tbuckley/cabot-search huggingface dataset:
Abstract 827: Correlation among early surrogate endpoints and survival in borderline-resectable pancreatic cancer: A trial-level meta-analysis
Authors: Chanbormey Leatheng, Alexander Khamechand, Gabriel A. Brooks, Hirotaka Miyashita
Journal: Cancer Research (2025)

Abstract Background: Multiple endpoints are used as surrogates for overall survival (OS) in clinical trials for borderline resectable pancreatic cancer (BRPC), including the R0 resection rate. However, consensus is lacking regarding the validity of this and other surrogate endpoints. This study aims to assess the relationship between common surrogate endpoints and median OS (mOS). Methods: We conducted a systematic review of PubMed and Web of Science to identify clinical trials investigating neoadjuvant treatment (surgery, chemotherapy, or radiation therapy) of BRPC. Eligible trials reported on OS and at least one surrogate endpoint (resection rate [RR], R0 resection rate [R0], 1-year OS [1yOS], and 2-year OS [2yOS]). We estimated the correlation of OS with each of the surrogate endpoints using both Spearman and Pearson coefficients (r). The confidence intervals (CI) of coefficients were estimated by 2, 000 times of bootstrapping resampling. Weighted linear regressions with calculation of R-squared were utilized to estimate correlations adjusted for the sample size in each cohort. Results: We identified 25 eligible clinical trials with 32 treatment cohorts. The range of mOS was 11 to 41 months, and the median mOS was 23.3 months. R0 and 2yOS were significantly correlated with mOS by the Spearman coefficient (r=0.51 [95% CI: 0.01-0.79] and r=0.74 [0.19-0.95], respectively) but RR and 1yOS were not. All early endpoints (RR, R0, 1yOS and 2yOS) were significantly correlated with mOS by the Pearson coefficient (r=0.49 [0.01-0.79], 0.58 [0.28-0.78], 0.75 [0.12-0.91] and 0.79 [0.43-0.92], respectively). Weighted liner regression revealed that RR, R0, 1yOS and 2yOS were significantly correlated with mOS (R-squared= 0.20, 0.32, 0.43 and 0.57, respectively with p &amp;lt; 0.05 for all). Conclusions: This study demonstrated significant correlations between early surrogate endpoints and mOS in BRPC. However, the correlation between mOS and resection-related endpoints (RR and R0) was modest. These findings provide important context for selection and interpretation of surrogate endpoints in studies of BRPC. Citation Format: Chanbormey Leatheng, Alexander Khamechand, Gabriel A. Brooks, Hirotaka Miyashita. Correlation among early surrogate endpoints and survival in borderline-resectable pancreatic cancer: A trial-level meta-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 827.
Abstract 770: ccRCC metastasis rewires tumor microenvironment to increase immunosuppression and fibrosis
Authors: Yufei Wang, Jae-Won Cho, Yasmin Nabil Laimon, Wenxin Xu, Aseman Bagheri Sheshdeh, Nithyassree Murugan, Hsien-Chi Yuan, Jon Wee, David Braun, Toni Choueiri, Catherine Wu, Sabina Signoretti, Gordon Freeman, Martin Hemberg, Wayne Marasco
Journal: Cancer Research (2025)

Abstract Tumor progression and metastasis is driven by interplays between cancer cells and their surrounding tumor microenvironment (TME). Investigating the spatiotemporal transcriptomic profile of primary and metastatic tumors sheds light on how the differences in spatial architecture shape the TME and promote tumor metastasis. Here, we profiled three primary and three lung metastatic clear cell renal cell carcinoma (ccRCC) samples using the CosMx platform, which provides a 999-gene transcriptome with spatial coordinates. After cell segmentation and annotation, we further incorporate the cellular context and spatial information to identify niches by grouping the cells with similar neighboring cells. Cell-cell communication and architecture were analyzed to understand the spatial organization in primary and metastatic ccRCC. From niche analysis, 12 distinctive niches were identified, including cancer, stroma, alveolar, tertiary lymphoid structure (TLS), and mast niches, formed by 25 different cell types. Analyzing cancer niches, we found that the metastatic TME is much more immunosuppressive compared to the TME in primary ccRCC. There is a higher infiltration of exhausted T cells, Treg and M2-like macrophages in metastases. Moreover, the fibroblasts in metastases have higher expression of VEGF and metalloproteinases, which led to angiogenesis and worse prognosis. Architecture analysis showed that lung metastatic ccRCC cells, surrounded by a stromal barrier, are not directly interacting with tumor infiltrating leukocytes (TILs), whereas primary ccRCC cells interact more with TILs. Moreover, compared to the TLSs in primary ccRCC, the ones in metastases showed features of dysfunction, which was correlated with a worse prognosis. Our results show the impact of spatial architecture on primary and metastatic ccRCC, as well as the relation between spatial organization of the cellular context and cell-cell communication. In addition, it suggests that immune cells and cancer-associated fibroblasts (CAFs) are essential components of the ccRCC TME. Their interaction constitutes a major factor not only for tumor progression but also limiting therapy response in metastatic ccRCC. Citation Format: Yufei Wang, Jae-Won Cho, Yasmin Nabil Laimon, Wenxin Xu, Aseman Bagheri Sheshdeh, Nithyassree Murugan, Hsien-Chi Yuan, Jon Wee, David Braun, Toni Choueiri, Catherine Wu, Sabina Signoretti, Gordon Freeman, Martin Hemberg, Wayne Marasco. ccRCC metastasis rewires tumor microenvironment to increase immunosuppression and fibrosis. [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 770.
Abstract 2547: The impact of aging on YAP activity in melanoma cells: nuclear localization and condensate formation
Authors: Ethan Black, Danfeng Cai, Ashani Weeraratna
Journal: Cancer Research (2025)

Abstract Melanoma is a highly lethal form of skin cancer which disproportionately impacts older patients, leading to increased rates of melanoma diagnosis and worse prognostic outcomes in this population. This is driven, in part, by higher rates of invasion and therapy resistance caused by age-related changes to the tumor microenvironment. One mechanism this occurs through is the increased senescence of fibroblasts which disrupts extracellular matrix (ECM) deposition, resulting in a more aligned and stiffer matrix. The Hippo pathway is known to shut off in response to matrix stiffness which allows for increased YAP nuclear localization. YAP is a known marker for increased invasion in melanoma. While the importance of YAP in melanoma is known, it is understudied in the context of an aging tumor microenvironment. Additionally, YAP’s ability to form transcriptionally active condensates and whether this activity is vital to its function has yet to be elucidated in melanoma. Our lab has previously shown that the increased stiffness of cell-derived matrices (CDMs) created with aged fibroblast cell lines when compared to CDMs from young fibroblasts is sufficient to increase YAP nuclear localization in HUVEC cells. We hypothesize that age-associated increases in ECM stiffness will also increase YAP nuclear localization in melanoma cells, resulting in increased YAP target gene activation, YAP condensate formation, and downstream pro-invasive melanoma cell behavior. To investigate this we employed several techniques, including the creation of CDMs from aged/young fibroblasts, immunofluorescence (IF) staining, and Airyscan super-resolution microscopy. Our data suggests that melanoma cells grown on cell-derived matrices (CDMs) created by aged dermal fibroblasts have increased nuclear YAP localization when compared to cells grown on CDMs created with young dermal fibroblasts. However, the downstream effects of this increased YAP activity on invasion and therapy resistance in melanoma cells as well as whether melanoma cells being plated on aged CDMs increases YAP condensate formation are still being examined. Our IF data from these melanoma cells also suggests that YAP condensates assemble endogenously in melanoma when plated on these CDMs, and the importance of their role in YAP target gene activation warrants further study. As we continue this work, it will allow us to better understand how the aging tumor microenvironment changes YAP activity and the downstream effect this has on the invasive behavior that is characteristic of melanoma in older patients. Citation Format: Ethan Black, Danfeng Cai, Ashani Weeraratna. The impact of aging on YAP activity in melanoma cells: nuclear localization and condensate formation [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 2547.
Abstract 275: Increased expression levels of <i>KISS1</i> in IDCC breast cancer induced by melatonin treatment
Authors: Kelly P. Ferreira, Bruna C. Almeida, Edmund C. Baracat, Katia C. Carvalho
Journal: Cancer Research (2025)

Abstract Introduction: Tumor suppressors encode proteins commonly expressed in non-cancer cells that avoid abnormal events that culminate to neoplasms development. In a deregulated expression case, they are useful as biomarkers for pathological stages or tumor progression. KISS1 (KiSS-1 metastasis suppressor), is a known metastatic suppressor and its expression is commonly downregulated in the metastatic tumors of various origins, including breast cancer. In this context, some researches showed that melatonin (Mel) can improve survival rates, suggesting that its application may be a tool for therapeutic use in some breast tumors. Thereby, we aimed to identify mRNA levels of KISS1 in invasive ductal carcinoma cells (IDCC) with metastasis in pleural effusion (MCF7) treated with Mel and compare with MCF7 non-treated cells (CC). Methods: MCF7 (ER+) cell line was cultured with RPMI 1640 (Sigma-Aldrich, Germany), with 10% fetal bovine serum (FBS - Gibco, USA) treated with activated charcoal, inactivated, sodium bicarbonate, pyruvic acid and antibiotics as recommended by ATCC and subsequently treated with 3000 μM Mel. After treatment the RNA was extracted using mirVana miRNA Isolation Kit (Ambion, USA) and then, purity and concentration of total RNA were accessed. The Reverse transcription synthesis was performed using High-Capacity cDNA Reverse Transcription Kit (ThermoFisher Scientific, Lithuania). Expression profile of 91 mRNA, including KISS1 and, 5 housekeeping mRNAs was performed by TaqMan Array Plates using Real-Time PCR (Applied Biosystems, USA). Data analysis was obtained by ExpressionSuit Software v1.3 (ThermoFisher Scientific). Results: The concentration of melatonin tested in MCF7 cells (ER+) from metastasis showed, a significant increase of mRNA KISS1 expression levels when compared to the levels presented in MCF7 cells that did not receive melatonin treatment (control cell - CC). Conclusion: Melatonin treatment was able to increase the expression of KISS1 in MCF7 cells, indicating that its use may bring benefits associated to an improved prognosis for similar tumors. Further studies are ongoing to confirm and expand our results. Citation Format: Kelly P. Ferreira, Bruna C. Almeida, Edmund C. Baracat, Katia C. Carvalho. Increased expression levels of KISS1 in IDCC breast cancer induced by melatonin 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 275.
Abstract 1318: Cytotoxic effect of plant-based alkaloid veratridine on patient-derived colorectal cancer spheroid cells
Authors: Kate Schraufnagel, Morgan Eikanger, Khosrow Rezvani
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) causes approximately 900, 000 deaths annually worldwide. The survival rate for patients diagnosed with localized CRC is 90 percent; however, once the cancer metastasizes or spreads to other parts of the body, the five-year survival rate drops to a dismal 15%. There is a clear need for a new generation of targeted therapies that can safely and efficiently target the metastatic features of CRC cells. Our lab has shown that veratridine (VTD), a lipid-soluble plant alkaloid, can enhance the expression of a ubiquitin-like protein called UBXN2A as a colon-specific tumor suppressor protein. UBXN2A binds and negatively regulates the Rictor protein, a key member of the mTORC2 signaling pathway. This results in suppression of mTORC2-AKT’s downstream signaling pathway in cancer cells. We hypothesize that the VTD-UBXN2A axis decreases migration in human CRC tumors. Human colon cancer cells and patient-derived xenograft cell lines in 2D and 3D spheroid forms were used to complete this project. Real-time cell migration and invasion analysis using xCELLigence technology and Cytation 1 cell imaging system revealed the VTD-UBXN2A axis can suppress metastatic characteristics of CRC cells, including cell proliferation and migration. Small molecule targeted compounds have been successfully developed in clinical medicine to prolong the survival time of patients with advanced tumors. This ongoing study will provide detailed insight into the therapeutic efficacy of a potential targeted therapy to safely and effectively target CRC cells while normal cells can remain intact. Citation Format: Kate Schraufnagel, Morgan Eikanger, Khosrow Rezvani. Cytotoxic effect of plant-based alkaloid veratridine on patient-derived colorectal cancer spheroid 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 1318.
Abstract 195: The transmembrane mucin MUC1 modulates MAPK signaling dynamics in pancreatic cancer cells
Authors: Seth Thesing, Ryan Lee Hanson
Journal: Cancer Research (2025)

Abstract The transmembrane mucin MUC1 plays several roles in the progression of pancreatic ductal adenocarcinoma (PDAC) and is associated with aggressive disease. One function of MUC1 is the regulation of intracellular signal transduction through association with transmembrane receptors like EGFR and Src. While multiple studies have shown that MUC1 can potentiate signaling mitogen activated protein kinases, such as ERK, it’s unclear how dynamic this process is in PDAC. Previous studies examining ERK signaling have shown that dynamics can play a major role in the overall response to cells to growth factor signaling. To examine the influence of MUC1 on dynamic signal transduction we established cell lines expressing fluorescent biosensors of mitogen activated protein kinase activity (ERK, JNK, and p38) using cell lines derived from either wildtype KPC tumors or MUC1 knockout tumors. Morphologically, MUC1 expressing KPC cells appeared more mesenchymal consistent with MUC1’s roles in mediating migration and invasion of tumor cells. By comparison, MUC1 knockout cells readily formed monolayers with epithelial morphology. Using time-lapse fluorescence microscopy, we examined whether these cells also exhibited differences in MAPK signaling over time and in response to EGF stimulation. At baseline, KPC wildtype cells showed sustained ERK activation consistent with constitutive activation via K-Ras G12D. In comparison, MUC1 KO cells while still exhibiting high levels of ERK activity would also undergo periodic pulses of on and off states suggesting that MUC1 contributes to sustained ERK activation in tumor cells. EGF stimulation was capable of inducing ERK activation in both KPC wildtype and MUC1 KO cells, but as before KPC wildtype cells exhibited sustained activation while MUC1 KO cells pulsed. Given the high constitutive ERK activity in KPC wildtype cells we hypothesized these cells may be more reliant on ERK activation to survive. Interestingly, while treatment with 25 nM trametinib had a stronger inhibitory effect on MUC1 knockout cells, viability assays suggest that MEK inhibition reduces KPC wildtype growth more strongly than in MUC1 KO cells. These findings suggest that the sustained ERK signaling promoted by MUC1 expression may make tumor cells more reliant on ERK signaling and more prone to MEK inhibition. Citation Format: Seth Thesing, Ryan Lee Hanson. The transmembrane mucin MUC1 modulates MAPK signaling dynamics in pancreatic cancer 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 195.
Abstract 656: Enhanced therapeutic effect of combining denosumab with PD-1 inhibitor in advanced KRAS-mutated lung adenocarcinoma
Authors: Chengming Liu, Hongshuai Li, Sufei Zheng, Nan Sun, Yan Wang, Jie He
Journal: Cancer Research (2025)

Abstract Background: Previous studies have suggested that the combination of RANKL inhibitors and immune checkpoint inhibitors (ICIs) may potentiate the therapeutic response in lung adenocarcinoma, particularly in cases with KRAS mutations. The exact mechanisms and clinical validation of this combination therapy are yet to be fully understood. Methods: We conducted a comprehensive analysis by integrating public datasets and retrospective clinical data to examine the relationship between RANKL alterations and the tumor immune microenvironment in KRAS-mutated lung adenocarcinoma. We also investigated the signaling pathways affected by RANKL manipulation in cancer cell lines and assessed the impact on macrophage function. A prospective clinical trial was carried out to evaluate the potential of the RANKL inhibitor combined with PD-1 inhibitor therapy. Results: Our analysis revealed that the combination therapy of RANKL inhibitor with PD-1 inhibitor demonstrated improved outcomes in patients with KRAS-mutated lung adenocarcinoma. Transcriptomic data and immunohistochemical staining showed that RANKL was upregulated in these tumors, which was inversely associated with PD-L1 expression and the secretion of CXCL9, CXCL10, and CXCL11, leading to a decrease in CD8+ T cell infiltration and a more immunosuppressive environment. We found that RANKL modulated PD-L1 levels via the PI3K/AKT pathway and reduced CD8+ T cell infiltration by decreasing the expression of CXCL9, CXCL10, and CXCL11. In a mouse model, KRAS-mutated lung adenocarcinoma treated with the combination therapy showed significant tumor growth inhibition compared to PD-1 inhibitor alone. Additionally, the combination therapy significantly enhanced macrophage and CD8+ T cell recruitment. The DEMAND trial confirmed the superior therapeutic efficacy of this combination regimen in patients with KRAS-mutated lung adenocarcinoma. Conclusion: Our study sheds light on the role of RANKL overexpression in promoting immunosuppression and ICI resistance in KRAS-mutated lung adenocarcinoma. Our results indicate that the combination of RANKL inhibitor and PD-1 inhibitor could be a promising therapeutic strategy for this patient subset. Citation Format: Chengming Liu, Hongshuai Li, Sufei Zheng, Nan Sun, Yan Wang, Jie He. Enhanced therapeutic effect of combining denosumab with PD-1 inhibitor in advanced KRAS-mutated lung 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 656.
Abstract 141: Utilizing multiplex imaging to characterize the extracellular matrix in cancer
Authors: Anton Villamejor, Joseph Lownik, Ben Falk, Larry Milshteyn, Akil Merchant
Journal: Cancer Research (2025)

Abstract The tumor microenvironment (TME) is known to be an essential component in the response to multiple therapeutics, including immunotherapies. The TME is comprised of the tumor itself, infiltrating immune cells, and the extracellular matrix (ECM). ECM has been shown to play a critical role in tumorigenesis, affect the efficacy of certain treatments, and regulate anti-tumor immunity. However, methods to study ECM have typically been limited to single-marker studies or have used dissociated methods which lose spatial context. Additionally, fluorescence-based approaches to study the ECM are challenging due to the auto-fluorescence properties of multiple ECM components. We chose to utilize the multiplex capabilities of Imaging Mass Cytometry (IMC) for its ability to detect up to 40 different proteins via metal-tagging and absence of auto-fluorescence. We selected and validated 40 markers which we believe play an integral role in ECM, including structural proteins as well as immune markers and metabolic enzymes. This 40-plex panel was validated using a tissue microarray (TMA) comprised of various healthy and diseased tissue samples such as Lung, Colon, Breast, Prostate, Kidney, and Liver and their respective tumor counterparts. After staining, our results underwent rigorous analysis through a multi-step image comparison of our staining results to those in the current literature, ensuring our staining was specific. We found significant differences in the protein expression of various ECM markers between the healthy tissue and their tumor counterpart. We found structural variations of multiple ECM proteins between the normal tissue and tumor tissue. However, the expression patterns of these ECM elements were not uniform between tumor types, with overexpression of HAPLN1 in breast cancer while decreased in colon cancer. The included immune markers allow for spatial studies to examine the role of ECM in regulating immune responses, such as CD8+ T-cell infiltration. Additionally, we found that tumors from non-small cell lung cancer (NSCLC) patients exhibit significant ECM heterogeneity. We used a patch-based analysis approach to examine the ECM phenotypes of a cohort of 35 NSCLC patients. Preliminary assessment demonstrates unique clusters of ECM phenotypes have a utility for predicting patient outcomes. Further analysis of this cohort will be presented. Overall, we present a highly-multiplexed IMC panel which allows for detailed assessment of the ECM. Citation Format: Anton Villamejor, Joseph Lownik, Ben Falk, Larry Milshteyn, Akil Merchant. Utilizing multiplex imaging to characterize the extracellular matrix in 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 141.