tbuckley/cabot-search huggingface dataset:
Abstract LB453: Elucidating the signaling mechanisms of Galpha13-mediated inflammation and tumor suppression in pancreatic cancer
Authors: Khadijeh Karbalaei, Anastasia E. Metropulos, Khulood Alzahrani, Apurba Majumder, Thao N. Pham, Hidayatullah G. Munshi, Mario A. Shields
Journal: Cancer Research (2025)

Abstract Host inflammation and tumor-driving genetic alterations significantly influence the immune microenvironment of pancreatic cancer. Indeed, chronic pancreatitis (CP) is a major risk factor for pancreatic ductal adenocarcinoma (PDAC), which is characterized by an early inflammatory response that evolves with tumor initiation and progression. Our previous work highlighted the role of the Pdk1/mTOR signaling axis in promoting pancreatic cancer development, particularly after genetic ablation of Gα13, a heterotrimeric G-protein frequently dysregulated in human tumors. To further investigate how Gα13 modulates the inflammatory response in both pancreatitis and pancreatic cancer, we employed mouse models to examine its role in inflammatory cytokines expression and mTOR signaling. We found that pancreas-specific loss of Gα13 exacerbated tissue injury, elevated pro-inflammatory cytokines, and increased macrophage recruitment in models of pancreatitis. Additionally, loss of Gα13 promoted mTOR signaling in these models, mirroring our earlier findings in pancreatic cancer. Interestingly, while mTOR inhibition alleviated tissue damage and suppressed inflammation in acute pancreatitis, it had no effect in the chronic phase. These findings align with our analysis of human tissue samples, where Gα13 expression was significantly reduced only in acute pancreatitis. Furthermore, in Gα13-deficient tumors, mTOR inhibition suppressed inflammatory cytokine expression and hindered tumor progression. Notably, targeting Pdk1 signaling resulted in a stronger anti-tumor response, with evidence for collagen remodeling and enhanced adaptive immune response. Overall, our findings uncover a novel, targetable pathway regulating both inflammation and tumor progression in pancreatic cancer, which could offer therapeutic opportunities depending on the G-protein status in patients. Citation Format: Khadijeh Karbalaei, Anastasia E. Metropulos, Khulood Alzahrani, Apurba Majumder, Thao N. Pham, Hidayatullah G. Munshi, Mario A. Shields. Elucidating the signaling mechanisms of Galpha13-mediated inflammation and tumor suppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB453.
Abstract LB168: Advancing cancer therapy: Evaluating ADCC with R3CE-derived organoids
Authors: Wen-Hung Kuo, Hao-Wei Han, Jia-Yang Chen, Chia-Chun Liu, King-Jen Chang, Ying-Chih Chang
Journal: Cancer Research (2025)

Abstract Antibody drugs have drawn significant attention due to their specific and dramatic therapeutic effects for cancer treatment in the past few years. For instance, the HER2-targeted monoclonal antibodies, trastuzumab, and pertuzumab, have been shown to improve survival rates in breast cancer patients with HER2-positive expression. Similarly, an alternative anti-EGFR monoclonal antibody, cetuximab, has been proven to be effective in the treatment of head and neck squamous cell carcinoma as well as in colorectal cancer patients. Mechanistically, the cytotoxic effects of these antibody drugs are at least partially mediated by the antibody-dependent cell-mediated cytotoxicity (ADCC) through immune cells. Recently, modifying the structure of antibodies has emerged as a promising strategy to enhance the affinity between the antibody and target protein. Meanwhile, a suitable assay platform to determine the therapeutic efficacy of these modified antibodies is under extensive investigation. Thus, a robust cell-based model that can be used to evaluate the efficacy of these antibodies for personalized medicine will further accelerate the development of antibody drugs. Here, we expanded and maintained the breast patient-derived organoids (PDOs) with varying levels of HER2 expression through the R3CE culture platform (AcroCyte Therapeutics) to assess the ADCC effects of natural killer (NK) cells ex vivo. By co-culturing NK cells and breast PDOs with trastuzumab, we observed highly positive correlation between the NK cell-to-PDO cytotoxicity with the levels of HER2 expression. The results demonstrated a reliable ex vivo model platform that could be used to evaluate ADCC relevant cytotoxicity for personalized applications and future therapeutic developments. Citation Format: Wen-Hung Kuo, Hao-Wei Han, Jia-Yang Chen, Chia-Chun Liu, King-Jen Chang, Ying-Chih Chang. Advancing cancer therapy: Evaluating ADCC with R3CE-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB168.
Abstract LB200: Simultaneous multi-omic analysis of plasma samples from prostate cancer patients to quantify inflammation markers and total circulating cell-free DNA
Authors: William H. Henley, Nathan A. Siegfried, Aashish Srivastava, Joe Gaiteri, Deepak Kumar
Journal: Cancer Research (2025)

Abstract Recent interest in non-invasive biopsy methods has led to many studies focusing on circulating, cell-free nucleic acids (ccfNAs) as a biomarker for cancer diagnosis, prognosis, and treatment response monitoring. Elucidation of profiles and trends in ccfNA corresponding to pathologies and treatment states is likely to be significantly enhanced through the simultaneous quantification of protein biomarkers, however current technological limitations require these determinations to be done through separate workstreams, introducing larger sample requirements, disparate sample processing and analysis mechanisms, along with additional equipment and costs and resources. The resulting data from these disparate methods must then be collated, requiring additional time and resources. We present here a novel, microfluidic-based detection technology that can quantify nucleic acid targets alongside protein biomarkers from a single sample using robust PCR amplification. In addition, this novel technology combines traditional qPCR and digital detection modalities within a single, fully automated run to cover a very wide dynamic range without requiring sample dilution, preserving precious samples in an unmanipulated state. This dynamic range capability is particularly useful to address potentially large changes in analyte concentration between healthy and disease state samples. Using Codetta’s Bio Concerto and their Platform technology, we analyzed plasma samples from prostate cancer samples for concentrations of three cytokines important to prostate cancer (IL-6, IL-7, and VEGF), as well as prostate-specific antigen (PSA) and two ccfDNA targets (MT-CO3 mitochondrial DNA and KRAS nuclear DNA) to quantify the concentration of ccfDNA in the samples. Healthy patient samples were analyzed in addition to disease state samples, and data is presented over a time course of patient treatment. Citation Format: William H. Henley, Nathan A. Siegfried, Aashish Srivastava, Joe Gaiteri, Deepak Kumar. Simultaneous multi-omic analysis of plasma samples from prostate cancer patients to quantify inflammation markers and total circulating cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB200.
Abstract LB151: Ultra-processed food intake and colorectal cancer risk in the US NIH-AARP cohort
Authors: Leila Abar
Journal: Cancer Research (2025)

Abstract Background and Rationale: Ultra-processed foods (UPF) account for more than 50% of calories consumed by US adults. Strong evidence links whole grain and calcium intake to decreased colorectal (CRC) risk and processed meat intake to increased CRC risk. UPF are major sources of all three dietary factors, and prospective studies of UPF intake and CRC risk have been inconsistent. Our aim was to estimate the prospective association between UPF intake and CRC risk and explore potential effect measure differences by overall diet quality. Methods: We analyzed data from 274, 269 men and 187, 413 women, aged 50 to 71, who participated in the NIH-AARP Diet and Health Study and were cancer-free at baseline in 1995-1996. Dietary intake was assessed using a validated food frequency questionnaire, and UPF intake (g/1000 kcal/day) was classified according to the Nova system and categorized as sex-specific quintiles. Cox proportional hazards models, adjusted for potential confounders and total energy using the nutrient density method, were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CRC risk, overall and by anatomic location (i.e., proximal colon, distal colon, or rectum). HR for the joint effect of UPF intake (quintiles) and diet quality (quartiles), measured using the Healthy Eating Index-2015, were estimated. Results: With more than 20 years of follow-up, 6420 and 3661 first primary CRC cases were identified in men and women, respectively. Mean UPF intake was 392 and 398 g/1000 kcal/day, representing 43% and 42% of total daily calories, for men and women, respectively. Higher UPF intake was not associated with higher CRC risk in men (HRQ5vs.Q1=0.91; 95% CI, 0.84-0.99; P-trend=0.32) or women (HRQ5vs.Q1=0.93; 95% CI, 0.84-1.04; P-trend=0.58) overall or by anatomic location (all P-trend≥0.05). Lower diet quality (i.e., HEI Q1) was associated with higher CRC risk across all quintiles of UPF intake (HRHEI-Q1 &amp; UPFQ1 vs. HEI-Q4 &amp; UPFQ1=1.16; 95% CI, 1.02-1.32 and HRHEI-Q1 &amp; UPFQ5 vs. HEI-Q4 &amp; UPFQ1=1.16; 95% CI, 1.03-1.31; P-heterogeneity=0.11). Notably, 83% and 32% of whole grain and dietary calcium intake and 74.3% of processed meat intake came from UPF sources. Conclusions: In NIH-AARP, higher UPF intake was not associated with CRC risk. UPF include a heterogenous array of foods, which may have opposing effects on CRC etiology. Poor diet quality, potentially irrespective of degree of food processing, is associated with increased CRC risk. Citation Format: Leila Abar. Ultra-processed food intake and colorectal cancer risk in the US NIH-AARP cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB151.
Abstract LB140: Preclinical development of therapeutic antibodies using humanized immune system mice
Authors: Emilie Bayon, Pierre Wallet, Joséphine Zangari, Sébastien Tabruyn, Dan Georgess
Journal: Cancer Research (2025)

Abstract The development of therapeutic antibodies, which improve specificity and efficacy over existing standards of care by engaging the patient’s own immune system, is expanding across various cancer indications but fraught by a high attrition rate in clinical trials. The availability and versatility of robust animal models containing human immune systems is poised to increase preclinical predictiveness and improve clinical success. To address this need, we present a modular design framework for the customization of preclinical oncology studies. The first module in this framework is the selection of mouse model with a complete humanized immune system. Such mice are generated by engrafting of human CD34+ hematopoietic stem cells into a variety of initially immunodeficient strains thus leading to the expansion of T, B, NK, and myeloid cells (which can be further enhanced through the hydrodynamic boost technique). From a variety of strains that can be humanized and are available (e.g. NSG, NCG, NCG-X, NOG-EXL, etc), we highlight certain advantages and limitations to facilitate tailoring of preclinical study designs. Subsequent modules in the framework include tumor model (e.g. melanoma, lymphoma, lung, ovarian, breast, pancreatic, prostate, etc), engraftment site (liver, mammary gland, lung, pancreas, subcutaneous), and molecular and cellular readouts (e.g. flow cytometry, histology, qPCR, ELISA, ELISpot, etc). We then describe a set of case studies whereby this framework has been successfully applied to assess the safety, PK/PD, efficacy, and mechanisms of action of clinically-approved antibodies and preclinical candidates. These include checkpoint inhibitors (e.g., PD-1, PD-L1, OX40), T-cell engagers, and tumor-targeting antibodies (e.g., EGFR, Her2, CD47) across diverse cancer types. This framework illustrates the flexibility of mouse model humanization for drug-specific preclinical assessment and highlights the potential in across cancer types and in diseases beyond oncology. Citation Format: Emilie Bayon, Pierre Wallet, Joséphine Zangari, Sébastien Tabruyn, Dan Georgess. Preclinical development of therapeutic antibodies using humanized immune system mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB140.
Abstract LB147: Cultural and social determinants of trust in clinical trials and genomic research among Black and Hispanic cancer patients treated in a safety-net hospital
Authors: Christina Wilkerson, Osato Eke, Naaja Davis, Nayya Jamison, Victoria Churchill, Amirah Burton-Obanla, Desiree Rivers, Brian M. Rivers
Journal: Cancer Research (2025)

Abstract Background: The construct of ‘Trust’ is a critical factor influencing participation in genomic research, particularly among minority populations who have historically faced systemic discrimination in healthcare. Investigating cultural and social determinants of trust is essential to inform public health interventions aimed at improving representation in genomic studies. Methods: Through the Clinical Trials and Genomic Education Program (CTC-GEP), a NCI-funded initiative, purposed to address the barriers and facilitators to research participation, recruited 250 Black and Hispanic cancer patients receiving care at a safety-net hospital. Participants engaged in a three-month navigator-guided educational program on clinical trials and genomic research, including an informational video and pre- and post-education surveys at baseline, one month, and three months. Key measures included trust in healthcare providers, perceptions of clinical trial ethics, and confidence in research oversight. Descriptive and inferential statistics were generated using SAS software. Results: Preliminary analysis at baseline revealed significant mistrust among participants, with 38.7% expressing skepticism toward information provided by researchers and 21.5% indicating fears of being exploited in research. Post- intervention, trust in healthcare providers increased by 15%, with 62.5% of participants agreeing that the reputation of the treatment center positively influenced their willingness to participate. Discussion: Public health initiatives that address historical inequities and foster cultural competence are vital for building trust in genomic research. This study demonstrates the potential of tailored interventions to promote equitable participation and highlights the importance of embedding trust-building efforts in broader public health frameworks addressing research participation among Black and Hispanic populations. Future research should explore long-term effects of trust-building strategies. Citation Format: Christina Wilkerson, Osato Eke, Naaja Davis, Nayya Jamison, Victoria Churchill, Amirah Burton-Obanla, Desiree Rivers, Brian M. Rivers. Cultural and social determinants of trust in clinical trials and genomic research among Black and Hispanic cancer patients treated in a safety-net hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB147.
Abstract LB300: Recapitulating the immune dynamics of cytokine release syndrome in humanized immune system mouse models
Authors: Audrey Wetzel, Joséphine Zangari, Pierre Wallet, Anaïs Meynet-Cordonnier, Sébastien Tabruyn, Emilie Bayon, Dan Georgess
Journal: Cancer Research (2025)

Abstract Cytokine release syndrome (CRS) is a severe and potentially fatal immune reaction that can be triggered by various immunotherapies including CAR-Ts, T-cell engagers, and immune checkpoint inhibitors. The preclinical assessment of such therapies therefore relies on a deeper understanding of human immune dynamics (e.g. T and myeloid cell interplay) and the availability of immunocompetent mouse models amenable to human tumor engraftment such that lead candidates can be assessed without needing to rely on murine analogs. Here, we induced CRS with the anti-human CD3 monoclonal antibody OKT3 in two mouse models that have human immune elements: PBMC humanized NCG mice (PBMC mice), where the only persisting human immune population is T lymphocytes, and CD34+ HSC humanized NCG mice (CD34 mice), which reconstitute a complete human immune system with B, T, NK, and myeloid cells albeit. Our findings reveal a dynamic cascade of common and model-specific physiologic and immune events at 1, 3, 6, and 24 hours post-OKT3 treatment. Indeed, within 6 hours of injection, OKT3 induced breathing difficulty, oedema, diarrhea, and hyperventilation in both models, but incidence and severity of these symptoms were greater, reaching loss of consciousness, in the PBMC model. Similarly, as the PBMC model harbors a superior circulating T cell count, it produced higher levels of circulating IFNγ (and TNF-α) compared to the CD34 model. However, CD34 mice had more circulating IL-2, likely explaining the increase in T-cell proliferation, which was not observed in PBMC mice where T cells retained an exhausted and predominantly apoptotic phenotype. Finally, as PBMC mice do not retain myeloid populations, we could only detect myeloid-produced cytokines CXCL10 and CCL12 in CD34 mice commensurate with marked expansion of circulating CD14+ monocytes and macrophage liver infiltration, underscoring the systemic and organ-specific dimensions of CRS pathology. Our comparative results validate feasibility and characterize CD34 humanized mice as a CRS model for tailored testing of specific therapeutic mechanisms of actions where a complete immune system is required. As CD34 mice offer significantly wider treatment windows due to longer, GvHD-free life spans, and produce less allogeneic response, they can be simultaneously leveraged to assess safety and efficacy of cell and antibody therapies. Citation Format: Audrey Wetzel, Joséphine Zangari, Pierre Wallet, Anaïs Meynet-Cordonnier, Sébastien Tabruyn, Emilie Bayon, Dan Georgess. Recapitulating the immune dynamics of cytokine release syndrome in humanized immune system mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB300.
Abstract LB458: Osimertinib treatment drives expression of TROP2, and combination treatment with datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, enhances its efficacy in PDX models of EGFR mutant non small-cell lung cancer
Authors: Matthew J. Martin, Alex Koers, Fernando Calero, Sara Talbot, Adina Hughes, Lukasz Magiera, Lucy Ireland, Nicolas Floc'h
Journal: Cancer Research (2025)

Abstract Osimertinib is a 3rd generation EGFR tyrosine kinase inhibitor with proven efficacy in the first-line advanced or metastatic EGFR-mutant (EGFRm) non-small cell lung cancer setting. Despite clinical benefit, most patients become refractory to drug, highlighting the need for combination strategies to maximize the duration of response. To understand the signaling changes induced by prolonged osimertinib treatment we characterised the mRNA expression of cell surface markers by RNAseq. We found that acute and prolonged osimertinib treatment leads to significant upregulation of TACSTD2, the transcript encoding the TROP2 protein. We further found that levels of TROP2 protein on the cell surface were increased by prolonged osimertinib treatment, but returned to baseline upon drug cessation, both in vitro and in vivo. Moreover, single-cell RNAseq analysis of osimertinib-treated tumours showed a specific cell subpopulation that upregulated TACSTD2 expression, which was eliminated when xenograft-bearing animals were treated with the combination of osimertinib and the TROP2-directed antibody-drug conjugate (ADC) Dato-DXd. Critically, we found that in vivo Dato-DXd/osimertinib combination treatment showed improved in vivo efficacy over osimertinib monotherapy in 4 out of 9 EGFRm patient-derived xenograft (PDX) models. Expanding these studies to PDX models derived from osimertinib-resistant patients showed superior efficacy of the combination compared to either agent alone, in 3 out of 4 models. Taken together these preclinical data highlight the ability for long-term osimertinib treatment to enhance TROP2 expression and demonstrate the potential utility of a novel combination treatment strategy with a TROP2-targeting ADC. Citation Format: Matthew J. Martin, Alex Koers, Fernando Calero, Sara Talbot, Adina Hughes, Lukasz Magiera, Lucy Ireland, Nicolas Floc'h. Osimertinib treatment drives expression of TROP2, and combination treatment with datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, enhances its efficacy in PDX models of EGFR mutant non small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB458.