tbuckley/cabot-search huggingface dataset:
Abstract 6532: Blockade of CD24 sensitizes pancreatic cancer to Kras inhibitors
Authors: Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Madelaine S. Theady, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Yong Zhou, Hong Zhao, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by KRAS oncogene. KRAS, long considered an undruggable target, has been targeted by drugs including a KRASG12C inhibitor (G12Ci), AMG 510, which is approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC). AMG 510 also exhibited promising anticancer activity in human PDAC, with 21% response rate and over 70% patients experiencing certain level of tumor control. However, targeting KRAS oncogenes faces the major challenge of therapy resistance, which severely limited its survival benefit. While multiple studies have elucidated potential resistance mechanisms to G12Ci in lung cancer, the molecular mechanisms underlying resistance in PDAC remains elusive. Here, using KRASG12C-driven mouse PDAC model, we found that similar to the clinical observation, KRASG12C tumors exhibit only partial response to AMG 510 treatment. CyTOF analysis indicates that such tumor persistence following G12Ci treatment occurs even in the presence of conversion from a ‘cold’ pro-tumor immune microenvironment to a ‘hot’ anti-tumor immune environment, as evidenced by the prominent increase in both cytotoxic T cells and M1-like macrophages. Interestingly, we discovered that the expression of CD24, which was recently identified as a new ‘do not eat me’ signal, is significantly upregulated on the surface of persist tumor cells after G12Ci treatment which suppresses the function of anti-tumor macrophages. Anti-CD24 blocking mAb enhanced macrophage-mediated phagocytosis in vitro and significantly sensitizes KRASG12C tumors to AMG 510 treatment in vivo in a macrophage-dependent manner. Similar findings were observed in KRASG12D-driven PDAC model. Our findings identified a novel immune combination to improve the outcome of KRAS targeted therapy in PDAC. Citation Format: Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Madelaine S. Theady, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Yong Zhou, Hong Zhao, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying. Blockade of CD24 sensitizes pancreatic cancer to Kras inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6532.
Abstract 6523: TOX upregulation promotes a GPX4-dependent CD8+ T cell ferroptosis in tumor microenvironments
Authors: Jiang Li, Qian Zhu, Xiufeng Liu
Journal: Cancer Research (2024)

Abstract Frequency and function of CD8+ tumor-infiltrating T cells (TILs) decide on clinical outcome of cancer immunotherapy; and TOX function as a crucial regulator of TIL dysfunction. In the present study, we found that multiplex factors, such as tumor cell, viral antigens and hypoxia, in tumor microenvironments (TME) induced CD8+ TIL ferroptosis by upregulating TOX. Single cell RNA-sequencing revealed that TOX modulated Havcr2, Pdcd1, Hmox1, Gpx4, and Ctsb transcription in human and murine CD8+ TILs. We further generated TOX conditional knockout in CD8+ T cell (Toxflox/floxCd8Cre, CKO) mice and the tumor-bearing CKO mice exhibited increased anti-tumor immunity and survival time. TOX upregulation increased reactive oxygen species (ROS), lipid peroxidation, and ferrous iron, leading to a GPX4-dependent CD8+ T cell ferroptosis. Genetic or antibody ablation of TOX, TIM-3, or HO-1 indicated that these molecules orchestrated CD8+ TIL ferroptosis by inducing iron overload and lipid peroxidation. Targeting TOX, PD-1, TIM-3, or ferroptosis boosted the anti-tumor suppression of tumor-specific T cell-based adoptive cell therapy (ACT) in murine tumor model. TOX, TIM-3 and GPX4 were prognostic predictors in human cervical cancer. This finding identifies a novel mechanism of tumor-induced CD8+ T cell ferroptosis underwent by TOX that provides new insights in improving TIL-based ACT immunotherapy. Key words: TOX, CD8+ T cells, ferroptosis, tumor microenvironments, cancer immunotherapy Citation Format: Jiang Li, Qian Zhu, Xiufeng Liu. TOX upregulation promotes a GPX4-dependent CD8+ T cell ferroptosis in tumor microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6523.
Abstract 3638: Pathologic endpoints as surrogates for survival endpoints in neoadjuvant immunotherapy clinical trials for non-small cell lung cancer
Authors: Robert B. Cameron, Jacobi B. Hines, Alessandra Esposito, Christine Bestvina, Marina C. Garassino, Valter Torri, Rajat Thawani
Journal: Cancer Research (2024)

Abstract Background: The use of neoadjuvant immunotherapy alone or in combination has rapidly evolved in the last 5 years. There is significant debate as to whether pathologic complete response (pCR) or major pathologic response (MPR) can be considered a surrogate endpoint for survival. We therefore performed a systematic review and meta-analysis to evaluate the surrogacy of pCR and MPR for event free survival (EFS) in neoadjuvant clinical trials for early-stage NSCLC. Methods: We performed a systematic literature search on PubMed and reviewed abstracts of the most relevant international conferences until June 2023. Relevant information relative to response rates, Odds Ratios (ORs) of response, 2-years EFS rates and Hazard ratios (HRs) were retrieved from all eligible clinical trials and the association were analyzed. To evaluate patients level surrogacy the association between response rate and 2-year EFS was evaluated. In trials presenting EFS rates by achievement of pCR and MPR a forest plot with random effect model was also produced. For trial level surrogacy, ORs for pCR and MPR and HRs for EFS were retrieved and analyzed using a linear regression model weighted by sample size. R2 and linear regression slope were used respectively to estimate the proportion of variation in EFS effect explained by pCR effect and the magnitude of change in EFS effect as a function of the magnitude of change in pCR effect. The R2 with 95% CI were calculated by bootstrapping approach. Results: Seven RCTs were identified for a total of 2940 patients. At patient level, the R2 of pCR and MPR with 2-years EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively, with slopes of 0.96 (0.68-1.19) and 0.64 (0.45-0.85), respectively. At trial level, R2 for association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97) for pCR and MPR, respectively. Conclusions: While we were able to show a strong correlation between pCR and EFS, trial level surrogacy was not proven. The lack of surrogacy can be related to the high heterogeneity among clinical trials and the still scarce number of data available. More research to reduce the heterogeneity (e.g., pathological evaluation, surgery, and staging harmonization) must be done to introduce pCR as a primary measure to predict EFS. Citation Format: Robert B. Cameron, Jacobi B. Hines, Alessandra Esposito, Christine Bestvina, Marina C. Garassino, Valter Torri, Rajat Thawani. Pathologic endpoints as surrogates for survival endpoints in neoadjuvant immunotherapy clinical trials for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3638.
Abstract 2976: The potential use of butyrate and propionate to inhibit oncogenic phenotypes in oral squamous cell carcinoma and triple negative breast cancer
Authors: Angel J. Amaral Maisonet
Journal: Cancer Research (2024)

Abstract Background Oral squamous cell carcinoma (OSCC) and triple-negative breast cancer (TNBC) are aggressive cancers with low survival rates, particularly in Hispanics. Since the underpinning mechanisms of oncogenesis for both OSCC and TNBC are multifactorial, the development of novel targeted therapies is limited. The tumor microbiome has been shown to modulate the microenvironment. The microbial product short-chain fatty acids (SCFA) may represent a putative target for treatment as they can potentially inhibit cell growth, proliferation, migration, and induce morphologic changes in cancer cells. We evaluated the impact of the SCFAs butyrate, acetate, and propionate on the oncogenic phenotypes of OECM-1 and MDA-231 cell line models for OSCC and TNBC respectively. Methods OECM-1 and MDA-231 cell lines were cultured in RPMI-1640 medium supplemented with 10% FBS. Cytotoxicity was determined using an alamarBlue assay by treating the cells with SCFA in a series of 7 concentrations starting at 125 mM (1:2 dilution factor) for 24, 48, and 72 hours (h). Proliferation quantification was performed using trypan blue dye after treatment with SCFA for 24h, 48h and 72h. Migration and invasion were measured after treatment for 24h with SCFAs. Comparative analysis of our results was performed using GraphPad Prism v10. Results Higher concentrations of all SCFA decreased cell viability in OSCC and TNBC at all time points. In OECM-1 cells, the average inhibitory concentration of 50% (IC50) was 3mM for butyrate, 382mM for acetate, and 64mM for propionate while in MDA-MB-231 cells, the average IC50 was 4.3mM for butyrate, 462mM for acetate, and 20mM for propionate. Both OECM-1 and MDA-MB-231 cells treated with butyrate and propionate at 5mM resulted in a slower migration after 24h of treatment. Additionally, there was a significant reduction of cell number and proliferation rate after 48h and 72h of butyrate treatment at the concentrations 1mM (p=0.0425) and 5mM (p=0.0007) in OSCC. Conclusions Our results show that butyrate and propionate can reduce oncogenic phenotypes in OSCC and TNBC and may represent a potential target for the development of alternative treatment strategies for both cancers. Future work includes measuring the impact of these SCFA in epithelial-mesenchymal transition, loss of adhesion, and cell death. Citation Format: Angel J. Amaral Maisonet. The potential use of butyrate and propionate to inhibit oncogenic phenotypes in oral squamous cell carcinoma and triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2976.
Abstract 3667: Nucleic acid quantification in uveal melanoma aqueous humor
Authors: Christina Chang, Sarah Pike, Mark Reid, Chen-Ching Peng, Benjamin Xu, Jesse Berry, Liya Xu
Journal: Cancer Research (2024)

Abstract Introduction: Uveal melanoma (UM) is the most common primary adult intraocular cancer. Though radiation brachytherapy is often employed for UM treatment, half of UM patients develop systemic metastases. In large tumors with macular involvement, the disease and its treatment can lead to blindness. Clinically, UM prognosis is estimated by tumor size, location, American Joint Cancer Commission (AJCC) staging, and histologic findings. Prognostic UM biomarkers have been established but lesions &amp;lt;2 mm in height, particularly near the fovea, are difficult to biopsy, and thus physicians often do not perform biopsies on such tumors. Therefore, the use of aqueous humor (AH) as a liquid biopsy is a promising methodology. The purpose of the study was to quantify analytes in AH samples collected at diagnosis and post-brachytherapy from UM eyes with varying tumor sizes and AJCC Stages to analyze correlations between analyte (dsDNA, microDNA, and protein) concentrations and tumor features. Methods: This case series study included 119 UM AH samples from 66 UM eyes and 16 control AH samples collected from age-matched non-UM glaucoma (GLC) eyes analyzed for unprocessed analytes using Qubit fluorescence assays. Results: Most UM AH samples contained quantifiable analyte concentrations (dsDNA: 94.1%, miRNA: 88.0%, protein: 95.2%) and at higher concentrations than GLC controls (dsDNA, P=0.008; miRNA, P&amp;lt;0.0001; protein, P=0.007). In samples taken at diagnosis, concentrations were higher at more advanced AJCC stages; comparing most advanced Stage III (n=8) to least advanced Stage I (n=24), median dsDNA was 4 times greater (P&amp;lt;0.0001), protein was 3 times greater (P&amp;lt;0.0001), and miRNA was 2 times greater (P=0.001). Analytes were quantifiable in &amp;gt;70% of pre-brachytherapy samples from eyes with tumors &amp;lt;2 mm tall (n=17). Height was positively associated with analyte concentrations at diagnosis (dsDNA: R=0.43, P=0.0007; miRNA: R=0.35, P=0.01; protein: R=0.39, P=0.005). In paired samples (n=53), all analyte concentrations were significantly higher post-therapy compared to diagnosis pre-therapy (Ps&amp;lt;0.01). Conclusions: Although AH analytes were also quantifiable in smaller, less advanced tumors, AH samples from eyes with larger, more advanced tumors had higher analyte concentrations. The detection of prognostic biomarkers in AH may allow for early UM recognition and guide personalized treatment. Citation Format: Christina Chang, Sarah Pike, Mark Reid, Chen-Ching Peng, Benjamin Xu, Jesse Berry, Liya Xu. Nucleic acid quantification in uveal melanoma aqueous humor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3667.
Abstract 1597: CD144+cancer-associated fibroblasts drive the malignancy of pancreatic cancer via stimulating inflammatory paracrine
Authors: Xugang Sun, Jun Yu, Tiansuo Zhao, Jihui Hao
Journal: Cancer Research (2024)

Abstract Purpose: Cancer-associated fibroblasts (CAFs) are highly heterogeneous in pancreatic ductal adenocarcinoma (PDAC). We previously reported that CAFs can acquire an endothelial phenotype under stress. Thus, we hypothesized that there are CAFs highly expressing endothelial markers and substantiated a novel subtype of CAFs promoting tumor progression. Experimental design: We performed single-cell RNA sequencing to identify the existence of CD144+CAFs. The prospective and retrospective analysis were combined to figure out the correlation between CD144+CAFs proportion and clinical outcome. The proliferation and invasion assay of cell lines, organoids and pancreatic cancer xenograft model were used to detect the effect of CD144+CAFs on tumor progression. Cytokine array assay, RNA-sequencing, IP-mass spectrum, Ch-IP and luciferase analysis were conducted to elucidate the underlying mechanism. siRNA delivery nanosystem was designed and administrated to precisely target CD144+CAFs in vivo. Results: CD144+CAFs were present in tumor microenvironment of PDAC and breast cancer and patients with a higher CD144+CAFs proportion have worse prognosis in PDAC. CD144+CAFs can promote the metastasis of PDAC through enhancing epithelial-mesenchymal transition. CD144-β-catenin-STAT3 signaling axis was activated and downstream inflammatory secreted cytokines were transcriptionally upregulated to maintain the functions and phenotype of CD144+CAFs. A novel CAF-targeting siRNA delivery nanosystem, loading FAPα and siCDH5, was designed and administrated to precisely target CD144+CAFs, which substantially inhibited the protumoral roles in vivo. Conclusion: CD144+CAFs can promote the growth and metastasis of PDAC by activating CD144-β-catenin-STAT3 signaling axis and stimulating inflammatory secretion. CAF-targeting siRNA delivery nanosystem can inhibit tumor progression by precisely targeting CD144+CAFs. Citation Format: Xugang Sun, Jun Yu, Tiansuo Zhao, Jihui Hao. CD144+cancer-associated fibroblasts drive the malignancy of pancreatic cancer via stimulating inflammatory paracrine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1597.
Abstract 4287: Serological quantification of fibroblast activation protein (FAP) cleaved type III collagen: A biomarker for FAP activity
Authors: Rasmus Sund Pedersen, Morten Karsdal, Nicholas Willumsen
Journal: Cancer Research (2024)

Abstract Introduction: Fibroblast activation protein (FAP) has unique proteolytic activity with very low expression in healthy tissues, while being upregulated in diseased tissues including many types of cancer for example non-small cell lung cancer (NSCLC). The disease specific expression and unique proteolytic activity have made FAP an interesting protein to be utilized for drug targeting purposes. Therefore, it is important to identify the patients with FAP activity. The aim of the study was to develop a tool to non-invasively quantify FAP activity and investigate its potential as a biomarker for patients with NSCLC. Methods: We developed an ELISA (named C3F), with monoclonal antibodies raised against a FAP generated fragment of type III collagen that was identified by MS, to quantify FAP-mediated cleavage of type III collagen in serum to reflect proteolytic activity of FAP. We confirmed that the biomarker reflects proteolytic activity of FAP by incubating type III collagen with or without FAP and measured C3F. In addition, we confirmed elevated FAP expression in NSCLC (adenocarcinoma and squamous cell carcinoma) compared to healthy tissue and correlation between FAP and COL3A1 expression using data from The Cancer Genome Atlas (TCGA). The comparisons between FAP expression in healthy and cancer tissue was done using one-way ANOVA and correlation between FAP and COL3A1 was done using Spearman correlation. Lastly, C3F was measured in serum samples from patients with NSCLC (n = 109) and healthy controls (n = 42) and the two groups was compared using Mann Whitney test and area under receiver operating characteristic curves (AUROCs). Results: A C3F signal only appeared after type III collagen incubation with FAP, supporting that C3F reflects FAP proteolytic activity. C3F was significantly elevated in serum from patients with NSCLC compared to healthy controls (p &amp;lt; 0.0001, AUROC = 0.78). In support, FAP expression (TCGA) was significantly elevated in NSCLC tissue compared to normal lung tissue (p &amp;lt; 0.0001) and FAP expression correlated with expression of COL3A1 (persons r = 0.83). Conclusion: The FAP-cleavage mediated type III collagen fragment C3F reflects FAP activity and can be quantified non-invasively in serum. In this study we show C3F as promising diagnostic biomarker in NSCLC, however as the biomarker reflects FAP activity the optimal use is more is potentially as a predicter of treatment response from FAP-based drug delivery systems. Citation Format: Rasmus Sund Pedersen, Morten Karsdal, Nicholas Willumsen. Serological quantification of fibroblast activation protein (FAP) cleaved type III collagen: A biomarker for FAP activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4287.
Abstract 6446: ResponderID™ KRAS: Biology-driven machine learning to personalize KRAS inhibitor therapeutics
Authors: Josh Wheeler, Anže Lovše, Klemen Žiberna, Miha Štajdohar, Luka Ausec, Janez Kokošar, Daniel Pointing, Aditya Pai, Rafael Rosengarten, Mark Uhlik
Journal: Cancer Research (2024)

Abstract Breakthroughs in targeted KRAS therapeutics (KRASi) have the potential to transform the treatment landscape for several of the most common cancers including lung, colorectal, and pancreatic. Despite the recent approvals of KRASi and the anticipation of more to come, both the rate of patient response and the durability of these responses remain significant areas requiring improvement. Biomarkers that can predict response to KRASi and guide effective patient selection and drug combination strategies will be key to realizing the full potential of this emerging therapeutic field. While most biomarkers predominantly rely on a single analyte (e.g. KRAS mutation status), Genialis’ biomarkers are constructed using high-dimensional and/or multimodal data that capture the underlying biological complexity unique to each individual patient. Genialis' ResponderID™ is a machine learning-based biomarker discovery framework that models fundamental aspects of cancer biology to predict the clinical benefit based on the patient’s own biology. Here we report progress towards the development of a first-in-class, RNA-based biomarker, ResponderID™ KRAS, capable of stratifying KRAS G12C inhibitor response in lung cancer patients using RNA sequencing data. Trained on thousands of lung cancer samples, our biomarker models therapeutic response by unifying two core KRAS biologic axes, dependency and activation, to identify those patients most likely to respond. The performance characteristics of ResponderID™ KRAS thus far has been evaluated on a real world dataset of lung cancer patients treated with Sotorasib. ResponderID™ KRAS serves as an independent biomarker designed to inform clinical trial design, select for therapeutic efficacy, identify rational combination strategies, and expedite approvals across various therapeutic contexts. Citation Format: Josh Wheeler, Anže Lovše, Klemen Žiberna, Miha Štajdohar, Luka Ausec, Janez Kokošar, Daniel Pointing, Aditya Pai, Rafael Rosengarten, Mark Uhlik. ResponderID™ KRAS: Biology-driven machine learning to personalize KRAS inhibitor therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6446.