tbuckley/cabot-search huggingface dataset:
Abstract 3665: Insilco evaluation of multiple ubiquitin-specific protease 1 (USP1) inhibitors and selectivity profiling over other USPs using Alphafold
Authors: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Appaji Baburao Mandhare, Rupesh Chikhale
Journal: Cancer Research (2025)

Abstract DNA damage triggers cell signaling cascades that mediate repair. This signaling is frequently dysregulated in cancers. The proteins that mediate this signaling are potential targets for therapeutic intervention. Ubiquitin-specific protease 1 (USP1) is one such target, with small-molecule inhibitors already in clinical trials. Here, we used USP1 crystal structures (PDB: 7ZH4 and 9FCJ) to study the comparison of multiple novel USP1 inhibitors alongside the clinical USP1 inhibitor KSQ-4279 and a well-established tool compound, ML323. Our findings indicate that each of these novel USP1 inhibitors binds to the same cryptic site on USP1 as ML323/KSQ4279, yet they induce subtle variations in the protein structure. Notably, one of the novel compounds exhibit additional interactions with D751 and D752 which we hypothesize may contribute to the unique structural disruptions associated with this novel inhibitor. This binding would likely enhance the thermal stability of USP1 significantly, potentially due to the inhibitors occupying a hydrophobic tunnel-like pocket within the USP1 structure. Furthermore, we have successfully employed AlphaFold structures of various USP proteins to demonstrate the selective binding of these novel compounds to USP1, setting them apart from all other known USP’s. Our results advance the in silico understanding of the binding modes of these novel ligands and underscore their selective potential. We aim to utilize this data for the design of new USP1 inhibitors. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Appaji Baburao Mandhare, Rupesh Chikhale. Insilco evaluation of multiple ubiquitin-specific protease 1 (USP1) inhibitors and selectivity profiling over other USPs using Alphafold [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 3665.
Abstract 7114: Carboplatin in combination with etoposide for advanced small cell lung cancer complicated with idiopathic interstitial pneumonia: A single-arm phase II study
Authors: Masaru Matsumoto, Yuji Minegishi, Katsuyuki Higa, Aya Fukuizumi, Naomi Onda, Susumu Takeuchi, Akihiko Miyanaga, Akihiko Gemma, Masahiro Seike
Journal: Cancer Research (2025)

Abstract Background: Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP. Methods: Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21-28 days at a dose of area under the curve 4-6 on day 1 and etoposide at a dose of 80-100 mg/m2 on days 1-3. Results: Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0-9.6%, p=0.038). The objective response rate was 83.9% (95% CI: 82.5-85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7-6.8) months and 14.0 (95% CI: 7.6-27.6) months, respectively. The 1-year survival rate was 61%. Conclusions: The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP. Citation Format: Masaru Matsumoto, Yuji Minegishi, Katsuyuki Higa, Aya Fukuizumi, Naomi Onda, Susumu Takeuchi, Akihiko Miyanaga, Akihiko Gemma, Masahiro Seike. Carboplatin in combination with etoposide for advanced small cell lung cancer complicated with idiopathic interstitial pneumonia: A single-arm phase II study [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 7114.
Abstract 7008: Development of a potent SOS1 degrader exhibiting superior combination effects with anti-cancer drugs in various tumor models
Authors: Jiyoung Kim, Ji Youn Park, Yeajin Woo, Soohyun Lee, Beomseon Suh, Han Wool Kim, So Hyuk Kim, Yongdae Kwon, Heejung Moon, Yeeun Kim, Jungmin Ahn, Jihye Lee, Je Ho Ryu, Song Hee Lee
Journal: Cancer Research (2025)

Abstract Background: Son of Sevenless 1 (SOS1) is a crucial guanine exchange factor (GEF) for KRAS, facilitating the activation of RAS family proteins by promoting the exchange of GDP for GTP at its catalytic site. It also binds GTP-bound KRAS at an allosteric site, enhancing its GEF activity through positive feedback. Loss or genetic inactivation of SOS1's GEF function reduces the survival of tumor cells with KRAS mutations. Additionally, SOS1 is subject to MAPK-mediated negative feedback inhibition and drugs targeting upstream and downstream nodes relieves SOS1 from this inhibition resulting in pathway reactivation. Results: UBX-144 demonstrated superior degradation activity, achieving sub-nanomolar DC50 levels in the NCI-H358 NSCLC (non-small cell lung cancer) cell line and in transiently transfected SOS1 mutant cells, where it effectively degraded SOS1. A time-course degradation assay demonstrated half-maximal degradation of SOS1 within 2 hours of treatment. A mechanism of action (MOA) study revealed that UBX-144 degrades SOS1 via the ubiquitination-proteasome system, mediated by CRBN E3 ligase. Both UBX-144 and UBX-164 inhibited cell proliferation across various cancer types, including gastric, colon, breast, lung, brain cancers, and chronic myeloid leukemia (CML). A combination synergy study showed that UBX-204 synergized with various inhibitors in NCI-H358 and MIA-PaCa-2 cell lines. In vivo pharmacodynamic (PD) data showed that UBX-144 effectively degraded SOS1 protein in tumors in a U87-MG xenograft model. Experiments using the glioblastoma cell line derived xenograft model demonstrated a compelling in vivo profile, with 10 mg/kg administration of UBX-144 resulting in significant tumor growth inhibition (TGI: 101%) and maximal degradation values exceeding 95% in tumors. Conclusion: We have successfully discovered novel SOS1 degraders exhibiting remarkable anti-tumor activities. In particular, the superior anti-cancer effects of combination treatments with other drugs were confirmed across various cancer cell lines, highlighting its potential as an excellent combination partner. We demonstrate that SOS1 degraders provide a promising therapeutic option for RTK/RAS/MAPK-dependent cancer patients. Citation Format: Jiyoung Kim, Ji Youn Park, Yeajin Woo, Soohyun Lee, Beomseon Suh, Han Wool Kim, So Hyuk Kim, Yongdae Kwon, Heejung Moon, Yeeun Kim, Jungmin Ahn, Jihye Lee, Je Ho Ryu, Song Hee Lee. Development of a potent SOS1 degrader exhibiting superior combination effects with anti-cancer drugs in various tumor models [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 7008.
Abstract 7099: Development of HPV awareness and prevention education materials for Hispanic/Latinx community health educators
Authors: Daisy Montoya, Laura Adame, Jesus Bastian, Najla Dabbagh, Yelitza Campos, Julie Dang, Laura Fejerman
Journal: Cancer Research (2025)

Abstract The human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Although there is no cure for HPV infections, implementation of highly effective preventable measures (screening tests, HPV vaccination) has reduced the incidence of HPV-related cancers. However, the Hispanic/Latinx (H/L) community continues to experience high incidences of HPV infections and some of its related cancers. H/L underutilization of preventative health services can be partly explained by limited health care access, low health literacy levels, and language barriers. To address some of these determinants, the program ‘Mas Vale Prevenir’ aims to develop culturally and linguistically appropriate HPV related cancer prevention educational materials to train community health educators (Promotores) in California. To inform material development, we conducted 4 informal feedback sessions (N=24) and 2 focus groups with Promotores (N=12) which were analyzed using qualitative methodology (Thematic Analysis). We identified insights related to pre-determined themes: learning preferences (e.g., use medical terminology) and opinions related to content (e.g., liked narrative format, relatability) as well as two emerging themes: importance of content (e.g., normalizing the material, H/L-specific statistics) and the role of Promotores (e.g., bridge between doctors and community). Results from the focus groups analysis were used to refine materials in an iterative manner. Engaging H/L Promotores in the development of health educational materials is essential for their effectiveness as community educators. The next step will be to implement and evaluate the ‘Mas Vale Prevenir’ program to assess its effectiveness in reducing HPV related cancer health disparities. Citation Format: Daisy Montoya, Laura Adame, Jesus Bastian, Najla Dabbagh, Yelitza Campos, Julie Dang, Laura Fejerman. Development of HPV awareness and prevention education materials for Hispanic/Latinx community health educators [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 7099.
Abstract 7190: Targeting KDM6A and KDM6B histone demethylases to exploit epigenetic vulnerabilities in IDH mutant gliomas
Authors: Sedef Sarac Yalcinkaya, Ebru Yilmaz, Alisan Kayabolen, Tugba Bagci-Onder
Journal: Cancer Research (2025)

Abstract Gliomas, accounting for 80% of malignant brain tumors, are notably aggressive and may harbor IDH1 mutations, leading to 2-hydroxyglutarate accumulation. This accumulation inhibits DNA and histone demethylases, creating a hypermethylated phenotype. Therefore, understanding and exploiting epigenetic vulnerabilities of IDH1-mutant gliomas may be a powerful therapeutic approach. This study aimed to investigate the roles of lysine demethylases, KDM6A and KDM6B, in the progression of IDH1-mutant gliomas. Using CRISPR/Cas9-mediated gene ablation, we generated IDH1-mutant glioma cell lines (MGG152 and TS603) with reduced KDM6A/6B expression. Our experiments incorporated molecular cloning, qRT-PCR, western blotting, apoptosis assays, oxidative stress assays, RNA sequencing, ATAC sequencing, and Cut&amp;Run sequencing to examine the effects of KDM6A/6B loss. We observed reduced growth rates, morphological changes, increased H3K27me3 levels, and upregulation of TGF-β signaling and senescence-related genes upon KDM6A/6B loss. Further assays revealed no significant apoptosis but highlighted reactive oxygen species (ROS) elevation linked to TGF-β regulation. ß-galactosidase staining confirmed ROS-associated senescence. Additionally, mouse tumor formation studies using KDM6A/6B-depleted TS603 cells confirmed glioma-relevant histological features. Our findings reveal the critical functions of KDM6A and KDM6B in IDH1-mutant gliomas and provide insights into their potential as therapeutic targets for epigenetic interventions. These results open pathways for new strategies in glioma treatment through the modulation of epigenetic mechanisms. Citation Format: Sedef Sarac Yalcinkaya, Ebru Yilmaz, Alisan Kayabolen, Tugba Bagci-Onder. Targeting KDM6A and KDM6B histone demethylases to exploit epigenetic vulnerabilities in IDH mutant gliomas [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 7190.
Abstract 1783: Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors
Authors: Bartłomiej Taciak, Maciej Białasek, Malgorzata Kubiak, Ilona Marszalek, Paulina Kucharzewska Siembieda, Tomasz Rygiel, Magdalena Krol
Journal: Cancer Research (2025)

Abstract The treatment of solid tumors remains a significant challenge, necessitating the ongoing development of innovative therapeutic strategies. Tumor-infiltrating macrophages play a crucial role in the tumor microenvironment, making them an attractive target for drug delivery systems. Here, we introduce the Macrophage-Drug Conjugate (MDC) platform, a pioneering approach that leverages macrophages as delivery vehicles for ferritin-drug complexes. We demonstrate that macrophages actively internalize human heavy chain ferritin (HFt) via macrophage scavenger receptor 1 (MSR1) in vitro. These drug-loaded macrophages transfer ferritin to neighboring cancer cells through a novel mechanism termed TRAnsfer of Iron-binding proteiN (TRAIN). This process requires direct cell-to-cell contact facilitated by an immune synapse-like structure, enabling precise drug delivery. MDCs were formulated with various anti-cancer drugs and evaluated for safety and efficacy in multiple preclinical models, including syngeneic mouse and orthotopic human tumor models. MDC-250 exhibited potent anti-tumor activity in an orthotopic human pancreatic cancer model (BxPC3). MDC-735 demonstrated remarkable efficacy across diverse cancer models, including pancreatic cancer (BxPC3), ovarian cancer (SK-OV-3), breast cancer lung metastases (EMT6), bladder cancer (MB49), and head and neck cancer (SCC7). These effects were observed both as a monotherapy and in combination with immune checkpoint inhibitors. Significantly, MDCs were prepared as off-the-shelf products, maintaining their activity upon thawing, highlighting their potential for clinical translation. This MDC platform represents a breakthrough in solid tumor therapy, offering a targeted, scalable, and effective treatment approach with broad applicability across multiple cancer types. Citation Format: Bartłomiej Taciak, Maciej Białasek, Malgorzata Kubiak, Ilona Marszalek, Paulina Kucharzewska Siembieda, Tomasz Rygiel, Magdalena Krol. Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors [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 1783.
Abstract 3100: Spatially resolved effects of oligonucleotide therapeutics on cellular phenotypes in cancer tissues
Authors: Corinne Ramos, Sandra Boute, Amandine Gerstenberg, Richard Ruez
Journal: Cancer Research (2025)

Abstract Introduction: Oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are promising tools for targeting oncogenic pathways in cancer. However, their impact on tumor microenvironment (TME) architecture and cellular phenotypes within cancer tissues remains insufficiently understood. This study integrates oligonucleotide-based treatments with advanced spatial phenotyping to explore their effects on cancer tissues at a high-definition, single-cell scale. Methods: Cancer tissues treated with oligonucleotide therapeutics were analyzed using multiplexed immunohistochemistry (mIHC) and spatial transcriptomics. Cellular phenotypes, including immune and stromal cell populations, were characterized in situ to assess changes in the TME. High-resolution imaging and transcriptomic profiling were used to localize therapeutic effects, while computational analysis integrated phenotypic and molecular data to uncover spatially resolved mechanisms. Results: Oligonucleotide treatment led to distinct spatial alterations in the TME, including reprogramming of tumor associated macrophages and increased infiltration of cytotoxic T cells in peritumoral regions. Spatial transcriptomics revealed suppression of target oncogenes, alongside upregulation of immune activation pathways in responsive regions of the tissue. Notably, these effects were localized to specific niches, suggesting cell-type-specific and spatially restricted therapeutic responses. Conclusion: This study highlights the power of integrating oligonucleotide therapeutics with spatial phenotyping to uncover their impact on the TME in cancer tissues. The findings provide valuable insights into the spatial dynamics of oligonucleotide therapy, paving the way for more effective design and deployment of these treatments in oncology. Citation Format: Corinne Ramos, Sandra Boute, Amandine Gerstenberg, Richard Ruez. Spatially resolved effects of oligonucleotide therapeutics on cellular phenotypes in cancer tissues [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 3100.
Abstract 1483: Effect of USP1 inhibitor with or without radiotherapy and chemotherapy on cell viability and biomarkers, independent of BRCA or HRD status
Authors: Mrinal Sivastava, Nirjharni Saha, Partha Pratim Sarma, Prashant Kashinath Bhavar, Uday Kumar Surampudi
Journal: Cancer Research (2025)

Abstract The efficacy of USP1 inhibitors, which target deubiquitinating enzymes critical to DNA damage response pathways, was evaluated in combination with radiotherapy and chemotherapy across different cellular types including BRCA1/2, BRCA null and, homologous proficient BRCA mutations. Here, we investigate the impact of USP1 inhibition, as single agent or in combination with RT or CT, in a panel of three distinct cell lines, UWB1.289, HCT-116 and NCI H-1792 representing diverse gene alterations and tumor types. Our results demonstrate that USP1 inhibition significantly sensitizes BRCA mutant and HRD proficient cell lines to both RT and CT, amplifying DNA damage and enhancing apoptotic responses. Interestingly, the combination of USP1 inhibitors with UV radiation resulted in significant reduction of cell proliferation in HCT-116, known to demonstrate significantly higher HR activity scores compared with the BRCA1/2 deficient cells, suggesting a broader role of USP1 inhibitor beyond HR deficient cell lines. The synergy between USP1 inhibition and radiotherapy was most pronounced in the HRD+ models, underscoring the potential of USP1 inhibitors as a therapeutic strategy in DNA repair deficient cancers. The activity was established using both the cell viability as well by performing immunofluorescence assay using PCNA as a marker. These findings provide novel insights into the role of USP1 in modulating the response to DNA damaging therapies, with implications for personalized treatment strategies in cancers independent of HRD status. Future studies will explore the underlying molecular mechanisms driving the observed therapeutic synergy and validate these results in-vivo. Citation Format: Mrinal Sivastava, Nirjharni Saha, Partha Pratim Sarma, Prashant Kashinath Bhavar, Uday Kumar Surampudi.. Effect of USP1 inhibitor with or without radiotherapy and chemotherapy on cell viability and biomarkers, independent of BRCA or HRD status [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 1483.
Abstract 5234: A novel strategy to inhibit colorectal cancer liver metastasis by targeting plasminogen activator inhibitor-1 in liver stromal cells
Authors: Tomokazu Ohishi, Yukinari Kato, Mika K. Kaneko, Shun-ichi Ohba, Akiko Harakawa, Hiroyuki Inoue, Junjiro Yoshida, Daisuke Tatsuda, Tomoko Nakanishi, Masanori Hatakeyama, Manabu Kawada
Journal: Cancer Research (2025)

Abstract Liver metastasis significantly contributes to mortality in colorectal cancer (CRC) patients, highlighting the urgent need for more effective therapeutic strategies. CRC liver metastasis develops within a complex tumor microenvironment that promotes cancer cell colonization and growth. The liver’s supportive role is well described in Paget's "seed and soil" hypothesis. It illustrates how metastatic cancer cells (the "seeds") spread and proliferate in a compatible microenvironment (the "soil"), which includes liver stromal cells. These stromal cells release various factors that aid tumor progression, making it crucial to understand these molecular interactions.This study aims to elucidate the contribution of liver stromal cell-derived factors in CRC metastasis and identify potential therapeutic targets. Using both in vivo and in vitro coculture systems, we found that plasminogen activator inhibitor-1 (PAI-1), a protein produced by liver stromal cells, significantly promotes CRC cell proliferation. Mechanistically, PAI-1 enhances CRC cell survival and proliferation by activating the Akt signaling pathway, which regulates key cellular processes. In xenograft models, therapeutically inhibiting PAI-1 markedly reduced liver metastasis. Furthermore, experiments using PAI-1 knockout mice showed a substantial decrease in metastatic burden, underscoring PAI-1's pivotal role in CRC progression.These results establish PAI-1 as a promising therapeutic target. Its inhibition could potentially reduce CRC liver metastasis and improve patient outcomes. Given the complex nature of tumor-stromal interactions, our findings provide critical insights into targeting liver stromal proteins for effective CRC metastatic treatment. Citation Format: Tomokazu Ohishi, Yukinari Kato, Mika K. Kaneko, Shun-ichi Ohba, Akiko Harakawa, Hiroyuki Inoue, Junjiro Yoshida, Daisuke Tatsuda, Tomoko Nakanishi, Masanori Hatakeyama, Manabu Kawada. A novel strategy to inhibit colorectal cancer liver metastasis by targeting plasminogen activator inhibitor-1 in liver stromal 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 5234.