tbuckley/cabot-search huggingface dataset:
Abstract 696: Shed Trop2 drives prostate cancer progression and Trop2 is a novel tissue prognostic biomarker and a candidate urinary marker for prostate cancer and bladder cancer
Authors: Shiqin Liu
Journal: Cancer Research (2025)

Abstract Distinguishing indolent from clinically significant localized prostate cancer and treatment of metastatic prostate cancer are two major clinical challenges in prostate cancer. The development of novel predictive biomarkers will help with risk stratification, and influence clinical decision-making between treatment and active surveillance, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2, an oncogenic transmembrane surface protein, is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that higher Trop2 expression is correlated with worse clinical features and elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detected shed Trop2 in urine from men with clinically significant prostate cancer and bladder cancer. We further define the functional role of shed Trop2 on metastasis in prostate cancer and identify that shed Trop2 increases cell migration, invasion, metastatic colonization, and spontaneous metastasis in vitro and in vivo. Proteomic profiling reveals that shed Trop2 modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. Shed Trop2 binds to EGFR and results in the activation of the EGFR-PI3K-AKT-mTOR pathway in prostate cancer. Our study reveals a new function of shed Trop2 in driving prostate cancer progression and identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer that could be used to optimize treatment decision-making. Citation Format: Shiqin Liu. Shed Trop2 drives prostate cancer progression and Trop2 is a novel tissue prognostic biomarker and a candidate urinary marker for prostate cancer and bladder 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 696.
Abstract 534: Sotorasib-resveratrol combination induces synergistic cytotoxicity by downregulating K-RAS signaling in K-RAS mutant lung cancer cell lines
Authors: Pedro Barrios Bernal, Norma Hernandez-Pedro, José Lucio-Lozada, Eunice Romero-Nuñez, Cesar Castillo-Ruiz, Brandon Lopez, Sandra Hernandez-Sanchez, Oscar Arrieta
Journal: Cancer Research (2025)

Abstract Background: K-RAS mutations are the most frequent (35-50%) in patients with non-small cell lung cancer (NSCLC) who have a smoking history. These mutations promote cancer development through constitutive activation of poliferative signaling pathways, metabolic modifications and mechanisms of apoptosis evasion. Sotorasib is a covalent inhibitor targeting KRAS G12C; however, the primary challenge lies in acquired resistance. Resveratrol is a natural compound that promotes apoptosis and inhibits proliferation through the MAPK and Wnt/β-catenin pathways in cancer cells. Therefore, this project proposes using resveratrol as an adjuvant therapy to sotorasib in cell lines with KRAS mutations. Methods: Dose-response curves were generated using MTT assays to determine the IC50 for sotorasib and the IC10 for resveratrol, in addition to determine the type of interaction between both drugs in the K-RAS mutant cell lines A549 (G12S) and H23 (G12C). Crystal violet assays were performed to measure the effect on cell proliferation. Mitochondrial membrane potential was assessed via flow cytometry. Finally, protein expression, activation, and inactivation were analyzed using western blot assays (K-RAS, BRAF, C-RAF, p-CRAF, GLUT1, GLUT3, HXK 1, AMPK and p-AMPK). Results: Our results revealed a synergistic effect of the combined sotorasib-resveratrol treatment in the H23 cell line, while an additive or antagonic effect was observed in the A549 cell line. Cell proliferation assays demonstrated significant growth inhibition in both cell lines when treated with sotorasib alone or in combination with resveratrol. Additionally, mitochondrial matrix collapse was predominantly observed with the combined treatments. Western blot analysis showed strong inhibition of the K-RAS signaling pathway and glucose transporters (GLUTs), along with AMPK activation, particularly in treatments involving resveratrol. Furthermore, the induced cytotoxicity was linked to the inhibition of K-RAS signaling, GLUTs, Hexokinase 1, and AMPK reactivation. Conclusions: The addition of resveratrol to sotorasib enhanced growth inhibition, independent of KRAS mutations, primarily through apoptotic mechanisms and the downregulation of the glucose metabolic pathway. Citation Format: Pedro Barrios Bernal, Norma Hernandez-Pedro, José Lucio-Lozada, Eunice Romero-Nuñez, Cesar Castillo-Ruiz, Brandon Lopez, Sandra Hernandez-Sanchez, Oscar Arrieta. Sotorasib-resveratrol combination induces synergistic cytotoxicity by downregulating K-RAS signaling in K-RAS mutant lung cancer 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 534.
Abstract 1877: Decoding cancer prevention: Exercise, dark proteome signatures, and spatial proteomics
Authors: Parthiban Periasamy, Patrick Sitjar, Xinru Lim, Jiangfeng Ye, Meng Jia, Jorming Goh, Yap Yoon Sim, Darren Wan-Teck Lim Wan- Lim, Roger Ho, Joe Yeong
Journal: Cancer Research (2025)

Abstract With rising cancer rates and widespread physical inactivity—a known risk factor for non-communicable diseases like cancer—exercise is increasingly recognized for its potential in cancer prevention and management. Despite strong evidence supporting its benefits, exercise remains underutilized in clinical oncology. Physical activity may reduce cancer risk and progression through mechanisms such as hormone regulation, reduced inflammation, improved insulin sensitivity, antioxidant enhancement, immune support, and direct tumor effects. Studies suggest that regular exercise could lower breast, colon, and lung cancer incidence by up to 40%. Exercise is generally safe for cancer patients, enhancing physical function, mental health, and potentially slowing tumor progression. Given that one-third of adults globally are inactive, incorporating exercise into cancer care offers a holistic approach to improve patient outcomes alongside conventional treatments. In our study, we used mass spectrometry-based serum proteomics to investigate exercise’s molecular effects on both the known and "Dark Matter" proteome—regions of proteins lacking structural characterization and potentially holding novel cancer biomarkers. We compared protein profiles between healthy individuals and pre-cancer patients, identifying early cancer signatures. Notably, Factor Xa (FA10), a vitamin K-dependent glycoprotein with pro-inflammatory effects, and fibulin-1 (FBLN1), a potential tumor suppressor involved in cell adhesion, were upregulated in pre-cancer patients. In an exercise intervention cohort, we observed that FA10 levels, initially elevated in pre-cancer patients, could be restored to baseline through exercise. This finding suggests that exercise may mitigate early cancer risk by reversing specific molecular changes associated with cancer progression. Ongoing work includes determining if unique proteins within the dark proteome can serve as distinctive cancer markers. We are currently performing spatial proteomics to determine the spatial distributions of selected dark proteome-derived proteins and to functionally characterize their roles in cancer prevention and progression. Citation Format: Parthiban Periasamy, Patrick Sitjar, Xinru Lim, Jiangfeng Ye, Meng Jia, Jorming Goh, Yap Yoon Sim, Darren Wan-Teck Lim Wan- Lim, Roger Ho, Joe Yeong. Decoding cancer prevention: Exercise, dark proteome signatures, and spatial proteomics [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 1877.
Abstract 1588: The novel trispecific tumor-conditional TRAIL-R agonist M0674 induces tumor cell apoptosis and deepens therapeutic efficacy of systemic and targeted chemotherapies
Authors: Christina Esdar, Doreen Musch, Carolin Sellmann, Ana Hecht, Achim Doerner, Enrico Guarnera, Julian Kreis
Journal: Cancer Research (2025)

Abstract Background: TRAIL death receptors are upregulated in a wide range of tumors, and their pharmacological activation induces apoptosis. Targeting TRAIL receptors (TRAIL-R) has emerged as a critical therapeutic strategy for cancer treatment. Despite some evidence for preclinical activity with past and present TRAIL-R agonists, only limited clinical efficacy has been reported so far, likely due to insufficient TRAIL-R clustering, decoy receptor binding, and hepatotoxicity. To address these limitations, M0674 has been designed as a trispecific antibody that simultaneously binds to tumor-associated (TA) MUC1, TRAIL-R1 and TRAIL-R2 but not to TRAIL decoy receptors. Methods: We conducted a detailed pharmacological characterization of M0674 compared to other TRAIL-R agonists through in vitro and in vivo studies. Apoptosis and viability assays were performed on cancer cells and human hepatocytes. The antitumor activity of M0674, both as a monotherapy and in combination with chemotherapy and an anti-CEACAM5 ADC with an exatecan payload (M9140), was evaluated using cell line-derived (CDX) and patient-derived (PDX) xenograft models. Results: Treatment with M0674 results in potent TA-MUC1-dependent induction of apoptosis and inhibition of viability in cancer cell lines, while human hepatocytes remain unaffected. M0674 demonstrates superior antitumor activity compared to other TRAIL-R agonists in both in vitro and in vivo studies. In vivo models show strong antitumor effects, including regressions, when M0674 is combined with systemic and targeted chemotherapies. MUC1-dependent single-agent activity and combination benefits with docetaxel are observed in three out of five nsqNSCLC PDX models that do not respond to docetaxel alone. Additionally, five out of six PDAC PDX models exhibit a strong combination benefit of M0674 with gemcitabine. Furthermore, the combination of M0674 with the anti-CEACAM5 ADC M9140 induces complete regression in a gastric CDX model. Conclusion: M0674 induces tumor-specific hyperclustering of TRAIL-R1 and R2 by binding to TA-MUC1, effectively triggering apoptosis in tumor cells without affecting healthy cells. The robust preclinical antitumor activity across various cancer types highlights the potential of M0674 as a safe and effective combination partner for systemic chemotherapies and ADCs. Citation Format: Christina Esdar, Doreen Musch, Carolin Sellmann, Ana Hecht, Achim Doerner, Enrico Guarnera, Julian Kreis. The novel trispecific tumor-conditional TRAIL-R agonist M0674 induces tumor cell apoptosis and deepens therapeutic efficacy of systemic and targeted chemotherapies [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 1588.
Abstract 2721: Mechanism Studies of HDACi combined with SP/KLF inhibitors in the treatment of H3K27M-mutant diffuse intrinsic pontine gliomas
Authors: Bo Wang, Yu Kong, Xuejiao Lv, Hao Zhuang, Xudong Wu
Journal: Cancer Research (2025)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) pose significant challenges in pediatric oncology with limited treatment options. Frequently harboring H3K27M mutations, these tumors are insensitive to histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Here we find that HDACi induce histone hyperacetylation including H3K27 acetylation, and increased accessibility at genomic regions linked to tumor microenvironment adaptation and invasiveness. And these regions gain occupancy of the SP/KLF family of transcription factors. Encouragingly, targeted intervention with EC-8042 effectively reverses this activated regulatory network by HDACi, thereby mitigating tumor adaptation and invasiveness. Furthermore, the combination of EC-8042 with HDACi enhances the repression of transcription in cell cycle-associated genes, leading to the inhibition of H3K27M-DIPG cell proliferation and impeding tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients. Therefore, employing DIPG models, this study provides critical mechanistic understanding of the limited responsiveness to HDACi in solid tumors, thereby laying the groundwork for the innovation of novel combination strategies. Citation Format: Bo Wang, Yu Kong, Xuejiao Lv, Hao Zhuang, Xudong Wu. Mechanism Studies of HDACi combined with SP/KLF inhibitors in the treatment of H3K27M-mutant diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2721.
Abstract 1522: High-throughput screening identifies HSP-90 inhibitor for pancreatic cancer therapy
Authors: Chiamaka Joy Ezeh, Darren Binder, Rohan Binder, Zeribe C. Nwosu
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Currently, it has an overall five-year survival rate of about 13%. This poor prognosis is attributed to the disease's late-stage diagnosis, rapid progression, and high resistance to available therapies. PDAC tumors often exhibit metabolic plasticity and oncogenic signaling dependencies, contributing to their ability to evade treatment, sustain growth under adverse conditions, and develop resistance to the current standard of care. These characteristics highlight the urgent need to identify novel therapeutic targets. In our study, a high-throughput drug screening was conducted to identify novel compounds capable of targeting key survival mechanisms and metabolic pathways in PDAC cells. Among the tested compounds, PU-H71, a heat shock protein 90 (HSP90) inhibitor, emerged as a promising candidate. Functional assays revealed that PU-H71 effectively inhibits the growth and proliferation in a panel of PDAC cell lines. Pathway analysis revealed that PU-H71 acts by disrupting multiple metabolic pathways. Our findings identify PU-H71 as a potent therapeutic candidate for PDAC treatment. Citation Format: Chiamaka Joy Ezeh, Darren Binder, Rohan Binder, Zeribe C. Nwosu. High-throughput screening identifies HSP-90 inhibitor for pancreatic cancer 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 1522.
Abstract 540: AVJ16 alleviates ABCB1-mediated doxorubicin chemoresistance via IGF2BP1 inhibition
Authors: Eveiyn Weng Yan Phoon, Kowit-Yu Chong
Journal: Cancer Research (2025)

Background: The efficacy of chemotherapy is often compromised by multidrug resistance (MDR), driven by the overexpression of ATP-binding Cassette Sub-family B Member 1 (ABCB1). While ABCB1 inhibitors are urgently needed, toxicity and pharmacokinetic challenges have limited clinical progress. Dysregulation of N6-Methyladenosine (m6A)—a key mRNA modification involved in gene regulation—is linked to chemoresistance, presenting a potential target to counteract ABCB1-mediated MDR. Aim: To examine m6A’s role in ABCB1-driven chemoresistance in uterine sarcoma and breast cancer and evaluate alternative ABCB1 inhibitors. Methods: RT-qPCR analysis identified Insulin-like Growth Factor 2 mRNA-binding protein 1 (IGF2BP1)—an m6A reader—as the most upregulated m6A regulator in MDR uterine sarcoma cells. Expression levels were validated in parental and MDR uterine sarcoma and breast cancer cells. GEO dataset of breast cancer patients treated with neoadjuvant chemotherapy was analyzed in silico to determine IGF2BP1-ABCB1 correlation. Functional assays were performed to evaluate IGF2BP1 knockdown and inhibition effects by AVJ16 (an IGF2BP1 inhibitor) on ABCB1 expression and doxorubicin resistance. Additionally, 3-deazaadenosine (DAA), an m6A inhibitor, was added to MDR cells with IGF2BP1 knockdown or AVJ16 treatment to confirm IGF2BP1’s role in m6A-dependent regulation of ABCB1 and chemoresistance. Results: IGF2BP1 and ABCB1 were significantly upregulated in MDR uterine sarcoma and breast cancer cells. In silico analysis confirmed a positive correlation between IGF2BP1 and ABCB1 expression, linking IGF2BP1 to ABCB1-driven chemoresistance clinically. IGF2BP1 knockdown in MDR uterine sarcoma cells reduced ABCB1 expression and doxorubicin resistance, evidenced by lower cell viability and colony formation. Moreover, AVJ16 significantly decreased doxorubicin’s half-maximal inhibitory concentration (IC50) in MDR uterine sarcoma by downregulating ABCB1 expression. DAA, combined with IGF2BP1 knockdown or AVJ16, markedly enhanced doxorubicin sensitivity, supporting IGF2BP1’s m6A-dependent role in MDR. Conclusion: IGF2BP1 is a novel m6A-dependent regulator of ABCB1-driven chemoresistance. These findings highlight AVJ16 as a promising therapeutic candidate for overcoming ABCB1-driven MDR cancers. Citation Format: Eveiyn Weng Yan Phoon, Kowit-Yu Chong. AVJ16 alleviates ABCB1-mediated doxorubicin chemoresistance via IGF2BP1 inhibition [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 540.
Abstract 3109: Pre-clinical efficacy of tumor treating fields and imipridones in glioblastoma and colorectal cancer cell lines
Authors: Viva Voong, Tyler Roady, Connor Purcell, Vida Tajiknia, Lanlan Zhou, Shengliang Zhang, Wafik El-Deiry
Journal: Cancer Research (2025)

Tumor treating fields (TTFields) utilize alternating electric fields of intermediate frequency and low intensity to disrupt cell division, demonstrating strong promise for tumor treatment. Currently, TTFields are approved for glioblastoma, unresectable mesothelioma and metastatic non-small cell lung cancer following progression on or after platinum based chemotherapy. This project aims to explore the synergistic effects and molecular mechanism of TTFields and imipridones in vitro using colorectal and glioblastoma cell lines. Imipridones are a class of anti-cancer drugs that target ClpP and GPCRs and lead to p53 independent apoptosis through chronic activation of the integrated stress response pathway. Both imipridones and TTFields have been shown to inhibit AKT and ERK phosphorylation. Thus, we theorized that co-treatment will have a synergistic effect. We performed ATP-based (Cell Titer Glo) viability assays to determine the IC50 dosage for imipridones ONC201, ONC206 and ONC212 in HT29 and HCT116 colorectal cancer (CRC) cell lines and U251 and T98G glioblastoma (GBM) cell lines. We then treated cells with imipridones at the identified IC50 doses either alone or together with 200kHz TTFields and collected cell lysate after 72 hours. We found differences in AKT phosphorylation across our treatment conditions (control, ONC201, ONC206, ONC212, TTF, TTF + ONC201, TTF + ONC206, and TTF + ONC212). These findings are significant in guiding future in vivo experiments and offering insight on whether TTField and imipridone treatment can be further explored in clinical trials. Citation Format: Viva Voong, Tyler Roady, Connor Purcell, Vida Tajiknia, Lanlan Zhou, Shengliang Zhang, Wafik El-Deiry. Pre-clinical efficacy of tumor treating fields and imipridones in glioblastoma and colorectal cancer 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 3109.
Abstract 2701: iRGD peptide therapy transforms immunosuppressive microenvironment to immune-favorable state in pancreatic ductal adenocarcinoma
Authors: Minji Kim, Yoon Ho Choi, Hotaka Kawai, Yukihito Kuroda, Norio Miyamura, Kazuki N. Sugahara, Tae Hyun Hwang
Journal: Cancer Research (2025)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits a complex, immunosuppressive tumor immune microenvironment (TIME), necessitating molecular-level understanding to identify therapeutic targets. We investigated how iRGD peptide therapy remodels the immunosuppressive TIME to an immune-favorable state using single-cell spatial molecular analysis. Methods: Single-cell level in situ molecular imaging was performed using Xenium analyzer with 5K gene panel on tumor samples from humanized PDAC mice (n=7) treated with iRGD monotherapy (n=3) or control (n=4), enabling comprehensive spatial molecular characterization of the TIME. Results: iRGD therapy significantly transformed the immunosuppressive TIME to an immune-favorable state through T-cell composition remodeling. We observed increased populations of CD4+ memory T cells, CD4+ helper T cells, and cytokine-secreting effector T cells, indicating enhanced immune memory and effector functions. Concurrent decreases in regulatory T cells and activated CD4+ T cells reflected reduced immune suppression. Additionally, decreased TGF-β signaling in the iRGD cohort suggested TGF-β antagonism as a mechanism for overcoming immunosuppression. Conclusions: iRGD therapy effectively converted the immunosuppressive PDAC microenvironment to an immune-favorable state by enhancing beneficial T cell populations and reducing immunosuppression through TGF-β pathway modulation. These findings support previous work by Kuroda et al. and provide mechanistic rationale for the ongoing iRGD-based immunotherapy clinical trial (iLSTA:ACTRN12623000223639).Acknowledgments: We thank DeepL for the English language editing. Citation Format: Minji Kim, Yoon Ho Choi, Hotaka Kawai, Yukihito Kuroda, Norio Miyamura, Kazuki N. Sugahara, Tae Hyun Hwang. iRGD peptide therapy transforms immunosuppressive microenvironment to immune-favorable state in 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 2701.