tbuckley/cabot-search huggingface dataset:
Abstract 3488: MERTK inhibition regulates tumor-associated myeloid cell phenotypes and potentiates host-versus-lung cancer immunity
Authors: Dan Yan, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Journal: Cancer Research (2025)

Abstract The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases are important for clearing apoptotic cells and maintaining tissue homeostasis. They promote an immunosuppressive environment during cell clearance, which can be hijacked by tumor cells to promote immune evasion. This study aimed to determine how MERTK inhibition affects immune cells within the tumor microenvironment (TME) in lung cancer using a subcutaneous Kras-mutant murine lung cancer tumor model in wild-type (WT), Axl knock-out (KO), or Mertk KO mice. Tumor growth was inhibited in Mertk KO mice compared to WT mice, while Axl KO mice had no significant change in tumor growth. The anti-tumor effect observed in Mertk KO mice was lost in Mertk KO scid mice, which lack functional T and B cells, suggesting MERTK as an immunotherapeutic target in Kras-mutant lung cancer. MRX-2843 is a novel first-in-class MERTK-selective inhibitor that is currently being tested in phase 1/1b clinical trials. The murine cancer cell line used in this study did not express detectable MERTK and was unresponsive to MRX-2843 in vitro. However, in vivo treatment with MRX-2843 led to dose-dependent inhibition of tumor growth. Conditional knockout of Mertk in LysM expressing (i.e. myeloid) cells resulted in reduced tumor growth compared to tumors in WT mice. These data suggest that MERTK functions in myeloid cells to inhibit anti-tumor immunity, although contributions of homozygous LysM KO could not be eliminated in this study. Additionally, MERTK was only expressed in WT tumor myeloid cells ; myeloid cell MERTK was not detected in the TME in conditional Mertk KO mice. Furthermore, tumors from Mertk KO mice had evidence of increased antigen-presenting capacity with significantly increased numbers of tumor-associated macrophages expressing high levels of MHC-II and increased incidence of dendritic cells. Together these findings suggest that MERTK inhibits anti-tumor immunity by regulating myeloid cell functions and implicate MERTK as an immunotherapeutic target in Kras-mutant non-small cell lung cancer. Citation Format: Dan Yan, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham. MERTK inhibition regulates tumor-associated myeloid cell phenotypes and potentiates host-versus-lung cancer 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 3488.
Abstract 5547: High resolution target identification by unbiased forward genetics
Authors: Moritz Horn, Georg Michlits, Andreia Rocha, Christoph Stelzer, Josef M. Penninger
Journal: Cancer Research (2025)

Abstract Forward genetic screens have revolutionized the field of target discovery, target deconvolution, and target validation, particularly in the oncology field. However, most approaches are limited to the interrogation of non-essential factors and identify gene networks rather than direct target structures. Therefore, the identification of druggable target structures and understanding an active molecules target space remains a challenge in drug discovery and development. To address this, we established a chemical mutagenesis approach in relevant cell types that allows entirely unbiased identification of small molecule targets at amino acid resolution, literally mapping compound-target interaction surfaces. Chemical mutagenesis randomly introduces single nucleotide variants into the entire genome resulting in cell populations which carry substitutions in statistically more than 90% of all amino acids. Challenging such mutagenized cell populations with a drug candidate of interest, followed by next generation sequencing and analysis, reveals direct drug target interactions, drug resistance mechanism, and potential off-targets or concealed efficacies. The alteration of single amino acids thereby allows interrogation of non-essential as well as most essential factors and increases screening resolution to the amino acid level. Several case studies will be shown. Citation Format: Moritz Horn, Georg Michlits, Andreia Rocha, Christoph Stelzer, Josef M. Penninger. High resolution target identification by unbiased forward genetics [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 5547.
Abstract 5553: Acquisition of adaptive and reversible drug-tolerance state to cabozantinib in renal cell carcinoma cell lines
Authors: Angela Zaccagnino, Hiresh Ayoubian, Kerstin Junker
Journal: Cancer Research (2025)

Abstract Drug-tolerant (DT) state has been recognized as a transient, adaptive process whereby tumour cells endure therapy with tyrosine kinase inhibitors (TKIs) through non-genetic/epigenetic mechanisms, which might be responsible for driving tumour relapse and therapy resistance. Considering that resistance to the targeted systemic therapies remains challenging in metastatic renal cell carcinoma (mRCC), here we elucidated the DT-state as response to the TKI cabozantinib (CBZ) targeting c-MET/Axl/VEGFR in RCC cell lines.After chronic exposure to CBZ (IC50) for 4 months, the 786-O/DTC, Caki-2/DTC and KTCTL-26/DTC cells were profiled for cell survival (WST-1), proliferation (BrdU), migration/invasion, apoptosis (caspase 3/7) and compared to untreated wild-type (wt) cells. Molecular analyses were carried out via immunoblotting and miRNA expression assays (hs-miRNA microarray and RT-qPCR).The DTC-cell lines were successfully induced. The DT-cell lines maintained viability after long-term therapy with a slow growing state. To investigate the mechanisms that drive DT-state, we compared the DTC and WT cells under CBZ. The DTC-cell lines showed higher proliferation (p&amp;lt;0.001), along with lower caspase 3/7 activity in KTCTL-26/DTC and Caki-2/DTC (p&amp;lt;0.001). CBZ impaired migration and invasion, except in KTCTL26/DTC, which displayed higher invasion (p&amp;lt;0.001). Phospho-TK c-MET was inhibited in DT-cells but not Axl. Yet, c-MET was partially restored in KTCTL-26/DTC. The downstream ERK was unchanged in Caki-2/DTC and KTCTL-26/DTC or boosted in 786-O/DTC. BCL-2 was enhanced in Caki-2/DTC or unaffected in the other two DTC- cell lines hinting at an ability to bypass cell death. The DTC-state was reversible, as the cells recovered cell growth after CBZ-withdrawal implying a dynamic regulation. Among 4 miRNAs, namely hs-miR-551b-3p, hs-miR-34a-5p, hs-miR-424-5p and hs-miR-9-3p that were commonly dysregulated in DTC-cell lines, the hs-miR-424-5p and hs-miR-9-3p (regulation of cell cycle, MAPK signalling and apoptosis) were consensually upregulated in DTC-cells by 2.5-fold change (p=0.001), but their expression was reversed after treatment discontinuation. Remarkably, their regulation matched the changes in We established CBZ-DT cell lines and characterised the related spectrum of molecular changes, while considering tumour heterogeneity crucial to drug-adaptation. We identified previously unrecognised miRNAs associated with DT to emphasise the dynamic epigenetic changes that are critical in the initiation of DT-state. Citation Format: Angela Zaccagnino, Hiresh Ayoubian, Kerstin Junker. Acquisition of adaptive and reversible drug-tolerance state to cabozantinib in renal cell carcinoma cell lines [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 5553.
Abstract 5530: Combination of BRAF and ACLY inhibition synergistically reduces melanoma cell viability
Authors: Anastasiia Vaska, Michael Ferretti, Daniel A. Ho, Rachel E. Harmon, Robert F. Green, Aaron B. Steiner, Nancy A. Krucher
Journal: Cancer Research (2025)

Abstract Fifty percent of Melanoma cases harbor the activating BRAF V600E mutation which prompted the development of BRAF inhibitors Vemurafenib, Dabrafenib and Encorafenib, used clinically in combination with MEK inhibitors Trametinib, Cobimetinib and Binimetinib. Together, these agents serve to inhibit the MAPK pathway, but the PI3K/AKT pathway is often upregulated in response to MAPK pathway inhibition which can lead to clinically important treatment resistance. AKT functions in numerous cellular processes including survival, growth, proliferation, invasion and metabolism. With respect to metabolism, AKT activates lipogenesis by direct phosphorylation and activation of the enzyme ATP-Citrate Lyase (ACLY). ACLY expression and activity are elevated in melanoma and are associated with a poor prognosis. A new inhibitor of ACLY, NDI-091143, was recently identified based on the structure of ACLY and was used in this study. A panel of BRAF mutant melanoma cell lines was used to investigate whether combining the ACLY inhibitor NDI-091143 with the BRAF inhibitor Vemurafenib would enhance the latter’s pro-apoptotic effects. Using concentrations of each drug that inhibited cell viability individually by 25%, we found that the combination exhibited synergistic reduction of cell viability in all melanoma lines tested, and similar results were obtained using melanoma cells grown in 3D culture. Normal human keratinocytes treated with the same concentrations of Vemurafenib and NDI-091143 did not exhibit reduced viability. In melanoma cell lines, the combination of BRAF and ACLY inhibition activated the ER stress pathway including phosphorylation of eIF, increased CHOP and ATF4 expression, and induced caspase-mediated apoptosis. In addition, the combination of these agents elicited an increase in reactive oxygen species (ROS) as well as activation of the Jun N-terminal kinase (JNK) pathway, both of which stimulate apoptosis. In vivo assessment of this combination treatment in a zebrafish model of melanoma is underway. Citation Format: Anastasiia Vaska, Michael Ferretti, Daniel A. Ho, Rachel E. Harmon, Robert F. Green, Aaron B. Steiner, Nancy A. Krucher. Combination of BRAF and ACLY inhibition synergistically reduces melanoma cell viability [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 5530.
Abstract 5540: Deconstructing the lethality of recurrence in ovarian cancer through multi-modal spatiotemporal analysis
Authors: James M. Whipman, Francis Jacob, Viola Heinzelmann, Bernd Bodenmiller
Journal: Cancer Research (2025)

Abstract Epithelial ovarian cancer (EOC) represents the world’s most lethal gynecological malignancy and is commonly associated with chemo-resistance and recurrence. Strikingly, up to 70% of EOC patients will relapse where subsequent care becomes palliative. Owing to a lack of model systems and a scarcity of matched treatment-naïve and recurrent clinical samples, few studies have addressed the complex relationship between first-onset EOC and its respective relapse. Identification of in situ tumor phenotypes that resisted initial chemotherapy treatment and initiate recurrent tumors, will allow us to understand which cellular features lead to relapse. This will allow us to better predict tumor recurrence and to ultimately suggest novel therapies. Here we analyze primary and recurrent tumor pairs using highly multiplexed imaging technologies. Through integration of spatial transcriptomics and imaging mass cytometry (IMC), we identify and classify resistance phenotypes in over 320 EOC patients, identifying phenotypes that persist in recurrent tumors. We leverage these technologies to assign novel proteo-transcriptomic resistance modules that allow us to independently observe these phenotypes across multiple single-cell modalities. To uncover phenotype-specific drug sensitivities, we utilized scRNA-seq data to predict in silico drug-response and validated these findings through large-scale image-based ex vivo drug screening. These screens revealed significant multi-drug resistance (MDR) properties of persistent phenotypes, but unveiled sensitivity to alternate FDA-approved drug classes. Together, our work represents the first-of-its-kind high-dimensional map of resistant and recurrent EOC, offering tangible therapeutic solutions for the treatment and prevention of recurrence. Citation Format: James M. Whipman, Francis Jacob, Viola Heinzelmann, Bernd Bodenmiller. Deconstructing the lethality of recurrence in ovarian cancer through multi-modal spatiotemporal analysis [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 5540.
Abstract 3291: Development of anti-B7H3 CAR T cells for treatment of osteosarcoma in a canine model
Authors: Theresa Higgins, Payal Agarwal
Journal: Cancer Research (2025)

Abstract Characterized as a highly aggressive and metastatic solid bone tumor, osteosarcoma (OS) remains a difficult to treat cancer. Even with the current treatment options of chemotherapy, radiation, and tumor removal surgery there is poor patient prognosis and low survival rates, highlighting the need for novel treatments. Over the last decade, chimeric antigen receptor (CAR) T cells have shown promising results in the treatment of certain leukemias and lymphomas and are further being explored in solid tumor types. We aim to develop CAR T cells against the immune checkpoint cell surface receptor B7H3 (anti-B7H3 CAR T cells), which is over expressed in several cancers, including OS. We hypothesize that anti-B7H3 CAR T cells will be able to successfully lyse osteosarcoma in a canine model. We have verified that B7H3 is expressed and demonstrates significant antibody binding in four canine OS cell lines (D17, CF11, MCKOS, and D22). We have successfully isolated and activated T cells by incubating in CD3 and CD28 coated plates. We will transduce active T cells with anti-B7H3 encoding lentivirus. The cytotoxic effects of anti-B7H3 CAR T cells will be explored in both two-dimensional (2D) and three-dimensional (3D) cell cultures. Additionally, IFNγ, TNFα, and IL-2 cytokine levels will be measured and analyzed. We expect cell lysis and increased cytokine levels post-CAR T therapy in our canine OS cell lines. Citation Format: Theresa Higgins, Payal Agarwal. Development of anti-B7H3 CAR T cells for treatment of osteosarcoma in a canine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3291.
Abstract 5392: Breast cancer cells that preferentially metastasize to lung are more adaptable to varying glucose levels compared to those that metastasize to the liver
Authors: Marjorie Anne A. Layosa, Mike Wendt, Stephen Hursting, Dorothy Teegarden
Journal: Cancer Research (2025)

Abstract Metastasis is the primary cause of breast cancer-related deaths. We investigated the metabolic adaptations of glucose, a major energy substrate, in breast cancer cells that metastasize to lung versus liver to determine the metabolic adaptations that may support site-specific metastasis. Utilizing a breast cancer model that preferentially metastasizes to the lung (metM-WntLung cells; MLg) or liver (metM-WntLiver cells; MLr), we measured 14C-glucose uptake, 13C6-glucose flux into metabolic pathways, and viability under varying glucose concentrations. Results show that in 5 mM glucose (normal), MLg is more glycolytic with greater flux of 13C6-glucose-derived carbons into the glycolytic intermediates pyruvate and lactate in comparison to MLr. In contrast, MLr showed higher levels of 13C6-glucose-derived carbons in the tricarboxylic acid cycle metabolites including oxaloacetate and malate indicative of higher oxidative phosphorylation and higher pyruvate carboxylase (PC) activity. Interestingly, high glucose (25 mM) exposure reduced viability of MLr by 39%, suggesting MLg’s adaptability to varying glucose levels. Although glucose uptake similarly increased in all cell lines under high glucose, flux results showed greater oxidative phosphorylation and increased PC activity in MLg, while MLr shifted to a more glycolytic phenotype. These results were consistent with improved oxidative stress protection in high glucose in MLg, but not MLr. Further, MLg deprived of glucose were more viable (9%) compared to MLr, suggesting a potential alternate use of other substrates to overcome glucose deprivation. Inhibiting the rate-limiting enzyme for gluconeogenesis, phosphoenolpyruvate carboxykinase, reduced viability of MLg by 9% compared to MLr. Further, inhibiting the catabolism of glutamine, a gluconeogenic substrate, reduced viability of MLg by 13% compared to MLr, suggesting that MLg utilizes the contribution of glutamine and gluconeogenesis in conditions of low glucose. Overall, breast cancer cells with preferential metastasis to lung are more adaptable to varying glucose concentrations than breast cancer cells with preferential metastasis to liver by shifting metabolism from glycolysis to oxidative phosphorylation under high glucose conditions and utilizing glutamine and gluconeogenesis under low glucose conditions. Citation Format: Marjorie Anne A. Layosa, Mike Wendt, Stephen Hursting, Dorothy Teegarden. Breast cancer cells that preferentially metastasize to lung are more adaptable to varying glucose levels compared to those that metastasize to the liver [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 5392.
Abstract 3289: Radiation supports the polarization of M1 macrophages against triple-negative breast cancer cells via the IKZF1 - CCL5 axis
Authors: Kuo Han-Hsi, Yu-Chan Chang
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC), known for its therapeutic challenges and high metastatic potential, is commonly treated with ionizing radiation (IR). In the tumor microenvironment (TME) of TNBC, macrophages occupy a place and are reprogrammed into two main types, M1 and M2, in response to different stimuli such as IR or various cytokines. However, the detailed molecular mechanism remains to be elucidated. Using our cell model, we applied IR dose-dependently (0.5/8 Gy) to observe macrophage polarization and found that high-dose IR could increase the proportion of M1 macrophages. These trends are consistent with polarization by LPS (M1) and IL-4/IL-13 (M2), respectively. By integrating transcriptomics and cytokine array profiling, we demonstrated that IKAROS family zinc finger 1 (IKZF1), a transcription factor involved in DNA repair, downregulates secretion of the downstream target, CCL5, in macrophages under high-dose IR exposure. In the collected conditioned medium, the high-dose IR group could significantly inhibit the migration and proliferation of TNBC cells. Even, recombinant CCL5 protein was recruited to modulate the TME of TNBC, and the migration ability of TNBC cells was reversed. In the direct co-culture system, phagocytic event was enhanced by high-dose IR. In conclusion, under high-dose irradiation conditions, IKZF1 is inhibited and CCL5 secretion is reduced. The TME environment is conducive to polarization of the M1 subtype and enhances its ability to phagocytose TNBC cells, thereby inhibiting TNBC progression. This finding suggests that the benefits of radiotherapy in TNBC may also be linked to a new chapter in immunotherapy. Citation Format: Kuo Han-Hsi, Yu-Chan Chang. Radiation supports the polarization of M1 macrophages against triple-negative breast cancer cells via the IKZF1 - CCL5 axis [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 3289.
Abstract 4629: Plasma exosomal miRNA and disease progression in metastatic breast cancer on CDK4/6 inhibitors: A feasibility study
Authors: Ding Quan Ng, Julia Trudeau, Casey Hudson, Khai Kober, Kord M. Kober, Munjal M. Acharya, Alexandre Chan, Ritesh Parajuli
Journal: Cancer Research (2025)

Abstract Background: Treatment resistance is common among metastatic breast cancer patients receiving CDK4/6 inhibitors (CDKi). Exosomal miRNA play a key role in intercellular communication and gene regulation that may predict treatment outcomes. We hypothesize that patient’s blood exosomal miRNA can uncover biological pathways critical for CDKi response and resistance. Methods: Plasma samples from metastatic breast cancer patients were prospectively collected every 12 weeks during CDKi treatment until discontinuation. Next generation sequencing was performed on isolated plasma exosomes for miRNA profiling. MiRNA independently associated with treatment response (hazard ratio [HR] &amp;lt; 1) and resistance (HR &amp;gt; 1) after Bonferroni correction were identified with mixed-effects Cox regression with time-to-disease progression as the outcome. We generated a miRNA-gene network using miRNet and performed pathway enrichment analysis of target genes using hypergeometric test. Results: Eleven patients provided 26 samples during CDKi treatment. Five (45%) progressed; they were more likely to be hormone receptor negative (40% vs 0%) and a race-ethnic minority (80% vs 17%). After adjustment, 54 and 18 miRNAs were associated with treatment response and resistance, respectively. A total of 48 pathways (false discovery rate [FDR] &amp;lt; 0.05) were identified in relation to treatment outcomes (Table 1). Of these, 25 pathways (52%, e.g. TGF-β, insulin, Jak-STAT) were associated exclusively with response, 2 (4%, long-term depression and oocyte meiosis) were associated with resistance, and 21 (44%, e.g. cell cycle, p53, neurotrophin) were shared by both. The study’s feasibility is demonstrated by the identification of numerous cell-cycle and cancer-specific pathways. Conclusion: This study highlighted the potential of exosomal miRNA as gene expression modulators to uncover key pathways underlying CDKi treatment outcomes. Findings warrant validation in independent studies. Citation Format: Ding Quan Ng, Julia Trudeau, Casey Hudson, Khai Kober, Kord M. Kober, Munjal M. Acharya, Alexandre Chan, Ritesh Parajuli. Plasma exosomal miRNA and disease progression in metastatic breast cancer on CDK4/6 inhibitors: A feasibility 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 4629.