utility across a range of applications, such as cancer classification and rare disease prognosis. For example, a recent population-scale study on breast cancer by Staaf et al showed that the combination of WGS and DNA methylation can be useful to detect BRCA1/BRCA2-deficient tumors with greater sensitivity than DNA sequencing alone. However, multiomic studies that employ single-ome technologies are often time-consuming, costly, and require considerable sample input. A streamlined workflow which provides both genome and methylome annotations stands to greatly accelerate discovery and translational research. Here we present a novel methyl-conversion technology, capable of simultaneous genome variant detection and DNA methylation profiling. This methodology introduces a simplified workflow, requires less than seven hours turnaround time, as little as 50ng of genomic DNA input, and comes with comprehensive analysis pipelines, the combination of which deliver accurate dual-omic annotations for discovery. Here were present a comparative analysis of our 5-base genome technology against existing methodologies, including Whole Genome Sequencing, Enzymatic Sequencing (EM-Seq) and Illumina Methylation EPIC arrays. Citation Format: Evgenii Chekalin, William Jordan, Oscar Murillo, Danielle Goldberg, James Baye, Joshua Beytebiere, Eric Brustad, Kayla Busby, Bridget Dorsey, Sophie Fertel, Stephen Gross, Rebekah Karadeema, Huy Lam, Valerie Montel, June Pais, Suzanne Rohrback, Angelica Schalembier, David Tse, Kat Tzeng, Ali Crawford, Lisa Watson, Allison Yunghans, Fiona Kaper. The 5-base genome, a simultaneous detection of genomic and methylation signatures using a concise, integrated multiomic library prep [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 3159.