tbuckley/cabot-search huggingface dataset:
Abstract 1297: Novel mouse models to study bone and brain metastasis
Authors: Hongyan Sun, Xue Wu, Fang Zhu, Jianming Xu, Xiang Gao, Jun Wang
Journal: Cancer Research (2025)

Abstract Metastasis refers to the dissemination of cancer cells from the primary (original) tumor to distant areas of the body, where they give rise to secondary and more aggressive cancers. This process constitutes a crucial aspect of cancer progression and is frequently linked with poor prognosis. Many cancer patients progress to metastasis at a later stage of tumor development before proper treatment is available. Hence, inhibiting metastasis is an important focus of cancer research. Common tissues where cancer metastasizes include the lung, liver, bone, and brain. Anti-metastatic drugs consist of antibody drugs, small molecule inhibitors, peptides and nucleic acids. According to the different mechanisms of action, they can be categorized into angiogenic factor inhibitors, cell adhesion molecule antagonists, metalloproteinase inhibitors, cellular messenger regulators and so on. Despite significant progress in the therapeutic strategy for treating cancer metastasis, several limitations such as drug resistance and limited druggable pathways remain unsolved. To better understand the underlying mechanism and support the discovery of novel biomarkers in cancer metastasis, we have developed robust mouse models for bone and brain metastasis. MDA-MB-231-Luc cell line was injected into the left ventricle of the mouse heart using an ultrasound-guided intracardiac injection technique. Through multiple rounds of in vivo and in vitro screening, we have successfully obtained MDA-MB-231-Luc subclone cell line, which can be colonized in the spine and lower limb bones, recapitulating bone metastasis in clinic. In another approach, we have successfully established a brain metastasis model by injecting the lung cancer cell line LLC1-Luc into the common carotid artery of mice via carotid artery injection. In vivo imaging analysis confirmed cancer cells colonization and proliferation in the correspondence tissue. In conclusion, we have developed preclinical mouse models which recapitulated bone and brain metastasis observed for cancer patients in clinics. Those models can be valuable tools to study metastasis mechanisms as well as for the biomarker discovery. Citation Format: Hongyan Sun, Xue Wu, Fang Zhu, Jianming Xu, Xiang Gao, Jun Wang. Novel mouse models to study bone and brain metastasis [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 1297.
Abstract 4235: PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma
Authors: Caroline M. Li, Robert G. Lingeman, Long Gu, Robert J. Hickey, Linda H. Malkas
Journal: Cancer Research (2025)

Abstract AOH1996, a small molecule designed to bind proliferating cell nuclear antigen (PCNA), demonstrates selective inhibition of cancer cell growth across the NCI60 cell line panel with a mean GI50 of 300 nM, while exhibiting minimal toxicity to nonmalignant cells. Mechanistic studies reveal that AOH1996 influences DNA replication, cell cycle progression, DNA damage response, and transcription-replication conflicts. Inspired by phosphoproteomic analyses of AOH1996-treated cells, we investigated its potential in combination therapy with the histone deacetylase inhibitors (HDACi) vorinostat and belinostat. Notably, vorinostat, an FDA-approved treatment for cutaneous T-cell lymphoma (CTCL), exhibited synergistic effects with AOH1996 in cell viability assays with three CTCL derived cell lines. To better understand enhanced cell killing, we show combination drug effects on apoptosis, DNA damage and PCNA protein expression. Enhanced growth inhibition was also observed when AOH1996 was combined with other HDACi, such as domatinostat and panobinostat. These findings highlight the therapeutic potential of AOH1996 in combination with HDACi, particularly for CTCL, and pave the way for further exploration of this approach in cancer treatment. Citation Format: Caroline M. Li, Robert G. Lingeman, Long Gu, Robert J. Hickey, Linda H. Malkas. PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma [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 4235.
Abstract 1675: Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids
Authors: Thomas S. Dexheimer, Nathan P. Coussens, Thomas E. Silvers, Eric M. Jones, Naoko Takebe, James H. Doroshow, Beverly A. Teicher
Journal: Cancer Research (2025)

Abstract RAS genes are among the most frequently mutated oncogenes in cancer. Though previously considered undruggable, agents have recently been developed that specifically target RAS. The agents can be categorized as (1) those that selectively target specific RAS oncoproteins and (2) pan-RAS inhibitors that target a wide range of RAS alterations, including oncogenic variants and amplifications. This study evaluated the activity of four novel RAS-targeted inhibitors in combination with other targeted agents in thirty solid tumor cell lines of diverse cancer types. These included twenty-six patient-derived cancer cell lines from the NCI Patient-Derived Models Repository (https://pdmr.cancer.gov/) and four established cell lines. The cells were grown as multi-cell type (mct) tumor spheroids from 60% malignant cells, 25% endothelial cells, and 15% mesenchymal stem cells. All agents were tested at concentrations up to the clinical Cmax value, if known or 10 µM. As single agents, the KRAS-G12C inhibitors RMC-6291 and divarasib, along with the KRAS-G12D inhibitor MRTX-1133, demonstrated selective activity against the mct tumor spheroids harboring the targeted variants. In contrast, the pan-RAS(ON) inhibitor RMC-6236 demonstrated activity against the mct tumor spheroids harboring a range of KRAS variants or wild-type KRAS. When used in combination, each of the four RAS-targeted inhibitors exhibited strong synergistic effects with SHP2 inhibitors as determined by the Bliss independence model and reductions in cell viability and spheroid volume. In tumor models harboring different KRAS variants, the pan-RAS(ON) inhibitor showed increased cytotoxicity with the MEK inhibitor cobimetinib, as well as PI3K-AKT-mTOR pathway inhibitors, such as inavolisib (PI3Kα), ipatasertib (AKT), and sapanisertib (mTORC1/2). When the same agents were combined with variant-specific KRAS inhibitors similar effects were observed in mct tumor spheroids carrying the corresponding RAS variant. These preclinical findings might provide guidance for the selection of combination regimens with KRAS inhibitors to improve clinical efficacy. Funded by NCI Contract No. 75N91019D00024. Citation Format: Thomas S. Dexheimer, Nathan P. Coussens, Thomas E. Silvers, Eric M. Jones, Naoko Takebe, James H. Doroshow, Beverly A. Teicher. Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids [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 1675.
Abstract 5568: The estrogen sulfotransferase drives pancreatic ductal adenocarcinoma
Authors: Syamprasad NP, Shijia S. Feng, Donovan Whitfield, Wen Xie
Journal: Cancer Research (2025)

Abstract Background: pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with only a 12% five-year survival rate. The complex nature of PDAC limits treatment options, highlighting the need to identify novel therapeutic targets. Males are more likely to develop PDAC than females, so we performed an initial screening of estrogen-metabolizing enzymes associated with PDAC development. Interestingly, Estrogen sulfotransferase (SULT1E1 or EST) was found to be the most over-expressed in pancreatic ductal adenocarcinoma (PDAC) compared to normal tissues, and it is associated with a poor prognosis for patients. A primary function of EST is sulfonating and deactivating estrogens. Hence, we aimed to investigate the role of EST in PDAC development and progression. Methods: Human PDAC transcriptome and proteome data were accessed from TCGA and CPTAC databases respectively. The expression pattern of EST in human PDAC tissues and genetically engineered PDAC mice model, KC (K-rasLSL.G12D/+; Pdx-1-Cre) and KPC (K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre) tissues was determined using IHC and immunofluorescence. MIA PaCa-2 (KRASMT TP53MT CDKN2AHD SMAD4WT) and CFPAC-1(KRASMT TP53MT CDKN2APM SMAD4HD) cells were used to investigate the role of EST in both in vitro and in vivo models. Results: In the TCGA pan-cancer atlas, we identified that EST is over-expressed only in PDAC compared to other cancer types. Analysis of single-cell RNA sequencing data, Immunohistochemistry, and immunofluorescence studies revealed that EST is overexpressed in PDAC-specific ductal cells in human tissue, as well as in tissues from KC and KPC mice, compared to normal tissues. Overexpression of EST in MIA PaCa-2 and CFPAC-1 cells increased proliferation, migration, wound healing, and sphere formation, along with significantly less stem cell frequency. Moreover, we observed increased Ki-67 positive nuclei, elevated nuclear Cyclin D1 levels, and the upregulation of cyclin D1 target gene signatures in EST overexpressed cells. Additionally, the overexpression of EST was linked to increased tumor growth in vivo in both male and female xenograft models, highlighting EST's significant role in the progression of PDAC. Enzyme activity dead mutant EST overexpression revealed that the pro-PDAC effect of EST depends on its enzymatic activity but is independent of estrogen. Conclusion: We have uncovered a novel function of EST in the development of PDAC, and it may represent a potential target for treating PDAC. Citation Format: Syamprasad NP, Shijia S. Feng, Donovan Whitfield, Wen Xie. The estrogen sulfotransferase drives 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 5568.
Abstract 3453: TNF augments ovarian cancer metastasis in an omentum-independent manner
Authors: Rachel L. Mintz, Emma E. Erlich, Heather S. Ruiz, Quazim Alayo, Mary Wohltmann, Gwendalyn J. Randolph
Journal: Cancer Research (2025)

Abstract The mechanistic role of the inflammatory cytokine tumor necrosis factor (TNF) in ovarian cancer pathogenesis has been widely debated. The Randolph lab has developed a new mouse model, TNFD69Au, in which CRISPR/Cas9 was used to target the 3’ AU rich-response element of TNF mRNA transcripts in immunocompetent C57BL/6J mice, resulting in increased stability of TNF RNA and thus elevated inflammation. When TNFD69Au mice and their wild-type (WT) littermate controls were intraperitoneally injected with the aggressive ID8p53-/-Brca2-/- murine ovarian cancer cell line that recapitulates high-grade serous ovarian cancer, the TNFD69Au mice had significantly increased tumor burden compared to their littermates as early as one-week post-injection. This discrepancy continued consistently until the endpoint when ascites accumulated. The greater omentum, a visceral fat pad along the stomach, is a well-established early and predominant metastatic niche in ovarian cancer. Yet, the TNFD69Au mice demonstrate broad tumor dissemination across peritoneal organs with minimized omental preference. When TNFD69Au mice were omentectomized, their tumor burden was equivalent to that of TNFD69Au mice that received sham surgery, while WT mice expectedly exhibited decreased tumor burden when omentectomized. Regardless of omentectomy, the tumor burden in these TNFD69Au mice was higher than in WT mice, highlighting how increased TNF production in the peritoneal cavity leads to increased tumor burden independent of the omentum. To determine if the source of TNF driving the elevated tumor burden was hemopoietic-derived, bone marrow from TNFD69Au mice or WT littermates was transplanted into WT or TNFD69Au mice recipients. TNFD69Au mice that received bone marrow from WT or TNFD69Au mice had increased tumor burden compared to WT mice that received WT bone marrow. These results suggest that the elevated TNF responsible for increased tumor burden can be stromal-derived, which is surprising given the canonical role of hematopoietic cells in TNF-signaling. Altogether, our data suggest that TNF increases peritoneal ovarian cancer spread and minimizes omental dominance, potentially through stromal signaling. Citation Format: Rachel L. Mintz, 1 Emma E. Erlich, 2 Heather S. Ruiz, 1 Quazim Alayo, 1 Mary Wohltmann, 1 Gwendalyn J. Randolph1. TNF augments ovarian cancer metastasis in an omentum-independent manner [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 3453.
Abstract 1296: Development of a novel NCG-hIL15-FcγR-KO model for precise drug efficacy evaluation
Authors: Hongyan Sun, Jun Xing, Jianming Xu, Shiying Guo, Xiang Gao, Jun Wang
Journal: Cancer Research (2025)

Abstract Humanized mice, particularly immunodeficiency mice reconstituted with human immune systems by the transplantation of human hematopoietic stem cells (HSCs) or human peripheral blood mononuclear cells (PBMCs), have been widely used in tumor immunology. The NCG-hIL15 model has been developed to reconstitute both human T and natural killer (NK) cells, which allows the study of immune checkpoint inhibitors (ICIs) and antibody-dependent cellular cytotoxicity (ADCC)-dependent drugs. However, the remaining murine cells from the myeloid compartment can interfere with the mAb-based drug clearance and efficacy. To precisely evaluate the function of mAb-based drugs, we have successfully developed the NCG-hIL15-FcγR-KO model by disrupting the murine FcγRI, FcγRII, FcγRIII, and FcγRIV genes in NCG-hIL15 mice, resulting in the absence of murine FcγRs. In this model, the interference from mouse FcγRs to induce ADCC was minimal. Compared to the parental NCG-hIL15 mice, NCG-hIL15-FcγR-KO mice can reconstitute comparable levels of human NK and T cells post-HSC transplantation. Both NCG-hIL15-FcγR-KO and NCG-hIL15 mice showed stable body weight changes with a long survival period. In our study, we found that rituximab could inhibit tumor growth through murine innate cells in the absence of human NK cells in NCG-hIL15 mice bearing Raji tumors, obscuring the interpretation of the results, while it had no inhibitory effect on tumors in NCG-hIL15-FcγR-KO mice bearing Raji tumors. Therefore it was suggested that the NCG-hIL15-FcγR-KO model was able to avoid false positives of ADCC drugs and was able to accurately evaluate the true drug efficacy. Furthermore, compared with the PBMC-NCG-hIL15 mice, nivolumab was able to significantly inhibit the growth of tumors in PBMC-NCG-hIL15-FcγR-KO mice bearing NCI-H1975 tumors. This demonstrated that NCG-hIL15-FcγR-KO mice may provide a good platform to study anti-tumor T cell responses in the absence of murine FcγRs. Taken together, the NCG-hIL15-FcγR-KO model is the ideal model to accurately reflect the true efficacy. We present this model as a valuable addition to the preclinical research toolkit, promising a deeper understanding of efficacy evaluation for clinical applications. Citation Format: Hongyan Sun, Jun Xing, Jianming Xu, Shiying Guo, Xiang Gao, Jun Wang. Development of a novel NCG-hIL15-FcγR-KO model for precise drug efficacy evaluation [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 1296.
Abstract 2139: Determination of first in human dose of the T cell-redirecting bispecific antibody CT-95 targeting mesothelin
Authors: Stanley A. Roberts, Kelly Byrnes-Blake, Eric Butz
Journal: Cancer Research (2025)

Abstract CT-95 is a mesothelin (MSLN) x CD3 bispecific T cell-redirecting antibody that is entering phase 1 clinical development. It is affinity tuned to avoid the soluble MSLN sink that has interfered with earlier MSLN-targeting programs. The first-in-human dose of CT-95 was determined using the minimal anticipated biological effect level (MABEL) approach, as required for immune agonist drugs. This is the dose level expected to lead to a minimal biological effect level in humans. The most sensitive and pharmacologically relevant measure of CT-95 activity was determined to be induction of CD25 expression on human T cells using a panel of six human MSLN expressing tumor cell lines. The median EC50 for this panel was 9.94 pM and resulted in an estimated target serum concentration of 1.98 ng/mL. Based on nonclinical PK data, the predicted volume of distribution is 123.5 mL/kg, which suggests a starting dose of 0.24 μg/kg. An additional safety factor was applied to obtain a proposed starting dose of 0.1 μg/kg. From the results of the GLP monkey study, the highest non-severely toxic dose (HNSTD) was considered to be 0.01 mg/kg, and the no-observed-adverse-effect level (NOAEL) was 0.003 mg/kg. Relative to doses in the one-month repeat dose GLP-compliant toxicology study, the proposed starting dose for CT-95 (0.1 μg/kg) is 30-fold lower than the NOAEL (3 μg/kg) and 100-fold lower than the HNSTD (10 μg/kg). The weight of evidence of these data supports the safety of the proposed clinical starting dose of 0.1 μg/kg for CT-95. Citation Format: Stanley A. Roberts, Kelly Byrnes-Blake, Eric Butz. Determination of first in human dose of the T cell-redirecting bispecific antibody CT-95 targeting mesothelin [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 2139.
Abstract 3414: PD-1 targeting increases the tolerance of IL-12 while maintaining potent anti-tumor immunity
Authors: Stephen Searles, Kritika Mohan, Wenjing Yang, Elena Galitovskaya, Lynn Wang, Haikuo Zhang, Lidia Mosyak, Changhua Ji, Javier Chaparro-Riggers, Tzu-Hsuan Huang, Gabriel Starbeck-Miller
Journal: Cancer Research (2025)

Preclinical studies have shown that IL-12 is a potent immunostimulatory cytokine that is capable of directly boosting CD8 T cell and IFNγ-dependent anti-tumor immunity. However, fully potent IL-12 therapies have limited clinical safety profiles. We have designed PF-07921585 to overcome this challenge by targeting IL-12 pharmacology on PD-1+ immune cells, a subset of CD8 T cells often enriched in the tumor microenvironment. PF-07921585 is a fusion protein consisting of an effector null bivalent anti-human PD-1 full length IgG1 and a single, potency reduced, human IL-12 mutein. PF-07921585 was specifically designed to permit simultaneous binding of PD-1 antagonists and enable combination with PD-1/L1 agents (PDx). Combination potential was confirmed in a mixed-lymphocyte reaction assay where we observed that PF-07921585 promoted robust IFNγ-responses as a single agent and boosted PDx-dependent IFNγ responses when given in combination. These data also suggested that targeted IL-12 receptor agonism and PDx checkpoint blockade have potential to non-redundantly amplify anti-tumor immune responses. In further support of this hypothesis, we found that combining a PF-07921585 mouse surrogate with PDx therapy can elicit greater efficacy in both PDx-sensitive and resistant mouse syngeneic tumor models than when either the surrogate or PDx therapy were administered as single agents. Administration of mouse surrogate as a single-agent also elicited potent anti-tumor CD8/IFNγ-dependent efficacy in PD-sensitive/resistant models and less peripheral toxicity compared to an untargeted, fully potent IL-12. Mechanistically, single-agent surrogate treatment enhanced the effector states (including increased IFNγ production) of several PD-1+ exhausted CD8 T cell subsets including the most dysfunctional subset, terminally exhausted cells. This latter effect was most striking as many published studies suggest PDx therapies only elicit efficacy by affecting the least dysfunctional exhausted T cell subsets, stem-like/progenitor cells. In summary, these data suggest that PF-07921585 may be better tolerated than other IL-12 therapies and has potential to deliver efficacy in PDx-refractory patients by heightening the effector function of CD8 T cell subsets not previously achieved by existing PDx therapies. Citation Format: Stephen Searles, Kritika Mohan, Wenjing Yang, Elena Galitovskaya, Lynn Wang, Haikuo Zhang, Lidia Mosyak, Changhua Ji, Javier Chaparro-Riggers, Tzu-Hsuan Huang, Gabriel Starbeck-Miller. PD-1 targeting increases the tolerance of IL-12 while maintaining potent anti-tumor immunity [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 3414.
Abstract 1302: A practical method of delivering induced electric field (iEF) therapy
Authors: Joseph West, Christopher Barron, Vish Subramaniam
Journal: Cancer Research (2025)

Abstract Among non-pharmacological treatments, induced electric field (iEF) therapy is the only bioelectric approach that is truly contact-free and non-invasive. In iEF treatment, the permeability of magnetic fields varying in time is exploited to induce electric fields inside cells and tissues without the need for electrodes or adhesive contact with the skin. Induced electric fields are a non-ionizing form of electromagnetic radiation demonstrated to have strong anti-metastasis and anti-tumor activity in vitro and in vivo against triple negative breast cancer (TNBC), including significant host immune response in a pre-clinical animal model. Moreover, combination treatment of MDA-MB-231 and MDA-MB-468 cells with standard of care chemotherapeutic agents (paclitaxel, capecitabine) plus iEF in vitro, significantly improve their anti-viability and anti-proliferation activity (half-maximal inhibitory concentrations or IC50 values decreased by ∼50% for both paclitaxel+iEF and capecitabine+iEF treatments). EMBioSys has developed technology translating iEF therapy into clinical treatment and delivered in the form of wearable, washable garments such as camisoles. Special conducting threads integrated into the camisole enable a current to be driven through the insulated threads at voltages less than 10 Volts. The time-varying current generates a temporally varying magnetic induction within the space enclosed by the camisole and generates iEFs by Faraday’s law. We measured the magnetic inductions, compared with their calculated values, and determined iEF distributions within the space enclosed by the garment. We find that iEF intensities found to have anti-metastasis and anti-tumor effects in animal models of TNBC can be easily attained at human anatomical scales and delivered in a practical manner for use by patients. Our work lays the foundation for first in human studies by extending a treatment developed in the laboratory into a wearable and washable treatment device for cancer patients. Citation Format: Joseph West, Christopher Barron, Vish Subramaniam. A practical method of delivering induced electric field (iEF) 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 1302.