tbuckley/cabot-search huggingface dataset:
Abstract 4459: Molecular docking and drug virtual screening of novel small molecule inhibitors of anti-apoptotic proteins for cancer treatment
Authors: Joongkyum Shin, Yao Chen, Brianna Feldmeier, Elinor Lee, Qinliang Zhao
Journal: Cancer Research (2025)

Abstract Bcl-2, an anti-apoptotic protein, is involved in cancer development and progression and has been considered as a promising target in cancer therapy. ABT-199, a Bcl-2 inhibitor, has been approved, as a single agent or in combinations, for the treatment of adult patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or newly diagnosed acute myeloid leukemia (AML) patients with age of 75 years or older. Although most patients can initially benefit from ABT-199 treatment, patients eventually develop resistance majorly due to BCL2 mutations, such as G101V and D103Y, or overexpression of Bcl-xL. Therefore, inhibitors that can target both wild-type and mutant Bcl-2 as well as Bcl-xL have the potential to overcome the resistance mechanisms to ABT-199. LP-118 is a novel inhibitor targeting wild-type Bcl-2, Bcl-2G101V and Bcl-2D103Y mutants, and has moderate activity against Bcl-xL. In preclinical and clinical studies, LP-118 had excellent anticancer activity in animal models and patients with CLL or SLL. However, there is no co-crystal structure information available to show exactly how LP-118 binds to Bcl-2, Bcl-2G101V, Bcl-2D103Y, or Bcl-xL. Molecular docking is one of the most frequently used methods in drug design and discovery, due to its ability to predict the binding-conformation of small molecule ligands to the appropriate target binding site. Using the molecular docking Software ICM-Pro, we are the first to illustrate how LP-118 binds to Bcl-2, Bcl-2G101V, Bcl-2D103Y, and Bcl-xL proteins in 3D. The molecule LP-118 is tightly tugged in the reception pocket of each protein where the interactions, including hydrogen bonding, electrostatic and π-stacking interactions, slightly vary in each case. These knowledge enables a better understanding of the mechanism of actions of LP-118 and provides a foundation for the rational design of future generations of Bcl-2/Bcl-xL inhibitor that will overcome the Bcl-2 mutation resistance. Based on the docking result, we designed over 1,000 analogues of LP-118 by fine-tuning the backbone and substituents on the molecule, used ICM-Pro/VLS software to virtually screen these analogues against Bcl-2, Bcl-2G101V, Bcl-2D103Y, or Bcl-xL, and successfully identified and prioritized 10 top-ranked analogues for chemical synthesis and anticancer activity testing. Citation Format: Joongkyum Shin, Yao Chen, Brianna Feldmeier, Elinor Lee, Qinliang Zhao. Molecular docking and drug virtual screening of novel small molecule inhibitors of anti-apoptotic proteins for cancer treatment [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 4459.
Abstract 2162: A potent and highly selective HPK1 inhibitor as a combination strategy to improve the clinical response of the immune checkpoint inhibitor
Authors: Joonseok Byun, Jong Hyun Lee, Seungjin Jo, Doyoung Kim, Hyunwoo Shin, Jong Ryoul Choi, Seunghee Ji, Hye-Jung Kim, Donghyun Kim, Bong Tae Kim
Journal: Cancer Research (2025)

Combining the HPK1 inhibitor with the anti-PD-1 antibody has demonstrated clinical benefit by restoring suppressed immune response. Here, we present our novel HPK1 inhibitor IN-122517 exhibiting good HPK1 inhibition potency and selectivity against 468 kinases including immune-related off-target kinases. Consistently, it potently reduced SLP76 phosphorylation and induced IL-2 production in human peripheral blood mononuclear cells (PBMCs). Preclinical studies have shown beneficial tumor response to IN-122517 as a monotherapy and also improved efficacy when combined with anti-PD-1 monoclonal therapy. In the combination group, complete responses (CRs) were observed in a subset of animals, and re-challenge experiments confirmed the absence of tumor regrowth, indicating the establishment of an immune memory response. Tumor-infiltrating lymphocytes showed increased infiltration of T cells, natural killer (NK) cells, and dendritic cells (DCs), demonstrating the compound's potency in activating and recruiting immune effectors within the tumor microenvironment (TME). These data supported the nomination of IN-122517 into IND-enabling studies as a combination partner with Immune checkpoint inhibitors (ICIs). Citation Format: Joonseok Byun, Jong Hyun Lee, Seungjin Jo, Doyoung Kim, Hyunwoo Shin, Jong Ryoul Choi, Seunghee Ji, Hye-Jung Kim, Donghyun Kim, Bong Tae Kim. A potent and highly selective HPK1 inhibitor as a combination strategy to improve the clinical response of the immune checkpoint inhibitor [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 2162.
Abstract 2242: Inhibition of the tumor cell TCA cycle suppresses ER stress-associated THBS2 to selectively potentiate antitumor response of CD36+ effector T cells
Authors: Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Yong Teng
Journal: Cancer Research (2025)

The tricarboxylic acid (TCA) cycle, occurring within the mitochondrial matrix, plays a pivotal role in mitochondrial metabolism, which is essential for generating energy to support tumor cell proliferation and survival. CPI-613 (devimistat) is a novel systemic therapeutic that targets the TCA cycle by inhibiting pyruvate dehydrogenase (PDH) through hyperactivation of its regulatory kinases and by inducing reactive oxygen species (ROS)-mediated inhibition of ketoglutarate dehydrogenase (KGDH). Here we report a novel mechanism by which CPI-613 potentiates the antitumor response of CD8+ T cells to head and neck squamous cell carcinoma (HNSCC). Using proximity biotinylation and LC/MS analysis, we found that CPI-613 inhibits the secretion of thrombospondin-2 (THBS2), a glycoprotein linked to poor prognosis and immune evasion in HNSCC patients. Mechanistically, CPI-613 blocks the TCA cycle in HNSCC cell mitochondria, leading to endoplasmic reticulum (ER) stress and upregulation of XBP1s, which transcriptionally suppresses THBS2 expression. As a result, CPI-613-treated HNSCC cells secrete reduced levels of THBS2, which leads to the inactivation of its receptor, CD36, on CD8+ T cells. This inactivation subsequently triggers the activation of the downstream AKT/mTOR signaling pathway, enhancing the proliferation and cytotoxic potential of CD8+ T cells. These results highlight the immunomodulatory effects of CPI-613 and provide a strong rationale for developing it as a promising treatment strategy for HNSCC. Citation Format: Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Yong Teng. Inhibition of the tumor cell TCA cycle suppresses ER stress-associated THBS2 to selectively potentiate antitumor response of CD36+ effector T 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 2242.
Per- and polyfluoroalkyl substances in eutopic endometrium tissue and risk of endometriosis: findings from the Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) Study
Authors: Joanna M. Marroquin, Jenna R. Krall, Karen Schliep, Leslie V. Farland, Vimalkumar Krishnamoorthi, Kurunthachalam Kannan, Anna Z. Pollack
Journal: Environmental Health Perspectives (2025)

Per- and polyfluoroalkyl substances (PFAS) exposure is widespread and has been linked with gynecologic disease. To our knowledge, no study has measured PFAS in endometrial tissue. Eutopic endometrial tissue specimens (n=434) were collected from Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) Study participants undergoing laparoscopy or laparotomy for any indication (2007-2009). Nine PFAS were measured by HPLC-tandem MS (perfluorodecanoic acid [PFDA], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA], perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorododecanoic acid [PFDoDA], perfluoroheptanoic acid [PFHpA], perfluorooctanesulfonamide [PFOSA], and perfluoroundecanoic acid [PFUnDA]. Surgeons diagnosed endometriosis by gold-standard visualization and evaluated the endometriosis staging as moderate and severe (stage 3-4) compared to minimal and mild (stage 1-2), using American Society of Reproductive Medicine (ASRM) classification. We used modified Poisson regression models adjusted for age (continuous), race (white, all other race/ethnicities), smoking status (serum cotinine > ng/mL), study site (Utah, California), and body mass index (continuous) to obtain relative risks (RR) of endometriosis diagnosis and 95% confidence intervals (CI) for each PFAS. PFAS mixtures were evaluated using Bayesian Kernel Machine Regression. Participants were, on average, 33 ± 7 years old, and 75% of participants were non-Hispanic white. Of the 181 participants with an incident endometriosis diagnosis, 73% had ASRM stage 1-2, while 27% had stage 3-4. Median (IQR) eutopic endometrium tissue levels, in ng/g, were 6.58 (6.44) for PFOS, 1.93 (1.71) for PFOA, 0.65 (0.75) for PFHxS, 0.58 (0.52) for PFNA, 0.12 (0.18) for PFOSA. PFAS in the endometrial tissue was not associated with endometriosis. However, select PFAS in the eutopic tissue were associated with a risk of more advanced (stage 3 or 4 vs. 1 or 2) endometriosis [(PFOSA RR=1.25 (95% CI: 1.10-1.43), PFHxS RR=1.37 (95% CI: 1.12, 1.68), PFOS RR=1.36 (95% CI: 1.02, 1.81)]. PFAS were widely detected in eutopic endometrial tissue. There was no evidence that PFAS in endometrial tissue were associated with a higher risk of endometriosis diagnosis. However, PFOS, PFOSA and PFHxS in the endometrial tissue were associated with risk of more severe stage of endometriosis. https://doi.org/10.1289/EHP15852.
Abstract 3281: CRISPR activation of endogenous STING as an innovative strategy for targeted immunotherapy
Authors: Emil L. Lauridsen, Stine H. Godsk, Anders Etzerodt, Martin R. Jakobsen
Journal: Cancer Research (2025)

Abstract Background: Stimulator of Interferon Genes (STING) has long been of interest within the field of cancer immunology, as the cyclic GMP-AMP synthase (cGAS)-STING pathway can drive inflammation in the tumor microenvironment through the sensing of cytosolic DNA and production of 2’3’-cGAMP. Importantly, in cancer cells with high levels of chromosomal instability (CIN), we and others have observed selective suppression of STING expression, which we hypothesize benefit cancer cells to avoid activating an immune response and to promote immune escape. Method: The murine triple-negative breast cancer model 4T1, which presents with CIN was explored. We conducted both in vitro and in vivo experiments to characterize cGAS-STING pathway signaling in response to exo- as well as endogenous DNA stimulation. Utilizing a CRISPR-dCas9 activation (CRISPRa) approach we selectively regulated STING expression in cancer cells and evaluated immune responsiveness in vitro. The anti-tumoral effect of activating the cGAS-STING signaling cascade was tested in vivo using aEpCAM-labelled lipid-nanoparticles (LNPs) for delivering mRNA to support selective uptake in 4T1 cells. Results: Initially, 4T1 cellswere found to have low STING expression, in conjunction with high levels of micronuclei and cGAS activity, supporting endogenous accumulation of 2’3’-cGAMP. Using CRISRPa of STING, we observed a rapid cGAS dependent type-I interferon and inflammatory cytokine response correlating with STING expression in a time-dependent manner. Using EpCAM-targeted LNPs we enabled specific mRNA delivery to 4T1 cells in vitro and in vivo. Our current efforts focus on exploring the in vivo anti-tumoral effects of this STING-targeting immunotherapy which will be presented at AACR. Conclusion: Our data reveal that reestablishing endogenous STING expression in cancer cells that exhibit elevated CIN, may result in an anti-tumoral inflammatory response. We believe that the altered immune profile determined by STING reactivation presents a therapeutic potential to promote tumor regression. Using this specifically targeted LNP-mRNA system, this type of epigenetic regulation may become a cornerstone of future personalized cancer therapies in addition to traditional immunotherapy. Citation Format: Emil L. Lauridsen, Stine H. Godsk, Anders Etzerodt, Martin R. Jakobsen. CRISPR activation of endogenous STING as an innovative strategy for targeted immunotherapy [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 3281.
Cycle-conditional diffusion model for noise correction of diffusion-weighted images using unpaired data
Authors: Pengli Zhu, Chaoqiang Liu, Yingji Fu, Nanguang Chen, Anqi Qiu
Journal: Medical Image Analysis (2025)

Diffusion-weighted imaging (DWI) is a key modality for studying brain microstructure, but its signals are highly susceptible to noise due to the thermal motion of water molecules and interactions with tissue microarchitecture, leading to significant signal attenuation and a low signal-to-noise ratio (SNR). In this paper, we propose a novel approach, a Cycle-Conditional Diffusion Model (Cycle-CDM) using unpaired data learning, aimed at improving DWI quality and reliability through noise correction. Cycle-CDM leverages a cycle-consistent translation architecture to bridge the domain gap between noise-contaminated and noise-free DWIs, enabling the restoration of high-quality images without requiring paired datasets. By utilizing two conditional diffusion models, Cycle-CDM establishes data interrelationships between the two types of DWIs, while incorporating synthesized anatomical priors from the cycle translation process to guide noise removal. In addition, we introduce specific constraints to preserve anatomical fidelity, allowing Cycle-CDM to effectively learn the underlying noise distribution and achieve accurate denoising. Our experiments conducted on simulated datasets, as well as children and adolescents' datasets with strong clinical relevance. Our results demonstrate that Cycle-CDM outperforms comparative methods, such as U-Net, CycleGAN, Pix2Pix, MUNIT and MPPCA, in terms of noise correction performance. We demonstrated that Cycle-CDM can be generalized to DWIs with head motion when they were acquired using different MRI scannsers. Importantly, the denoised DWI data produced by Cycle-CDM exhibit accurate preservation of underlying tissue microstructure, thus substantially improving their medical applicability.
Abstract 4765: Suppression of triple-negative breast cancer metastasis by a new glyco-humanized polyclonal antibody
Authors: Carine Ciron, Ophélie Dauphouy, Pierre-Joseph Royer, Pierre Morice, Odile Duvaux, Firas Bassissi
Journal: Cancer Research (2025)

Abstract Context: Triple-negative breast cancer (TNBC) is an aggressive subtype accounting for 15-20% of breast cancer cases, characterized by poor prognosis, high recurrence rates, and limited treatment options. The lack of hormone receptors associated with a high level of molecular heterogeneity of TNBC hinders the development of effective therapies. Chemotherapy remains the standard of care but is often compromised by resistance and toxicity, emphasizing the urgent need for innovative treatments. Here, we assess the efficacy of XON7, a first-in-class glyco-humanized polyclonal antibody (GH-pAb), in preclinical models of TNBC. Methods: The anti-tumor efficacy of XON7 was assessed in TNBC cell lines for its capacity to induce complement-dependent cytotoxicity (CDC) and apoptosis, compared to paclitaxel and the ADC Sacituzumab Govitecan. Apoptotic mechanisms were explored by evaluating caspase 8/9 activation, reactive oxygen species (ROS) levels, and mitochondrial membrane potential. In vitro 3D cultures, XON7's ability to inhibit tumor growth, spheroid formation, and metastasis was tested. In vivo antitumor efficacy was evaluated in orthotopic and metastatic models in SRG rats inoculated with MDA-MB-231-Luc cells, using bioluminescence imaging. Results: XON7 demonstrated potent and selective cytotoxicity across human TNBC cell lines (80-100% cytotoxicity), sparing healthy PBMCs. Apoptotic induction involved both intrinsic and extrinsic pathways, evidenced by caspase 8/9 activation, ROS generation, and mitochondrial membrane potential loss. In 3D cultures, XON7 reduced spheroid size by 50% after two treatments (300 µg/ml) and significantly decreased cancer cell viability (28% remaining). Pre-treatment with XON7 prevented spheroid formation, outperforming paclitaxel and sacituzumab govitecan. XON7 also inhibited metastasis in transwell invasion assays. In vivo, bi-weekly XON7 treatments reduced tumor growth by 50% and eliminated lung metastases in an orthotopic rat model. In a metastatic model, tri-weekly XON7 treatments reduced total metastases (lung, liver, etc.) by 90%. Conclusion: XON7 is a multi-target antibody currently under clinical evaluation, it represents a promising candidate for advancing treatment paradigms in TNBC. Citation Format: Carine Ciron, Ophélie Dauphouy, Pierre-Joseph Royer, Pierre Morice, Odile Duvaux, Firas Bassissi. Suppression of triple-negative breast cancer metastasis by a new glyco-humanized polyclonal antibody [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 4765.
Abstract 6152: The inhibition of USP18 enhanced cancer immunogenicity in triple-negative breast cancer
Authors: Chartinun Chutoe, Valerie G. Brunton, Alexander Von Kriegsheim
Journal: Cancer Research (2025)

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer, which exhibits highly metastasis and shows poorly response to many treatments. Immune checkpoint blockage (ICB) treatment induces anti-tumor effect by innate immune activation for tumor clearance. Nevertheless, ICB was shown to be effective in “hot” tumor microenvironment representing highly immune infiltration. Turning “cold” tumor into “hot” tumor may enhance ICB treatment in TNBC. Type I interferon (IFN) response regulates inflammation and immune modulation. However, IFN-response is abated by USP18, suggesting that inhibiting USP18 could enhance IFN signaling and tumor immunogenicity. To study USP18 inhibition, we employed CRISPR-Cas9 to engineered mutated-USP18 in TNBC cell lines. Mass spectrometry-based proteomic study of mutated-USP18 revealed the induction of IFN-response, cytokine response, MHC-I antigen presentation, while reduced cell proliferation- and cell motility- related pathways under IFN-modulation in TNBC cells. These proteome alterations further caused enhanced-cytotoxic effect of NK cells by inducing apoptotic-mediated cancer cell death in co-culture system. In vivo tumors with mutated USP18 also showed increased immune activation, suggesting that this loss of USP18 functions could enhance the immune response within the tumor microenvironment. This may lead to the enhancement of ICB treatment for TNBC. Our finding demonstrated that the inhibition of USP18 potentially enhanced IFN-response mediating hot tumor microenvironment by promoting cancer immunogenicity in TNBC. This inhibition of USP18 approach may hold promise for boosting the effectiveness of ICB therapies in TNBC. Citation Format: Chartinun Chutoe, Valerie G. Brunton, Alexander Von Kriegsheim. The inhibition of USP18 enhanced cancer immunogenicity in triple-negative breast 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 6152.
Abstract 5246: Chromosomal instability promotes colorectal cancer progression through manipulation of gamma delta T cells
Authors: Paulino Tallón de Lara, Aviad Ben-Shmuel, Wen-Hao Hsu, Chaohao Li, Kyle Labella, Chi Wut Wong, Yonghong Liu, Shan Jiang, Xiaoying Shang, Scott Kopetz, Ronald DePinho
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) can be divided into 2 genetically different subtypes: Microsatellite instable CRC (MSI-CRC; ∼15% of CRC), and microsatellite stable (MSS-CRC; ∼85%). While MSI-CRC develops point mutations that increase neoantigen burden and enhanced response to immunotherapy, MSS-CRC develops chromosomal instability (CIN) and resistance to immunotherapy. Current mouse models do not recapitulate the key genetic defect of MSS-CRC: CIN. This limits our understanding of CIN‘s role in regulating tumor immunity in CRC, and therefore our capacity to generate new immunotherapies for MSS-CRC. To address this gap, we developed the first genetically engineered mouse model of MSS-CRC with human-like CIN. To recapitulate human CIN caused by telomere erosion, we incorporated the conditional null Apc and Trp53, and inducible Lox-Stop-Lox (LSL) mouse telomerase reverse transcriptase (mTert) alleles, referred to as iTAP. Due to LSL-mTert, mice lack mTert expression and therefore telomerase activity, which leads to telomere erosion upon successive generational intercrosses, evolving from G0 mice (LSL-mTert+/-) that have no CIN (CIN- iTAP) to G3 mice after 3 breeding generations with the mTert+/+ allele that develop CIN (CIN+ iTAP). Colonoscopy-guided submucosal administration of 4-OHT activates Villin-driven Cre-ER in colonocytes leading to Apc and Trp53 deletion and deletion of the stop cassette of LSL-mTert causing activation of telomerase in cancer cells. Oncogenesis in cells with telomere erosion leads to CIN. Consistent with worse OS in human MSS CINhigh, CIN+ iTAP tumors were more aggressive than CIN- iTAP. Single-cell RNA sequencing (scRNA-seq) confirmed that CIN+ iTAP tumors developed more copy number variations. Subclustering of the infiltrating immune populations revealed that γδ T cells expanded and changed their phenotype in CIN+ iTAP tumors, which was confirmed by flow cytometry. Treatment with a blocking antibody towards γδ TCR in mice with established tumors lead to increased survival in CIN+ iTAP mice but not in CIN- iTAP mice. ScRNA-seq of primary tumors of patients with MSS-CRC revealed that γδ T cells also exhibit phenotypic changes upon different levels of CIN in human MSS CRC. Citation Format: Paulino Tallón de Lara, Aviad Ben-Shmuel, Wen-Hao Hsu, Chaohao Li, Kyle Labella, Chi Wut Wong, Yonghong Liu, Shan Jiang, Xiaoying Shang, Scott Kopetz, Ronald DePinho. Chromosomal instability promotes colorectal cancer progression through manipulation of gamma delta T 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 5246.