tbuckley/cabot-search huggingface dataset:
Abstract 1740: Histone proteomic profiling of EMT-transformed MCF10A breast cells demonstrates a loss in novel histone arginine methylation sites via dual p53 and PTEN deletion
Authors: Charlotte B. McGuinness, Megan A. Wilson, Margaret V. Leonard, Maria Ouzounova, Hasan Korkaya, Austin Y. Shull
Journal: Cancer Research (2024)

Abstract Metastatic potential of basal-like breast cancers typically is initiated by genetic alterations that lead to a process known as epithelial-mesenchymal transition (EMT). However, much is currently not understood regarding the role of epigenetic modifications that lead to invasive characteristics and EMT phenotype of metastatic breast cancers. Based on the previous notion connecting epigenetic changes to breast cancer metastasis, we performed DIA-based mass spectrometry of isolated histones from an isogenic panel of MCF10A breast cell lines where the tumor suppressor genes TP53 and PTEN were silenced and induced EMT. With this approach, we determined which histone modifications were differentially enriched in the non-EMT and EMT-induced MCF10A cell lines. From approximately 72 histone modifications identified and annotated from our mass spectrometry results, we were able to identify 5 histone events that were differentially enriched in our MCF10A cell line panel. Two events of note were histone H3 lysine-14 acetylation (H3K14ac) significantly increasing and histone H4 arginine 55 dimethylation (H4R55me2) significantly decreasing in our EMT-transformed MCF10A p53-/PTEN- cell lines when compared to the parental, non-tumorigenic MCF10A cell line, showing these events are differentially affected during the EMT process in breast cancer cells. Furthermore, significant arginine demethylation of H4R55me2 &amp; H3.1R83me in the EMT-transformed MCF10A p53-/PTEN- cell lines corresponded with JMJD6, an established histone arginine demethylase, being overexpressed in basal-like breast cancer cell lines as well as basal-like breast cancer patients from The Cancer Genome Atlas (TCGA) and METABRIC datasets. Based on histone proteomic profiling of our isogenic cell line model, the loss of specific histone arginine methylation events corresponding with JMJD6 overexpression could highlight the potential for a targetable epigenetic mechanism in breast cancer metastasis. Citation Format: Charlotte B. McGuinness, Megan A. Wilson, Margaret V. Leonard, Maria Ouzounova, Hasan Korkaya, Austin Y. Shull. Histone proteomic profiling of EMT-transformed MCF10A breast cells demonstrates a loss in novel histone arginine methylation sites via dual p53 and PTEN deletion [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 1740.
Abstract 1738: Precise detection of benign and malignant renal tumor via epigenetic characteristics of urinary cell-free DNA
Authors: Wen Kong, Hang Dong, Haoran Tang, Pan Du, Shidong Jia, Jin Zhang
Journal: Cancer Research (2024)

Abstract Early detection of clear cell renal cell carcinoma (ccRCC) and accurate differentiation between malignant and benign lesions pose clinical challenges. Profiling the epigenetic pattern of patients through liquid biopsy offers a promising strategy for non-invasive cancer identification. This study utilizes the methylation characteristics of urinary cell-free DNA to enhance the precise diagnosis of ccRCC. In this study, 32 patients with malignant RCC, 20 patients with benign kidney lesions, and 28 age- and sex-matched healthy donors were enrolled. Urine samples were collected and applied by PredicineEPIC assay to analyze the whole genome methylation profiles. We assessed the methylation differences on cancer-specific altered regions and constructed a machine learning model for malignant and benign classification. Beta values were calculated for differentially methylated regions identified through literature mining and our current work. These features carry methylation signals that are recognized by gradient boosting machine and used for classification training. The leave-one-out cross-validation method compensated for the shotage of sample size. The sensitivity and specificity of the optimal model in the training set are both greater than 0.97, and it can achieve an accuracy of 0.95 on the validation set. This performance surpasses traditional diagnostic methods such as contrast-enhanced CT and MRI. This study demonstrated the technical feasibility of leveraging epigenetics profiles to discriminate malignant from benign lesions, suggesting a promising liquid biopsy-based approach for the precise detection of renal cell carcinoma. Citation Format: Wen Kong, Hang Dong, Haoran Tang, Pan Du, Shidong Jia, Jin Zhang. Precise detection of benign and malignant renal tumor via epigenetic characteristics of urinary cell-free DNA [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 1738.
Abstract 2391: Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions
Authors: Samuel Protich, Madison Stoddard, Lin Yuan, Douglas White, Dean Bottino, Arijit Chakravarty
Journal: Cancer Research (2024)

Abstract Late-stage cancers in the clinic present as a set of dispersed tumors, each with distinct growth kinetics. As most patients enrolled in trials of experimental anticancer therapeutics have late-stage malignancies, it is important to understand the impact of data analysis methodologies on the ability to detect treatment effect. In particular, we are interested in the potential risk posed by aggregating individual tumor measurements from multiple-lesion clinical data into a single tumor burden measurement, as this may cause a loss of information. In this work, we use quantitative modeling to assess how analyzing multiple lesions separately versus using an aggregated readout affects tumor response and detection of progression free survival and relapse. To assess the impact of data aggregation, we built a two-population clonal dynamics model consisting of sensitive and resistant tumor cells undergoing growth in the presence or absence of treatment. We performed parameter sweeps to assess the impact of individual model parameters on progression free survival and relapse. We then extended these sweeps to the multi-lesion situation, using nonlinear regression to compare parameter values of aggregated models and the parameter values of the individual models that comprised it. From our simulations, the most influential parameters in determining rebound are the growth rate of the resistant cells and the fraction of these cells, while growth rate of sensitive cells and growth rate inhibition affect effectiveness of treatment. In analyzing the multiple lesion model in different situations, we found that estimates for progression free survival were significantly more sensitive when the lesions were analyzed separately, rather than being aggregated. Our work suggests that aggregating the lesions into a single readout loses impact of individual lesion growth rate inhibitions, impairing early detection as the ability to detect fast growing, small, resistant lesions (despite overall tumor burden decreasing) is lost. Taken together, our findings suggest that data aggregation causes a loss of information. Relapse can be predicted at earlier times when using the multiple lesion model compared to an aggregated model. Citation Format: Samuel Protich, Madison Stoddard, Lin Yuan, Douglas White, Dean Bottino, Arijit Chakravarty. Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions [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 2391.
Abstract 206: Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity
Authors: Tanvi Visal
Journal: Cancer Research (2024)

Abstract Background- Triple-negative breast cancer (TNBC) is challenging to treat due to fewer clinically detectable targets and its propensity to metastasize. Epithelial to mesenchymal transition (EMT) is a key feature of the metastatic cascade. Recent data highlights the enhanced metastatic potential of hybrid epithelial-mesenchymal (EM) phenotypes from partial activation of EMT. However, mechanistic insights and targetable vulnerabilities within hybrid EM remain elusive. We identified that hybrid EM tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies. Hence, we sought to investigate role of CD38 in hybrid EM-driven metastasis. We hypothesize that hybrid EM tumors drive metastasis via intratumoral accumulation of CD38, promoting an immunosuppressive tumor microenvironment (TME). Methods- Reverse Phase Protein Array, cell migration/invasion assays, flowcytometry and immunohistochemistry were used to evaluate phenotype, immune cell populations and molecular mechanisms upon CD38 knockdown (KD) and overexpression (OE) in vivo. Results- CD38 KD weakened the process of EMT and reduced cell migration and invasion. Tumors lacking CD38 showed increased infiltration of CD8 T cells and M1-like (anti-tumor) macrophages coupled with a decrease in immunosuppressive regulatory T cells (Tregs) and M2-like (pro-tumor) macrophages. In contrast, cancer cells with CD38 OE maintained a hybrid phenotype through co-expression of epithelial and mesenchymal markers and also showed significant increase in cell migration and invasion. Tumors arising from CD38 OE cells displayed a significant increase in Tregs. Most strikingly, hybrid EM tumors that no longer express CD38 show reduction in lung metastases and circulating tumor cell colonies. Taken together, these findings suggest that CD38 is important for the metastatic and immune evasive potential of hybrid EM breast cancers. Conclusion- Our data exposes CD38 as a survival strategy in hybrid EM tumors to suppress immune cells and sustain metastasis with strong implications in other carcinomas which have hybrid EM properties. Citation Format: Tanvi Visal. Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity [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 206.
Abstract 2380: The bispecific antibody KA-3004, targeting PD-L1 and 4-1BB, is designed to enhance anti-tumor activity
Authors: Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu
Journal: Cancer Research (2024)

Abstract Checkpoint inhibitors (CPI) have transformed the treatment landscape for advanced solid tumors; however, a majority of cancers still do not respond to immune checkpoint therapy. In this study, we developed a bispecific antibody (BsAb) named KA-3004, targeting PD-L1 and human 4-1BB, with the aim of enhancing the functionality and survival of stimulated CD8+ T cells in the tumor microenvironment. This antibody was designed using our nanobody antibody discovery platform. KA-3004, in IgG1 format, incorporates mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It features two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PD-L1 with two Fabs at the N-terminal. KA-3004 binds to PD-L1 with high affinity, blocking the interaction of PD-1 and PD-L1. It also binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PD-L1 with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3004 effectively suppresses the growth of NCI-H292 tumors expressing PD-L1. Additionally, KA-3004 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3004 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3004, developed with our nanobody antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of solid cancers. Citation Format: Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu. The bispecific antibody KA-3004, targeting PD-L1 and 4-1BB, is designed to enhance anti-tumor 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 2380.
Abstract 6059: Discovery of ETS-007, a first-in-class degrader targeting N-terminal domain of androgen receptor derived from AR liquid-liquid phase separation inhibitor
Authors: Yingjie Li, Mingyue Fei, Yingke Miao, Lijian Feng, Xiaofei Fan, Jinping Li, Yaozhong Chen, Ming Xu, Wenqi Cui, Qiangang Zheng, Jidong Zhu
Journal: Cancer Research (2024)

Abstract Patients with advanced prostate cancer inevitably acquire resistance to anti-androgen therapies, and progress to lethal castration-resistant prostate cancer (CRPC). The resistance mechanisms involve AR gene amplification and overexpression, constitutively active ligand-independent splice variants such as AR-V7, and the mutations in the AR ligand-binding domain (LBD). Our previous study has shown that the AR N-terminal domain (NTD) is responsible for AR liquid-liquid phase separation (LLPS) capability, which is essential for AR/AR-V7 transcriptional activity. We conducted a compound library screening using an AR LLPS phenotypic assay and identified ET0516 as a hit to specifically inhibit AR LLPS and its downstream gene expression, indicating that inhibition of AR. LLPS through targeting its NTD is a feasible approach to overcome the resistance to current anti-androgens therapy. Here we report the identification of a novel AR degrader, ETS-007 which is originated and evolved from internal LLPS phenotypic screening, that effectively degrades both AR and AR-V7 proteins with DC50 of single-digit nM by inducing a protein-protein interaction between AR NTD and an E3 ligase complex. ETS-007 induced AR and AR-V7 polyubiquitination, followed by degradation which could be blocked by the protease inhibitor MG132. ETS-007 significantly inhibited cell proliferation in AR and/or AR-V7 positive cell lines, e.g. LNCaP and 22RV1, and downregulated the androgen responsive genes such as PSA and TMPRSS2. Compared with enzalutamide and ARV-110, ETS-007 could block transcriptional activities of AR-V7, and AR mutants in luciferase report assay. Oral administration of ETS-007 in an enzalutamide-resistant 22RV1 xenograft model led to intratumoral AR-V7 degradation and concomitant decrease in PSA protein levels, resulting in a remarkable tumor regression. Taken together, our findings provide preclinical evidence that ETS-007 as a potent AR-NTD degrader derived from our LLPS platform can effectively block the transcriptional activities of both AR and AR-V7 for the treatment of metastatic CRPC. Citation Format: Yingjie Li, Mingyue Fei, Yingke Miao, Lijian Feng, Xiaofei Fan, Jinping Li, Yaozhong Chen, Ming Xu, Wenqi Cui, Qiangang Zheng, Jidong Zhu. Discovery of ETS-007, a first-in-class degrader targeting N-terminal domain of androgen receptor derived from AR liquid-liquid phase separation inhibitor [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 6059.
Abstract 3338: Development of a CK2α inhibitor for treatment of wnt-driven colorectal cancer
Authors: Darren Cawkill
Journal: Cancer Research (2024)

Abstract A novel, potent and highly selective orally bioavailable small molecule inhibitor of Casein Kinase 2α (CK2α) has been developed and validated in pre-clinical models of wnt-driven colorectal carcinoma; and is poised to enter clinical development.CK2α is considered as a positive regulator of wnt signaling and tumorigenesis. The wnt pathway is known to be sensitive to and amplified by CK2α activity at multiple nodes and can be inhibited by loss of CK2α function. The human genetics of colorectal cancer (CRC) have been well characterized and approximately 80% tumors are identified as being wnt pathway mutation driven. CRC tumors can be further stratified into consensus molecular subtypes (CMS), with iCMS2 representing 37% of CRC patients, being characterized by ongoing wnt pathway upregulation. Development of CK2α inhibitors as a targeted therapy for CRC is therefore mechanistically well aligned to the wnt signaling drive and may serve as a promising therapeutic strategy for this cancer. A novel small molecule binding site on CK2α has been exploited to design and develop an inhibitor with Ki of 95 pM and exquisite selectivity over the kinome. This inhibitor has been comprehensively characterized using in vitro, ex vivo and in vivo pharmacology studies. Cellular mechanism of action studies in CRC cell lines have quantified the potency of target engagement, inhibition of known CK2α phospho-sites, inhibition of tumorigenic wnt pathway activity, and induction of apoptosis. This CK2α inhibitor was also profiled in a high content screen of CRC patient-derived organoids established from various driver mutation backgrounds. Use of these ex vivo models has validated the potent cytotoxic activity of CK2α inhibition in tumor samples with wnt-driven characteristics and highlights the potential therapeutic efficacy of CK2α inhibition in this setting. In vivo CRC xenograft studies have confirmed anti-tumor efficacy and developed the understanding of pharmacokinetic pharmacodynamic relationship between free plasma concentration of drug and inhibition of CK2α-specific biomarker in the tumor. The preclinical data presented establishes the strong rationale for clinical development of a novel CK2α inhibitor for the treatment of locally advanced or metastatic solid tumors, with an emphasis on wnt-driven CRC. Citation Format: Darren Cawkill. Development of a CK2α inhibitor for treatment of wnt-driven colorectal 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 3338.
Abstract 2379: The bispecific antibody KA-3007 against B7H3 and CD28 enhances T cell activation in solid tumors
Authors: Guojin Wu, Zhengcheng Guo, Hao Peng, Feng Hao, Feng He, Jinying Ning
Journal: Cancer Research (2024)

Abstract Immunotherapy, revolutionizing the treatment of advanced solid tumors by blocking PD1 signaling, faces challenges as most cancers remain unresponsive to anti-PD-1 therapy. CD28, a key immune co-stimulatory receptor on T cells, often lacks ligands expressed on tumor cells. B7H3 is highly expressed in various solid tumors. In this study, we developed a bispecific antibody (BsAb) named KA-3007, targeting B7H3 and human CD28 to activate T cells in the tumor microenvironment. KA-3007, featuring an identical light chain, was developed using our common light chain bispecific antibody discovery platform with knob-into-hole technology. This BsAb is in regular IgG1 format with mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. Its two Fabs bind to B7H3 with high affinity and CD28 with relatively low affinity. Co-culturing T cells with tumor cells expressing B7H3 enhances T cell activation. In PBMC humanized immunodeficient mouse tumor models, KA-3007 effectively suppresses the growth of NCI-H292 tumors, with or without a PD1 antagonist antibody. Furthermore, this antibody exhibits a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of KA-3007 with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and it shows neither aggregation nor degradation. In conclusion, the BsAb KA-3007, developed with our common light chain antibody discovery platform, emerges as a promising pre-clinical candidate drug for the treatment of solid cancers. Citation Format: Guojin Wu, Zhengcheng Guo, Hao Peng, Feng Hao, Feng He, Jinying Ning. The bispecific antibody KA-3007 against B7H3 and CD28 enhances T cell activation in solid tumors [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 2379.
Abstract 2654: HPK1 inhibits CD8+ T cell effector gene expression following T cell activation
Authors: Rachel Y. Ames, Rongqi Zhao, Parker Mace, Adam Grant, Guorui Xie, Heather Milestone, Molly Grandcolas, Eva Fang, Nicolae Kiosea, Stephen Wong, Martin Brovarney, Scott Jacobson, Danilo Nebalasca, Jorge Arguello, Blanca Gomez, Hiranmayee Kandala, Michelle Y. Ko, Lan Nguyen, Omar Robles, Grant Shibuya, Anton A. Shakhmin, Parcharee Tivitmahaisoon, Vi-Anh Vu, Ashkaan Younai, Mikhail Zibinsky, Babu Subramanyam, Daniel Poon, Mohsen Sabouri Ghomi, David J. Wustrow, Paul D. Kassner, George E. Katibah, Dirk G. Brockstedt
Journal: Cancer Research (2024)

Abstract Hematopoietic progenitor kinase 1 (HPK1) has been shown to act as a negative regulator of T cell receptor signaling and of subsequent effector T cell function. Inhibiting HPK1 to enhance T cell activity has emerged as a promising strategy for cancer immunotherapy. Upon T cell receptor engagement, the kinase domain of HPK1 is activated and targets components of the T cell receptor (TCR) signaling pathway for degradation, including SLP76. However, the molecular events connecting HPK1 kinase activity to observed T cell functions downstream of proximal TCR signaling are not well understood. Through transcriptional profiling of HPK1-kinase-dead (HPK1-KD) versus wild-type CD8+ T cells following an acute, attenuated Listeria monocytogenes infection, we observed increased expression of many genes associated with T cell activation and effector function, including changes in expression of several key transcription factors and their targets. Upon activation, HPK1-KD T cells, as well as T cells treated with our small-molecule HPK1 inhibitor, produce higher levels of a wide range of effector cytokines in vitro and in vivo. Treatment of mice with the HPK1 inhibitor also inhibited tumor growth in several syngeneic tumor models. These data expand our understanding of the role of HPK1 in inhibiting CD8+ T cell effector programs, and, importantly, the impact of HPK1 inhibitors on T cell function. Citation Format: Rachel Y. Ames, Rongqi Zhao, Parker Mace, Adam Grant, Guorui Xie, Heather Milestone, Molly Grandcolas, Eva Fang, Nicolae Kiosea, Stephen Wong, Martin Brovarney, Scott Jacobson, Danilo Nebalasca, Jorge Arguello, Blanca Gomez, Hiranmayee Kandala, Michelle Y. Ko, Lan Nguyen, Omar Robles, Grant Shibuya, Anton A. Shakhmin, Parcharee Tivitmahaisoon, Vi-Anh Vu, Ashkaan Younai, Mikhail Zibinsky, Babu Subramanyam, Daniel Poon, Mohsen Sabouri Ghomi, David J. Wustrow, Paul D. Kassner, George E. Katibah, Dirk G. Brockstedt. HPK1 inhibits CD8+ T cell effector gene expression following T cell activation [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 2654.