tbuckley/cabot-search huggingface dataset:
Abstract 2320: Cardiovascular disease mortality among breast cancer survivors in Puerto Rico: 2004-2019
Authors: Carola T. Sánchez-Díaz, Genesis Rodriguez-Ortiz, Liliana Castro-JImenez, Barbara Segarra-Vazquez, Francisco Cordova, Vivian Colón-Lopez, Cynthia Perez-Cardona
Journal: Cancer Research (2025)

Abstract Purpose: Cancer and Cardiovascular disease (CVD) are the two leading causes of death in both the United States and Puerto Rico (PR). Breast cancer (BC) survivors, considered since the time at diagnosis, face an elevated risk of CVD mortality, largely due to the cardiotoxic effects of cancer treatments and the presence of shared cardiometabolic risk factors with BC. However, there is a need for studies examining the risk of CVD mortality specifically among BC survivors in PR, one of the most rapidly aging populations in the world. This study aims to assess and compare the risk of CVD mortality among BC survivors and the general population in PR from 2004 to 2019. Methods: Data on BC survivors were obtained from the PR Central Cancer Registry for the period 2004 to 2019. Follow-up started approximately 12 months after diagnosis to account for treatment completion and extended through 2021. Standardized Mortality Ratios (SMRs) were calculated to compare CVD mortality risk between BC survivors and of the general population of women in PR aged 18 and older. The expected number of deaths was determined using age-, sex- and calendar year-specific mortality rates from the general population, obtained from the National Vital Statistics System. Results: The overall SMR for CVD mortality among BC survivors was 2.18 (95% CI: 1.99-2.38), with 470 observed, compared to 215.89 expected CVD deaths during the study period. The total person-years at risk amounted to 66, 388. A significant positive trend in increased risk of CVD mortality was observed by calendar year (p &amp;lt; 0.001), starting with a SMR of 1.51 (95% CI: 1.13-2.03) in 2004 and peaking in 2019 (SMR: 8.39; 95% CI: 4.64-15.15). Women under 60 years of age faced a particularly elevated risk (SMR: 8.48; 95% CI: 5.82-12.37), with SMRs declining to 1.73 (95% CI: 1.53-1.95) in women over 80 years of age. Conclusion: Our findings reveal a significantly elevated CVD mortality risk among BC survivors in PR, particularly in younger survivors, compared to the general population. Increasing SMRs over time highlight the importance of understanding cardiometabolic risk factors and stress-related social drivers throughout survivorship to guide targeted interventions for improving cardiovascular health. Citation Format: Carola T. Sánchez-Díaz, Genesis Rodriguez-Ortiz, Liliana Castro-JImenez, Barbara Segarra-Vazquez, Francisco Cordova, Vivian Colón-Lopez, Cynthia Perez-Cardona. Cardiovascular disease mortality among breast cancer survivors in Puerto Rico: 2004-2019 [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 2320.
Abstract 4270: Targeting CNTN4 with exatecan-based antibody-drug conjugate for the treatment of solid tumors
Authors: Mi Young Cha, Mira Kim, Seungmin Byun, Youngeun Ha, Kitae Park, Bu-Nam Jeon, Hyunuk Kim, Hyunkyung Yu, Hyunjin Yoo, Soojung Moon, Gyeong-Jin Cheon, Boeun Ju, Hansoo Park
Journal: Cancer Research (2025)

Abstract As a novel immune checkpoint, we previously confirmed that contactin 4 (CNTN4) expressed on tumors negatively regulates T cell activity by binding to amyloid precursor protein (APP) on T cells. Immunohistochemistry analysis revealed high expression of CNTN4 in various tumors, including gallbladder, pancreatic, gastric, endometrial, hepatic, prostatic, bladder cancers, melanoma, and others, while its expression remains low in normal tissues, including immune cells. Based on the tumor-specific expression profile of CNTN4, we have developed an antibody-drug conjugate (ADC) targeting CNTN4. This ADC utilizes GENA-104A16.hIgG1 (A16.1), an anti-CNTN4 antibody with reduced effector function of human IgG1, conjugated via cysteine-maleimide linkage to linker including hydrophilic moiety and the topoisomerase I inhibitor (exatecan) with high drug-to-antibody ratio (DAR)(A16.1-Exa). To evaluate its potential, the internalization performance of A16.1 was compared with trastuzumab (anti-HER2) using SK-BR3 cells engineered to overexpress CNTN4, which exhibited a higher HER2 target count than CNTN4 target count. A16.1-Exa demonstrated potent and highly specific cytotoxicity in CNTN4-positive cancer cells, accompanied by a robust bystander effect comparable to the Dxd conjugate. Additionally, A16.1-Exa exhibited high plasma stability and retained its immune checkpoint-blocking function, supporting T cell-mediated cytotoxicity alongside payload delivery. Treatment with A16.1-Exa demonstrated a very promising anti-tumor effect in a fibrosarcoma xenograft mouse model (HT1080/CNTN4). Investigation of the anti-tumor efficacy in a PDX model was conducted with GENA-104A16 (human IgG4 S228P) antibody in the IND-approved stage, conjugated with MMAF (low DAR) in a pancreatic cancer model. Once the tumor volume reached 195 mm3, mice were randomly divided, and the A16-MMAF conjugate (5 mg/kg) was administered intravenously twice post-grouping. The treatment showed strong anti-tumor activity, leading to tumor regression. Future studies will expand the PDX models and optimize the therapeutic potential of exatecan conjugates to advance the development of CNTN4-targeted therapies, offering a promising approach for treating diverse cancers. Citation Format: Mi Young Cha, Mira Kim, Seungmin Byun, Youngeun Ha, Kitae Park, Bu-Nam Jeon, Hyunuk Kim, Hyunkyung Yu, Hyunjin Yoo, Soojung Moon, Gyeong-Jin Cheon, Boeun Ju, Hansoo Park. Targeting CNTN4 with exatecan-based antibody-drug conjugate for the treatment of solid tumors [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 4270.
Abstract 2208: <i>Phocaeicola vulgatus</i> mediates immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production
Authors: Caining Zhao, Shanshan Li, Thomas Yau, Wenqi Chen, Ren Ji, Xinyuan Guan, Fengming Spring Kong
Journal: Cancer Research (2025)

Abstract Background: Gut microbiota has been widely reported to influence anti-PD-1 efficacy in melanoma and lung cancer, in both clinical specimens and animal models. However, the role of gut microbiota in hepatocellular carcinoma (HCC) remains less explored, with limited understanding of the underlying mechanisms. Method: Advanced HCC patients treated with anti-PD-1 with/without anti-CTLA-4 were prospectively enrolled, and categorized into responders and non-responders groups based on their radiological response after 6 months of immunotherapy according to modified Response Evaluation Criteria for Solid Tumors (mRECIST) guideline. The fecal metagenomics and plasma metabolome data were integrated to reveal the profiles of gut microbiota. Meanwhile, fecal microbiota transplantation (FMT), single strain and metabolite intervention animal models, as well as in vitro CD8+T cell culture were employed to study its mechanism of modulating immunotherapy efficacy in HCC. Results: In the metagenomic analysis of 65 patients, the responders and non-responders exhibited distinct gut microbiota profiles, which were replicated in mice via FMT. Lefse analysis revealed a higher abundance of Phocaeicola vulgatus (P. vulgatus) in non-responders compared to responders. Moreover, patients with higher P. vulgatus had a mean progression free survival (PFS) of 11.1 months and overall survival (OS) of 22.9 months, which were significantly shorter than those with lower P. vulgatus (PFS: 30.8 months, p = 0.047; OS: 63.2 months, p = 0.037). Notably, P. vulgatus enriched in non-responders restrained anti-PD-1 efficacy in syngeneic and orthotopic tumor models and inhibited the CD8+T cell cytotoxicity, evidenced by decreased IFN-γ+ and GzmB+ populations. Mechanistically, P. vulgatus reduced gut microbiota-derived indoleacetic acid (IAA), weakening CD8+ T cell effector functions and impairing immune response. Supplementation with IAA restored CD8+ T cell cytotoxicity and counteracted the immune-suppressive effects of P. vulgatus. Conclusion: P. vulgatus impaired anti-PD-1 efficacy in HCC via reducing IAA production, which in turn diminishes the effector functions of CD8+ T cells. This study establishes a causal link between P. vulgatus and anti-PD-1 resistance in HCC, highlighting gut microbiota-derived IAA as a potential therapeutic target. Citation Format: Caining Zhao, Shanshan Li, Thomas Yau, Wenqi Chen, Ren Ji, Xinyuan Guan, Fengming Spring Kong. Phocaeicola vulgatus mediates immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production [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 2208.
Abstract 2321: Longitudinal evidence of healthy lifestyles slowing biological aging and reducing cancer risk
Authors: Junlin Jia, Chi Pang Wen, Huakang Tu, Junlong Pan, Wanzhu Lu, Min Yang, Andi Xu, Sicong Wang, Wenyuan Li, Xifeng Wu
Journal: Cancer Research (2025)

Abstract Background: Aging is an important risk factor of cancer, and a healthy lifestyle is one possible measure to delay aging. Limited research has investigated the relationship between a healthy lifestyle, biological aging, and cancer incidence. Methods: This prospective study enrolled 122, 023 individuals from the Taiwan MJ cohort. The multivariable logistic regression model was utilized to examine the associations between the healthy lifestyle scores (HLS, integrating never or quitted smoking, non-harmful drinking, active physical activity, healthy body fat percentage, and healthy diet) and biological aging acceleration alteration, which was measured by changes in multi-dimensional aging measure acceleration (ΔMDAgeAccel). The Cox regression model was used to evaluated the joint association of HLS and ΔMDAgeAccel with cancer risk. Results: Compared to individuals with HLS of 0, increasing HLS was associated with decreased odds of MDAgeAccel increase, with the adjusted odds ratio (aOR) of 0.684 (95% CI 0.557 to 0.841), 0.589 (0.483 to 0.718), 0.500 (0.411 to 0.610), 0.426 (0.349 to 0.519), and 0.379 (0.310 to 0.464) for HLS of 1, 2, 3, 4, and 5, respectively. These results remained consistent across stratifications by baseline aging acceleration status, age group, and sex. Individuals with accelerated aging at baseline and higher HLS exhibited lower odds ratio of persistent aging acceleration. The hazard ratio (HR) for cancer incidence was 0.774 (0.665 to 0.900) for individuals with a higher HLS and decreased MDAgeAccel, 0.932 (0.779 to 1.116) for individuals with a higher HLS and increased MDAgeAccel, compared with those with a lower HLS and increased MDAgeAccel. Conclusions: Adherence to healthy lifestyle may lower aging acceleration, and reducing cancer risk. Citation Format: Junlin Jia, Chi Pang Wen, Huakang Tu, Junlong Pan, Wanzhu Lu, Min Yang, Andi Xu, Sicong Wang, Wenyuan Li, Xifeng Wu. Longitudinal evidence of healthy lifestyles slowing biological aging and reducing cancer risk [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 2321.
Abstract 2583: A T cell engager targeting cancer associated fibroblasts inhibits tumor growth and modulates the tumor microenvironment
Authors: Joshua R. Tagore, Robert Joseph Norgard, Pratha Budhani, Sai Charan Penikalapati, Jessica N. Egan, Di Feng, Leticia Corrales-Pecino, Anna Bachmayr-Heyda, Claudia Reichel-Voda, Abhishek Kashyap, Youli Xia, Sarah A. O’Brien
Journal: Cancer Research (2025)

Abstract Fibroblast activating protein (FAP) is an attractive target for therapeutic intervention being mainly expressed in malignant tissues. Previous studies have targeted FAP using a variety of methods yet failed in clinics. Here, we utilize FAP-targeted T cell engager (TcE) in KPCY tumor models to recapitulate a pre-clinical environment. The use of FAP- TcE efficiently depleted FAP+ fibroblasts in vitro and in vivo from tumors. This resulted in bystander killing of tumor cells and tumor growth control in vivo. This therapeutic effect was not dependent on priming via lymph node activation as shown in other publications. To understand the complex interactions with FAP expression, we perform comprehensive single cell RNA-sequencing profiling before and after FAP-TcE depletion to understand the pivotal genetic roles of FAP depletion in all cell types. This analysis initially revealed a T cell exhaustion phenotype with upregulated of PD-1 on T cells after FAP-TcE treatment. However, while addition of anti-PD-1 therapy significantly enhanced tumor efficacy, complete control was absent. RNA sequencing of the fibroblasts identified depletion of a myCAF-like fibroblast and an outgrowth of a mixed CAF population with phenotypes of both myCAF and iCAF. This population correlated with tumor growth, and cell cycle gene signatures. Future work will investigate the implications of this fibroblast population’s role in subverting immune suppression. Citation Format: Joshua R. Tagore, Robert Joseph Norgard, Pratha Budhani, Sai Charan Penikalapati, Jessica N. Egan, Di Feng, Leticia Corrales-Pecino, Anna Bachmayr-Heyda, Claudia Reichel-Voda, Abhishek Kashyap, Youli Xia, Sarah A. O’Brien. A T cell engager targeting cancer associated fibroblasts inhibits tumor growth and modulates the tumor microenvironment [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 2583.
Abstract 4140: Non-proteolytic regulation of oncogenic transcription factors by deubiquitinases
Authors: Yunsik Choi
Journal: Cancer Research (2025)

Abstract Oncogenic transcription factors (TFs) such as ETS2 and TEAD4 are critical regulators of genes driving cancer progression, including those involved in proliferation, survival, and metastasis. Despite their importance, the mechanisms modulating their activity through ubiquitination remain poorly understood. This study investigates deubiquitinases (DUBs) that interact with and regulate ETS2 and TEAD4, aiming to uncover novel insights into their transcriptional control.A DUB sub-library screening identified USP39 and OTUD6A as regulators of ETS2 and TEAD4, respectively. USP39 interacts with ETS2 via their amino-terminal regions, independent of the zinc finger and PNT domains, and deubiquitinates ETS2. This interaction reduces ETS2’s nuclear localization and transcriptional activity without affecting its stability, indicating a negative regulatory role. In contrast, OTUD6A interacts with TEAD4 at its YAP-binding domain and deubiquitinates TEAD4. OTUD6A further enhances TEAD4 transcriptional activity and cofactor interactions, notably by promoting YAP binding. Similar to USP39 and ETS2, OTUD6A does not influence TEAD4 stability but positively regulates its activity.These findings highlight the distinct, non-proteolytic roles of USP39 and OTUD6A in modulating transcriptional activity of ETS2 and TEAD4, respectively. Our findings underscore the functional diversity and opposing regulatory mechanisms of DUBs in oncogenic transcriptional control. Citation Format: Yunsik Choi. Non-proteolytic regulation of oncogenic transcription factors by deubiquitinases [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 4140.
Abstract 2567: CX3CR1 surface expression on metastatic prostate cancer cells is increased by the target organs and is associated with a distinct metabolic phenotype
Authors: Ruxu Zhai, Jieyi Zhang, Olimpia Meucci, Alessandro Fatatis
Journal: Cancer Research (2025)

Abstract Studies from us and others have shown that the chemokine receptor CX3CR1 drives cancer cells to the skeleton, activates pro-survival signaling pathways and bears unique therapeutic potential. We have recently reported that the small subsets of prostate cancer cells that expose CX3CR1 on their surface (CX3CR1Surf+) are endowed with stemness features and behave as metastasis-initiating cells (MICs). Interestingly, their CX3CR1Surf- counterparts can re-express CX3CR1 on the cell surface while undergoing partial EMT, thus re-acquiring MIC features. This phenotypic plasticity can be temporally monitored in vitro, with cultures of 100% CX3CR1Surf- cells reaching a phenotypic equilibrium (5-7% of CX3CR1Surf+) in ∼ 8 days. However, when cells at phenotypic equilibrium are grafted in mice via systemic blood circulation, the resulting tumors in the skeleton and soft tissues show a dramatic increase in the CX3CR1Surf+ fraction. This suggests that the stroma of target organs promotes CX3CR1 plasticity, an effect not observed when the same cells are grafted subcutaneously. We also show that FX-68, a potent and specific antagonist of CX3CR1, dramatically reduces the number of disseminated tumors and total tumor burden in mice. FX-68 does not alter the percentage of CX3CR1Surf+ cancer cells in disseminated tumors, suggesting that its anti-tumor effects are exerted by functional inactivation of CX3CR1. Notably, we found a strong association between the CX3CR1Surf+ status and a metabolic shift away from the OXPHOS pathway and towards glycolysis. Based on these findings, we conducted further studies by assessing the short- and long-term effects of CX3CR1 activation on the metabolic profile of prostate cancer cells. Furthermore, in vivo studies with tumor-bearing mice treated with FX-68 revealed the effects of this compound on the metabolic profiles of cancer cells harvested from tumors in the skeleton and soft tissues. Our work reports for the first time the association of CX3CR1 with the metabolic status of prostate cancer cells. We also provide evidence that interfering with CX3CR1 signaling could impede a metabolic switch promoted by target organs and sustaining metastatic progression. Citation Format: Ruxu Zhai, Jieyi Zhang, Olimpia Meucci, Alessandro Fatatis. CX3CR1 surface expression on metastatic prostate cancer cells is increased by the target organs and is associated with a distinct metabolic phenotype [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 2567.
Abstract 4141: PDE3A promotes ER positive beast cancer progression by preventing ERα ubiquitination degradation
Authors: Shengyu Pu, Heyan Chen, Bohong Chen, Jianjun He, Na Hao
Journal: Cancer Research (2025)

Background: ER+ breast cancer (ER+BC) is the most common subtype, which characterized by high risk of recurrence and metastasis after treatment. ERα is considered to be a key driver in the malignant progression of ER+BC, and it is necessary to understand the signaling mechanism of ERα. PDE3A, a member of the phosphodiesterases (PDEs) family, can hydrolyze the cAMP and cGMP, and is an important regulator of intracellular signaling. However, there are few studies on the effect of PDE3A on the malignant progression of ER+BC, and the specific mechanism is still unclear. Aim: (i) To investigate the prognostic role of PDE3A in ER+BC and its links with breast cancer proliferation and metastasis; (ii) to explore the regulatory mechanism of PDE3Ain ER+BC biological process; (iii) to screen effective molecule inhibitor targetingPDE3A. Methods: The expression level of PDE3A in ER+BC was determined by immunohistochemical staining and the mRNA expression profiles from the TCGA database. Roles of PDE3Ain cancer cell growth, metastasis were determined by molecular and cell biology methods. Co-Immunoprecipitation (CO-IP) was used to examine the binding of PDE3Aand ERα. Chromatin immunoprecipitation (ChIP) and promoter luciferase reporter assay were included for detecting the transcription of PDE3A in ER+BC. ER+BC xenograft mice were used to study the inhibition of tumor development. Results: PDE3A is a novel ER+BC target, which is overexpressed in ER+BC tissues and significantly associated with clinical pathology of advanced TNM stage and poor prognosis of patients. In vitro and in vivo studies have demonstrated that PDE3Apromotes ER+BC proliferation and metastasis. Mechanically, PDE3A regulates ERαproteasome degradation through competitive binding to ERα with its E3 ligase SPOP, independently of the catalytic activity of PDE3A. In addition, ERα directly facilitates the transcription of PDE3A and up-regulate the expression level of PDE3A.Furthermore, we screened out brequinar, a small molecule inhibitor targeting PDE3A, can inhibit breast cancer cell proliferation and metastasis, and reverse endocrine resistance. Conclusion: We identified an important role of PDE3A-ERα feedback loop in the ER+BC progress and resistance to endocrine therapy, representing a future biomarker and therapeutic target of ER+BC. Citation Format: Shengyu Pu, Heyan Chen, Bohong Chen, Jianjun He, Na Hao. PDE3A promotes ER positive beast cancer progression by preventing ERα ubiquitination degradation [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 4141.
Abstract 415: Metformin sensitizes non-small cell lung cancer to CDK4/6 inhibitor treatment by reducing lysosomal trapping
Authors: Yaqi Liu, Yalei Wang, Ni Zhang, Haijuan Xiong, Lipan Zhao, Jiping Xie, Xiaofeng Duan, Dongsheng Yue, Shuo Qie
Journal: Cancer Research (2025)

Abstract Hyperactivation of cyclin D1-CDK4/6 signaling is correlated with tumour metastasis, and poor prognosis in patients with non-small cell lung cancer (NSCLC), suggesting the therapeutical potential of targeting CDK4/6 to treat NSCLC. Our preliminary data suggest CDK4/6 inhibitors are sequestered in lysosomes in NSCLC cells, a phenomenon termed lysosomal trapping that is correlated with intrinsic resistance. It’s promising to search for new compounds that could be co-administered with CDK4/6 inhibitors to reduce lysosomal trapping, hence enhancing the sensitivity of NSCLC cells. Here, we find metformin reduces the activity of lysosomal pathway through genome-wise analyses; in accordance, metformin efficiently reduces lysosomal trapping of CDK4/6 inhibitors in NSCLC cells. Biologically, metformin enhances the suppressing effects of CDK4/6 inhibitors on cell cycle progression, cell proliferation, and colony formation. Mechanistically, metformin suppresses lysosomal trapping by: 1) reducing translocation of TFEB into nuclei that leads to decreased lysosome biogenesis, and 2) disrupting lysosomal acidic environment through reduced V-ATPase activity and decreased interaction between LAMP1/LAMP2 and TMEM175. Clinically, combined treatment with metformin and CDK4/6 inhibitors significantly retards the growth of mouse xenografts and tumour cell organoids. Taken together, our study provides a new mechanistic dimension on utilizing metformin to treat NSCLC by reducing lysosomal trapping, therefore, increasing cellular sensitivity to CDK4/6 inhibitors. Citation Format: Yaqi Liu, Yalei Wang, Ni Zhang, Haijuan Xiong, Lipan Zhao, Jiping Xie, Xiaofeng Duan, Dongsheng Yue, Shuo Qie. Metformin sensitizes non-small cell lung cancer to CDK4/6 inhibitor treatment by reducing lysosomal trapping [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 415.