tbuckley/cabot-search huggingface dataset:
Abstract 5697: MILIP drives triple-negative breast cancer through complexing with transfer RNAs to promote protein production
Authors: Yuchen Feng, Simin Zheng, Xiaohong Zhao, Yuanyuan Zhang, Ran Xu, Liang Xu, Thomas Preiss, Lei Jin, Jinnan Gao, Xu Dong Zhang
Journal: Cancer Research (2024)

Abstract Despite the progress in endocrine therapy, targeted therapy and immunotherapy, the treatment of triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, is challenging. This is closely associated with the lack of effective molecular targets in TNBC cells for therapeutic intervention. Here we report that the long noncoding RNA (lncRNA) MILIP drives TNBC cell survival, proliferation and tumorigenicity through complexing with transfer RNAs (tRNAs) to promote protein production, and thus represents a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, yet MILIP silencing diminished TNBC cell viability and retarded TNBC xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its well-established role in repressing p53 in other types of cancers. Mechanistical investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with tRNALeu and tRNASer, type II tRNAs, through their variable loops, thus facilitating the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein production and cell viability, with therapeutic potential revealed where targeting MILIP using Gapmers inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identified MILIP as an RNA translation elongation factor to promote protein production in TNBC cells and demonstrated that experimental therapy with MILIP Gapmers inhibits TNBC growth, indicating MILIP targeting is a potential avenue for developing improved TNBC treatment through blocking protein synthesis. Citation Format: Yuchen Feng, Simin Zheng, Xiaohong Zhao, Yuanyuan Zhang, Ran Xu, Liang Xu, Thomas Preiss, Lei Jin, Jinnan Gao, Xu Dong Zhang. MILIP drives triple-negative breast cancer through complexing with transfer RNAs to promote protein production [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 5697.
Abstract 2260: Transcriptomic immuno-oncology investigation of B-cell lymphomas using a novel comparative workflow
Authors: Naomi Rapier-Sharman, Michael T. Told, Sehi Kim, Kim L. O'Neill, Brett E. Pickett
Journal: Cancer Research (2024)

Abstract Patients with B-cell lymphoma currently have limited treatment options, often with serious side effects; for example, B-cell lymphoma patients undergoing chemo- and radiation therapies experience poor health from off-target toxicity. Similarly, though CD19 CAR T-cell therapy is very effective, patients suffer lifelong B-cell aplasia as a side effect. Comparing a cancer to an autoimmune disease in the same tissue type may grant us additional insights on the immune dysregulation of the cancer, leading to development of more immune-aware cancer treatments. We introduce a new data-driven comparative workflow for the analysis of immuno-oncology attributes by comparing a cancer and an autoimmune disease in the same tissue type. As an example use case, we compare primary B-cell lymphomas to primary B-cells from systemic lupus erythematosus with the goal of delineating new mechanisms that can be leveraged to treat B-cell lymphomas. Our analysis will utilize bulk RNA-sequencing (RNA-seq) of B-cells for initial discovery, followed by single-cell RNA-sequencing (scRNA-seq) of Peripheral Blood Mononuclear Cells (PBMCs) for validation. Our analytical framework incorporates differential gene analysis, GO Terms, known protein-protein interactions, principal component analysis, and machine learning for biomarker detection. Here, we describe our novel tool in detail and share the results of our lymphoma use case to gain a better understanding of the targetable immune-related attributes of B-cell lymphoma. We expect that this novel tool, along with the results of our B-cell lymphoma use case, will contribute to the continued development of immune-focused treatment options for B-cell lymphoma and other cancers. Citation Format: Naomi Rapier-Sharman, Michael T. Told, Sehi Kim, Kim L. O'Neill, Brett E. Pickett. Transcriptomic immuno-oncology investigation of B-cell lymphomas using a novel comparative workflow [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 2260.
Abstract 2448: Field cancerization proteomic analysis provides a novel class of functional risk biomarkers for non small cell lung cancer
Authors: Rayan Ibrahim Alhammad, Ngoc Bao Vuong, Weidong Zhou, Donald J Johann, Barbara Birkaya, Lance Liotta, Alessandra Luchini
Journal: Cancer Research (2024)

Abstract Lung cancer carcinogenesis is the outcome of a field of premalignant changes that occur in the bronchial tree leading to the overt emergence of the malignant lung cancer (field cancerization). A tissue or blood proteomic signature of these premalignant changes represent a novel concept of risk biomarkers that can predict the probability of future emergence of Lung Cancer. In this study, we analyzed two independent cohorts of non-small cell lung cancer (NSCLC) patients. One cohort consisted of 18 patients who donated blood before and after tumor resection surgery and matched tissue samples (UAMS Medical Center). The second set derived from a longitudinal case-control study of plasma sample collected during the physician health study that were donated at different times prior to the diagnosis of Non-Small Cell Lung Cancer (N=272). We used affinity-enriched mass spectrometry analysis and statistical learning techniques to identify a set of common markers that discriminated plasma cases and controls and were conserved in different bronchial tissue compartments including tumor and adjacent tissue. The tumor microenvironment adjacent to and surrounding cancer cells undergoes to progressive stages of carcinogenesis during field cancerization. We identified 22 proteins involved in cell adhesion, protein folding, immune response, angiogenesis, and cancer proliferation. This is a novel class of functional risk biomarkers to determine the probability of NSCLC onset. In conclusion, our findings shed light on a new class of functional biomarkers that underly tumor pathogenesis mechanisms and can provide hints for new strategies of tumor prevention therapy or lifestyle modification. Citation Format: Rayan Ibrahim Alhammad, Ngoc Bao Vuong, Weidong Zhou, Donald J Johann Jr, Barbara Birkaya, Lance Liotta, Alessandra Luchini. Field cancerization proteomic analysis provides a novel class of functional risk biomarkers 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 2448.
Abstract 3500: Refining diagnosis of renal cell carcinoma subtypes through single-cell resolution transcriptomic signatures
Authors: Minjun Kim, Ariel Madrigal, Zohreh Mehrjoo, Kate I. Glennon, Madeleine Arseneault, Morag Park, Fadi Brimo, Simon Tanguay, Hamed S. Najafabadi, Yasser Riazalhosseini
Journal: Cancer Research (2024)

Abstract A remaining challenge in the field of renal cell carcinoma (RCC) is diagnosis of rare or mixed subtypes, which hampers the delivery of the most effective healthcare to patients. While a new classification scheme, integrating molecular characteristics of tumors, is emerging, it requires a deep understanding of the tumor heterogeneity and etiopathogenesis of each subtype. We have generated and analyzed single-cell transcriptome profiles of 38 human RCCs and normal kidneys 16 RCCs with diverse histological subtypes and established gene signatures specific to each cell type. We have applied these gene signatures to bulk RNA-sequencing data of 1000 RCC tumors with different histological subtypes and normal kidneys from The Cancer Genome Atlas (TCGA) to characterize different cancer types and cellular origins. Unsupervised clustering analysis of TCGA data shows diagnostic discrepancies for 9.3% cases and subclassifies each major subtype (clear cell, papillary and chromophobe) into clusters with differential clinical outcomes.[KM1]. The pathological marker expression in misdiagnosed tumors is consistent with clustering-based classification, not their original diagnosis. Notably, using unique and subtype-specific gene signature patterns, we identified clear cell papillary renal cell tumor (ccpRCT), which is a newly classified benign entity and the main tumor type representing the mis-diagnosed tumors. These observations have further been confirmed by reviewing histological images of the tumors by an experienced genitourinary pathologist. Interestingly, our gene signatures reveal that ccpRCT does not originate from proximal tubule cells unlike clear cell and papillary RCCs. Taken together, our approach suggests a potential new classification method connected to clinical behaviors and drug responses based on overall transcriptomic differences. Citation Format: Minjun Kim, Ariel Madrigal, Zohreh Mehrjoo, Kate I. Glennon, Madeleine Arseneault, Morag Park, Fadi Brimo, Simon Tanguay, Hamed S. Najafabadi, Yasser Riazalhosseini. Refining diagnosis of renal cell carcinoma subtypes through single-cell resolution transcriptomic signatures [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 3500.
Abstract 5721: Dual targeting of CDK4/6 and CDK7 pathways augments tumor response in breast cancer
Authors: Eugene Son, Sungsoo Kim, Haram Park, Minah Kim, Hee Won Yang
Journal: Cancer Research (2024)

Abstract CDK7 plays a pivotal role in cell proliferation, serving as both a cell-cycle CDK regulator and a transcription machinery component. Clinical trials are currently exploring CDK7 inhibitors (CDK7i) as a second-line treatment for hormone receptor-positive (HR+) breast cancer post-CDK4/6 inhibitor (CDK4/6i) therapy progression and as a first-line treatment in triple-negative breast cancer (TNBC). This study evaluates the impact of CDK7i on transcription and CDKs activities and the synergistic potential of CDK7i in combination with CDK4/6i. Kinetic analyses indicate that CDK7i preferentially target global transcription over CDKs activities. Furthermore, a combination of CDK7i and CDK4/6i effectively suppresses cell proliferation in drug-naïve cells, albeit without the same efficacy in CDK4/6i-resistant cells. Our findings provide valuable insights into the evolving field of CDK inhibition strategies and provide critical guidance on the potential therapeutic application of CDK7i in breast cancer treatment. Citation Format: Eugene Son, Sungsoo Kim, Haram Park, Minah Kim, Hee Won Yang. Dual targeting of CDK4/6 and CDK7 pathways augments tumor response in 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 5721.
Abstract 3196: Overcoming lung cancer drug resistance: Enhanced cellular delivery using lipid-extracted nanoliposomes
Authors: Mohammed Alqaryan, Rashad Allahyani, Dayeoun Lee, Robert B. Campbell
Journal: Cancer Research (2024)

Abstract Background: Lung cancer causes substantial cancer deaths in the U.S. Drug resistance remains a major issue. Nanoliposomes demonstrate enhanced drug targeting and resistance-overcoming potential. Incorporating lipid extracts derived from target cells shows improved delivery over conventional nanoliposomes. This study examined the effects of lung cancer cell lipid extract nanoliposomes against target and non-target cell populations from different environments. Method: Cellular Membrane Lipid-Extracted Nanoliposomes (CLENs) were fabricated with DOPC, DOTAP, ChaGo-K-1 lipid extract, cholesterol, PEG5000, and rhodamine fluorescent label was incorporated for uptake studies. The liposome size was reduced by probe sonication. Particle size and polydispersity index (PDI) were measured by dynamic light scattering. Zeta potential was quantified by laser Doppler micro-electrophoresis. Four cell lines were utilized: ChaGo-K-1 NSCLC target, A549 pulmonary microenvironment control, 4T1 extra-pulmonary control, and normal lung fibroblasts off-target control. All cell lines were cultured in 48-well plates at a seeding density of 10,000 cells/mL and incubated for 24 hours. Freshly prepared CLENs were added to all cell lines and incubated for an additional 24 hours. Cells were washed with PBS, and fluorescence intensity was then quantified and qualified by a microplate reader to measure the cellular uptake of the CLENs. Results: The mean particle size and PDI of the ChaGo-K-1 CLENs were 117 ± 0.7 nm and 0.216 ±0.009, compared to 126 ± 0.5 nm and 0.195 ± 0.008 for the control, respectively. Both formulations were within the optimal size range for drug delivery and tumor cell penetration. The zeta potential of the ChaGo-K-1 CLENs was -1.75 ± 1.81 mV compared to -1.74 ± 6 mV for the control. Quantification and qualification of cellular uptake using fluorescence intensity measurements revealed a 3.2-fold increase in ChaGo-K-1 CLENs compared to conventional liposomes without ChaGo-K-1 lipid extracts. This demonstrates that the inclusion of the lipid extracts in the CLEN significantly enhanced selectivity and delivery to target cancer cell populations. Conclusion: Higher uptake occurred with target cells using CLENs with lipid extracts versus standard liposomes. NSCLC-derived CLENs show potential to improve selective delivery and overcome drug resistance. Further, in vivo studies evaluating selective NSCLC tumor accumulation and efficacy enhancement are warranted. Citation Format: Mohammed Alqaryan, Rashad Allahyani, Dayeoun Lee, Robert B. Campbell. Overcoming lung cancer drug resistance: Enhanced cellular delivery using lipid-extracted nanoliposomes [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 3196.
Abstract 3967: ISM9182A, a novel HPK1 inhibitor, exhibits immune modulatory activity and robust monotherapy anti-tumor effects in preclinical studies
Authors: Celia X.-J. Chen, Congying Pu, Jingjing Peng, Xiaoyu Ding, Hongfu Lu, Xiao Ding, Man Zhang, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov
Journal: Cancer Research (2024)

Abstract The hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a member of the Ste20 serine/threonine kinase super family that negatively regulates immune cells, including T cells, B cells and dendritic cells (DCs). Thus HPK1 is an attractive immuno-oncology target in many tumor types. Here, we report ISM9182A as a novel, potent, and selective inhibitor of HPK1.ISM9182A demonstrated nanomolar enzymatic potency against HPK1 with &amp;gt;100-fold selectivity against other MAP4K family kinases. ISM9182A inhibited the phosphorylation of SLP-76 at Ser376 dose-dependently with an IC50 of 30nM in human peripheral blood mononuclear cells. Moreover, ISM9182A enhanced IL-2 and IFNγ secretion upon CD3/CD28 co-stimulation in a dose-dependent manner without affecting T cell proliferation. Treatment of human pan T cells with ISM9182A also significantly reversed PGE2-mediated immunosuppression of human pan T cell activation and further boosted IL-2 and IFNγ secretion compared to CD3/CD28 co-stimulation. In monocyte-derived DCs stimulated with TNF-α/IL-1β/PGE-2, ISM9182A significantly upregulated CD80, CD86, and CD83 expression, demonstrating its potency to promote DC maturation. ISM9182A showed no obvious toxicity towards human T cell, B cells, and monocytes without CD3/CD28 co-stimulation. In vivo PK data revealed favorable ADME properties and good oral bioavailability of ISM9182A across different species. In a CT-26 murine syngeneic mouse model, oral administration of ISM9182A exhibited potent antitumor effects with p-SLP76 inhibition in both murine spleen and tumor, without body weight loss. In summary, ISM9182A is a potent and selective HPK1 inhibitor and a promising immuno-oncology agent. Citation Format: Celia X.-J. Chen, Congying Pu, Jingjing Peng, Xiaoyu Ding, Hongfu Lu, Xiao Ding, Man Zhang, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. ISM9182A, a novel HPK1 inhibitor, exhibits immune modulatory activity and robust monotherapy anti-tumor effects in preclinical studies [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 3967.
Abstract 3724: Targeting the LIFR-LCN2 pathway to sensitize liver cancer to immunotherapy
Authors: Yalan Deng, Li Ma
Journal: Cancer Research (2024)

Abstract Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options and no biomarker to predict therapy response. The current frontline therapies for liver cancer, including sorafenib and the combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF), have limited therapeutic benefits, which could be attributed, at least in part, to the highly immunosuppressive tumor microenvironment in liver cancer. Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in HCC. My recent studies revealed that in oncogene-induced liver tumors, overexpression of LIFR increased, while knockout of Lifr decreased CD8+ T cell infiltration, which may be mediated by LCN2-dependent inhibition of T cell viability, proliferation, and effector function. In ongoing and future work, I will investigate whether LIFR or therapeutic LCN2 neutralization can sensitize HCC to immunotherapy. If successful, this project will illuminate how to improve liver cancer immunotherapy by targeting the LIFR-LCN2 pathway. Low LIFR expression and high LCN2 expression may be used to select HCC patients who will likely benefit from the combination therapy with the LCN2-neutralizing antibody plus immune checkpoint inhibitors. Citation Format: Yalan Deng, Li Ma. Targeting the LIFR-LCN2 pathway to sensitize liver cancer to immunotherapy [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 3724.
Abstract 4386: Androgen hormone signaling regulates the association between the hippo pathway component YAP1 and RNA binding protein NPM1
Authors: Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Bekir Cinar
Journal: Cancer Research (2024)

Abstract Prostate cancer represents a major health concern for men in the United States and globally, disproportionately affecting men of African descent. Despite recent advances, the precise etiology and molecular mechanisms underpinning fatal prostate cancer in humans remain inadequately understood. RNA binding proteins (RBPs) regulate various aspects of RNA biology, and when their regulation is disrupted, they can lead to human diseases, including cancer. However, the comprehensive alterations in RBP-mRNA interactions in prostate cancer have not been explored. In this study, we investigated the dynamics of RBPs and their interactions with polyadenylated mRNA in the castration-sensitive LNCaP and castration-resistant C4-2 prostate cancer cell lines. Using an enhanced RNA interactome capture assay in combination with mass spectrometry, we discovered that LNCaP and C4-2 cells showed distinct RBP-mRNA interaction patterns in steady-state growth conditions and in response to androgen treatment. Additionally, we investigated the interplay between the oncogene Yes-associated protein 1 (YAP1) and the RNA-binding protein nucleophosmin (NPM1). We identified NPM1 as a component of the YAP1 protein complex through mass spectrometry-based proteomics. Our proximity ligation assay demonstrated that androgen signaling could regulate the interaction between YAP1 and NPM1. Also, our GST-pulldown revealed that NPM1 binds to the proline-rich domain of YAP1 in LNCaP cells, while the WW/SH3 domain of YAP1 mediates the interaction with NPM1 in C4-2 cells. Genetic and pharmacological inhibition of NPM1 activity reduced prostate cancer cell growth in culture by modulating cell cycle progression. Furthermore, our computational and immunological analysis of prostate tumor tissues indicated that the upregulation of NPM1 might be associated with the clinical advancement of human prostate cancer. These findings underscore the critical role of the molecular functional connection between YAP1 and RBPs and the global changes in RBP and RNA interaction patterns, in the progression and recurrence of prostate cancer. Citation Format: Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Bekir Cinar. Androgen hormone signaling regulates the association between the hippo pathway component YAP1 and RNA binding protein NPM1 [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 4386.