bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1489: MicroRNA-1 targets CXCR4/FOXM1/RRM2 axis regulating small cell lung cancer growth and metastasis
Authors: Khan Parvez , Siddiqui Jawed A. , Maurya Shailendra Kumar , Mirzapoiazova Tamara , Kanchan Ranjana , Venkata Ramakanth Chirravuri , Atri Pranita , Tang Wemin , Perumal NaveenKumar , Kshirsagar Prakash , Fatima Mahek , Khan Md Arafat , Chaudhary Sanjib , Rehman Asad Ur , Lakshmanan Imayavaramban , Mahapatra Sidharth , Kulkarni Prakash , Ganti Apar Kishor , Jain Maneesh , Oupicky David , Salgia Ravi , Batra Surinder Kumar , Nasser Mohd Wasim 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is a high-grade neuroendocrine metastatic lung cancer subtype having a universal relapse and poor prognosis. Limited or extensive-stage SCLC patients have limited therapeutic options due to a lack of potential drug targets. In the quest for novel therapeutic molecules, we performed micro-RNA sequencing from the serum samples and also analyzed bulk RNA-sequencing data from tumors of SCLC patients. We found a consistent downregulation of miR-1 in SCLC. These results were recapitulated in SCLC cell lines and tumor tissues compared to their matched normal. To assess the therapeutic potential of miR-1, we overexpressed miR-1 in SCLC cell lines that translated into decreased cell growth and oncogenic signaling. Mechanistic studies revealed that CXCR4 is a direct target for miR-1 in SCLC. Intracardiac injection of SCLC cell lines in the mouse models showed that overexpression of miR-1 decreases the distant organ metastasis, whereas miR-1 sponging potentiates aggressiveness and metastasis. Furthermore, we identified FOXM1-RRM2 as a unique downstream target of the miR-1/CXCR4 axis involved in the growth and metastasis of SCLC. Our results showed that FOXM1 directly binds to the promoter site of RRM2 and regulates its activity. Overexpression of miR-1 decreases the expression and activity of FOXM1-RRM2 through CXCR4 that reduces cell growth and metastasis. Taken together, our results suggest that miR-1 decreases SCLC metastasis by targeting the CXCR4/FOXM1-RRM2 axis and has a high potential for the development of novel SCLC therapies.
Citation Format: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Ranjana Kanchan, Ramakanth Chirravuri Venkata, Pranita Atri, Wemin Tang, NaveenKumar Perumal, Prakash Kshirsagar, Mahek Fatima, Md Arafat Khan, Sanjib Chaudhary, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, David Oupicky, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. MicroRNA-1 targets CXCR4/FOXM1/RRM2 axis regulating small cell lung cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1489.
Abstract 1554: Functional analysis of human circular RNA_0001587 and its target miRNAs in oral cancer
Authors: Khan Muhammad Jawad , Rabia Ghulam , Dandare Abdullahi , Awan Hassaan Mehboob , Raja Afraz Ahmad 
Published: June 2022

Abstract
Oral cancer is the sixth most aggressive malignancy around the world and accounts for 90% of head and neck lesions. It is the most prevalent type of cancer in South Asian countries and contributes to around 25% of all new cancer cases in the region. The involvement of non-coding circular RNAs (circRNAs) in various disease pathology has been reported. However, their role as diagnostic or therapeutic biomarkers is still unclear and needs to be further explored. This study was aimed to identify the role of hsa_circ_0001587 and competing endogenous RNA (ceRNA) mechanism in early diagnosis or as a therapeutic target for oral cancer. For this purpose, lists of circRNAs, miRNAs, and differentially expressed genes (DEGs) involved in oral squamous cell carcinoma (OSCC) were identified from the reported literature. Circinteractome was used to obtain target miRNAs that potentially bind to hsa_circ_0001587. Five miRNAs were selected for further in silico analysis on the basis of maximum target sites. Data were subjected to functional enrichment analysis, pathway analysis, and gene homology studies.Our results showed active participation of both hsa_circ_0001587 and its target miRNAs (miR-548c-3p, miR-520h, miR-1827, miR-607, and miR-579) in oral carcinogenesis via the regulation of genes including AKT, GADD45, PKA, PKC, and CASP8. Dysregulation of these genes disturbed the immune system, signaling pathways, cellular compartment activities, and molecular functions, indicating their role in tumor initiation and progression. Furthermore, it was predicted that hsa_circ_0001587 enhances the expression of genes for the RAS signaling pathway via its sponging effect on miR-548c-3p and miR-607. Noncoding RNAs including hsa_circ_0001587 and target miR-548c-3p and miR-607 play a critical role in the pathogenesis of OSCC. It is therefore suggested that hsa_circ_0001587 and its target miRNAs could be used as potential biomarkers for oral cancer.
Citation Format: Muhammad Jawad Khan, Ghulam Rabia, Abdullahi Dandare, Hassaan Mehboob Awan, Afraz Ahmad Raja. Functional analysis of human circular RNA_0001587 and its target miRNAs in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1554.
Abstract 1563: Spatial transcriptomics reveals heterogeneity and pathway dependencies of cancer associated fibroblasts in pancreatic ductal adenocarcinoma
Authors: Caligiuri Giuseppina , Thalappillil Jennifer , Hinds Juliene , Courtois Elise T. , Flynn William F. , Robson Paul , Dobin Alexander , Park Youngkyu , Tuveson David A. 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a deadly disease characterized by an immunosuppressive microenvironment and a dense stroma that encapsulates the tumor, making therapeutic targeting particularly challenging. One of the main cellular components of PDA tumor microenvironment (TME) is cancer associated fibroblasts (CAFs), whose function is to sustain tumor growth and provide structural support to the TME. Previously, we established the existence of three transcriptional subtypes of CAFs, myCAF, iCAF and apCAF, each with distinct functions and location in respect to cancer cells. Two of these subtypes, myCAF and iCAF, display a highly plastic potential in vitro and can transdifferentiate into one another upon activation of specific signaling pathways. The plasticity observed supports the existence of transitional CAF sub-states that have previously eluded observation due to technical limitations to their isolation. Through a combination of spatial transcriptomics and fluorescent in situ hybridization (FISH) on tumor samples obtained from KPC (KrasLSL-G12D; p53LSL-R172H; PDX-CRE) and FPC (KrasFrt-LSL-G12V-Frt; p53LSL-R172H; PDX-CRE; Rosa26FlpOERT2) mice, two PDA mouse models displaying a Kras G12D and G12V mutation respectively, we were able to confirm the presence of the previously identified CAF subtypes and two additional CAF sub-states. These sub-states are associated with the expression of specific markers and display different pathway enrichment. Notably, Kras G12D and G12V mutations generate similar organization of the stroma and heterogeneity of the CAF population. Subsequently, to understand the contribution of activating Kras mutation to these CAF phenotypes, we utilized the unique feature of the FPC mouse model which allows the excision of Kras G12V once the tumor has fully developed. Through FISH analysis, we observed deep reorganization of the stroma and a shift in marker expressions within the CAF populations upon Kras excision. Overall, the data here presented offers insight into the diversity of PDA CAFs and the role of mutated Kras in regulating CAF subtypes and stromal organization.
Citation Format: Giuseppina Caligiuri, Jennifer Thalappillil, Juliene Hinds, Elise T. Courtois, William F. Flynn, Paul Robson, Alexander Dobin, Youngkyu Park, David A. Tuveson. Spatial transcriptomics reveals heterogeneity and pathway dependencies of cancer associated fibroblasts in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1563.
Abstract 1581: Uncovering mechanisms of biogenesis and secretion of small extracellular vesicles in non small cell lung cancer (NSCLC)
Authors: Vargas Zulaida M. Soto , Sohal Ikjot Singh , Hasan Humna , Arteaga David , Kasinski Andrea L. 
Published: June 2022

Abstract
Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is the leading cause of cancer related deaths in United States. Only 24% of NSCLC patients survive 5-years post diagnosis, which could be attributed to the lack of efficient treatment strategies at the metastatic stage. Thus, understanding the biological mechanisms that promote NSCLC metastasis is critical for developing effective cancer-specific therapeutic agents. The development of cancer metastasis is greatly driven and influenced by intercellular communication. Key mediators of cell-to-cell communication are small extracellular vesicles (sEVs) of approximately 100-150 nm in diameter, often referred as exosomes. Previous report revealed that increased levels of exosomes in NSCLC patients correlated with lower overall survival. Indeed, secretion of sEVs by cancer cells can induce malignant transformation of non-cancerous cells nearby or at distant locations through influencing pre-metastatic niche formation. Therefore, biogenesis and release of cancer derived sEVs are determinant steps for the development of tumor metastasis. However, the mechanisms through which sEVs are produced and secreted by cancer cells are yet to be determined. Here, we isolated and characterized sEVs from a panel of NSCLC cell lines (H358, Calu6, H460, SKMES-1) and non-tumorigenic cells (BEAS-2B and HBEC) to identify mechanisms involved in the elevated secretion of EVs by cancer cells. Contrary to what has been previously reported in literature, our data demonstrated that not all cancer cell lines release high levels of sEVs. Our data suggests that elevated secretion of sEVs could be driven by specific mutations and oncogenic signaling in cancer cells. Among all the cell lines tested, H358 cells which harbor the infamous G12C mutation in KRAS, had the highest sEV release. Therefore, we hypothesize that the KRASG12C can drive high sEV production and secretion in H358 cells. Our preliminary data suggests that siRNA mediated knockdown of oncogenic KRAS signaling in H358 cells significantly decreases secretion of sEVs. Ongoing studies aim to pinpoint the detailed mechanisms by which cancer cells utilize KRAS oncogenic signaling to promote EV biogenesis pathways and tumorigenesis. The current study will provide the foundation to developed new therapeutic strategies against tumor sEVs-driven metastasis.
Citation Format: Zulaida M. Soto Vargas, Ikjot Singh Sohal, Humna Hasan, David Arteaga, Andrea L. Kasinski. Uncovering mechanisms of biogenesis and secretion of small extracellular vesicles in non small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1581.
Abstract 161: Regulation of Abl at mitotic centrosomes and survival by ILK in glioblastoma cells
Authors: Dresselhuis Jonathan , Brown Maddisen , Robinson Nicole , Tan Jacqueline , Cox Michael E. , Mills Julia 
Published: June 2022

Abstract
Many cancer cells possess supernumerary centrosomes, having more than one centrosome at each pole during mitosis which can lead to aberrant mitotic division and cell death. To prevent this fate, cancer cells cluster their centrosomes at two poles during division to divide in a pseudobipolar manner. As the presence of supernumerary centrosomes is rare in normal cells, targeting the declustering of supernumerary centrosomes in cancer cells is a promising strategy for cancer treatment. Integrin-linked kinase (ILK) is an oncogenic protein and chemotherapeutic target shown to be found at the centrosome where it has a role in facilitating centrosome clustering. Inhibition of ILK, via an anti-ILK chemotherapeutic drug QLT-0267, has been shown to increase centrosome declustering causing mitotic arrest and cell death. However, not all cancers cells are susceptible to anti-ILK treatment alone. Therefore, we investigate a combination treatment strategy targeting ILK and another oncogenic kinase, Abelson kinase (Abl). Both ILK and Abl are involved in cancer cell survival, regulated by the same signalling pathways and share common binding partners that occur at the centrosome and are critical for mitosis. The ILK inhibitor QLT-0267 induced a significant sub-G1 peak following propidium iodide FACS analysis and an increase in MTT labelling, indicating that QLT-0267 significantly decreased survival in glioblastoma cell lines. These effects were augmented in the presence of imatinib, an Abl inhibitor. Moreover, QLT-0267 and imatinib, in combination, significantly increased mitotically arrested cells over the ILK inhibitor alone. Increased levels of cytosolic Abl have been associated with its transformative abilities. The ILK inhibitor effects on survival correlated with its ability to decrease cytosolic Abl levels and inhibited Abl’s localization to mitotic centrosomes in dividing glioblastoma cells. These effects were reversed by the proteasomal inhibitor MG132 (a drug that inhibits the degradation of Abl). Together these results indicate that combination treatment with QLT-0267 and imatinib are more effective then QLT-0267 alone at decreasing successful mitoses and survival in glioblastoma cells. Future studies will unravel the relationship between these oncogenic kinases at centrosomes and its effect on cancer cell cycle progression and survival.
Citation Format: Jonathan Dresselhuis, Maddisen Brown, Nicole Robinson, Jacqueline Tan, Michael E. Cox, Julia Mills. Regulation of Abl at mitotic centrosomes and survival by ILK in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 161.
Abstract 1736: Local treatment of lung cancer by inhaled monoclonal antibodies: A pre-feasibility screening approach for spray drying
Authors: Landry Madeleine , Pluntze Amanda , Shepard Kimberly 
Published: June 2022

Abstract
Local treatment of asthma and COPD by inhaled therapies has been standard of care for decades. A similar approach for lung cancer treatment could bring many benefits to the patient, including ease of administration, non-invasiveness, and potential for reduced side effects. Spray drying is a versatile, scalable manufacturing technique used to engineer therapies for delivery to the lung by dry powder inhaler. It is applicable to nearly all classes of molecules, including RNA, small molecules and proteins. Spray dried inhalation powders eliminate the need for cold chain storage, and can improve product shelf life compared with liquid formulations, improving access for developing nations and rural populations. Recently, inhaled delivery for a VEGF inhibitor, bevacizumab, has shown in preclinical studies to reduce tumor burden in rats at 1/10th the dose of injected bevacizumab, when combined with chemotherapy. To enable the next generation of inhaled monoclonal antibody (mAb) therapies by spray drying, mAb structural integrity is key. Spray dried materials undergo thermal and shear stresses, which can damage delicate mAbs. Herein we identified a set of analytical tests to evaluate the upper limits of heat and shear mAbs can withstand during spray drying. We exposed five cancer-relevant, FDA-approved mAbs to varying heat and shear stress then characterized changes to primary (1°), secondary (2°), and tertiary (3°) structure and binding activity indicative of degradation. Using the following analytical techniques we detected graduations of degradation: capillary electrophoresis-isoelectric focusing (1°), Fourier transform infrared spectroscopy (2°), Raman spectroscopy (2°), size exclusion chromatography (3°), absorbance and fluorescence spectroscopy (3°), dynamic light scattering (3°), multi-cell differential scanning calorimetry (3°), SDS-PAGE (3°), and binding activity ELISAs. Using these techniques, we developed a materials-sparing protocol to first assess whether an antibody is a candidate for spray drying, and second, to identify ideal process conditions for mAb spraying drying success. This approach will help to accelerate the development of inhaled protein therapies for lung cancer and other lung diseases.
Citation Format: Madeleine Landry, Amanda Pluntze, Kimberly Shepard. Local treatment of lung cancer by inhaled monoclonal antibodies: A pre-feasibility screening approach for spray drying [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1736.
Abstract 1743: Identification of mesothelin binding peptide for targeted therapy against pancreatic cancer
Authors: Park Min-Sung , Lee Byungheon 
Published: June 2022

Abstract
Pancreatic cancer is the main cause of cancer-related deaths worldwide and is difficult to diagnose before the extensive local invasion and distant organ metastasis. Mesothelin is abnormally overexpressed in tumors such as ovary cancer and pancreatic cancer. Studies show a significant link between mesothelin overexpression and short survival in patients with pancreatic cancer. In this study, we screened a phage displayed-peptide library for peptides that selectively bind to mesothelin using mesothelin-overexpressing cells. After five rounds of screening, we selected a 9-mer peptide (named MSLN-Pep) that preferentially bound to mesothelin-high pancreatic cancer cells such as ASPC-1 and Panc-1 cells over mesothelin-low cells such as HEK 293 cells. MSLN-Pep was efficiently internalized into ASPC-1 cells and inhibited the cell migration and invasion while little affected the phosphorylation of Akt. Moreover, a MSLN-Pep-guided proapoptotic peptide (MSLN-Pep-KLA) exerted selective cytotoxicity against pancreatic cancer cells over mesothelin-low cells. MSLN-Pep-KLA when combined with gemcitabine, a chemotherapeutic agent against pancreatic cancer, sensitized ASPC-1 cells to the gemcitabine treatment. These results suggest that MSLN-Pep is a promising tool for a targeted therapy against pancreatic cancer expressing mesothelin at high levels.
Citation Format: Min-Sung Park, Byungheon Lee. Identification of mesothelin binding peptide for targeted therapy against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1743.
Abstract 1745: Exploiting vulnerabilities to nanoparticle induced lipid peroxidation and proteotoxicity to treat drug resistant lung cancer
Authors: Snyder Christina , Rohde Monica , Singh Ravi N. 
Published: June 2022

Abstract
Protein quality control plays an essential role in cell survival. Clinically translated strategies to target protein quality control in cancer show some efficacy, but off-target effects are severe. We are investigating a new approach using nanomaterials to induce lipid peroxidation to trigger a cascade of protein oxidation, protein misfolding, and decreased protein degradative capacity in cancer cells without affecting normal cells. Our studies show that silver nanoparticles (AgNPs) cause dramatic increases in lipid peroxidation, 4-hydroxynonenal adducts (4-HNE), protein oxidation, protein aggregation, and proteotoxic stress signaling in a mesenchymal-like subset of non-small cell lung (NSCLC) and other cancers at doses that do not affect normal cells in vitro or vivo. Notably, AgNP sensitive NSCLCs are inherently resistant to clinically relevant therapies including epidermal growth factor receptor tyrosine kinase inhibitors ((EGFR-TKIs) e.g. erlotinib, gefitinib, olfatinib) and cisplatin. We identified two defining characteristics causing some cancers to be sensitive to AgNPs. The first is enrichment of cell membranes in polyunsaturated fatty acids (PUFAs), especially arachidonic (AA) and adrenic acid (AdA), which are prone to oxidation. The second is high-level synthesis and secretion of extracellular matrix (ECM), especially fibronectin and collagen, which places AgNP sensitive cancers under substantial baseline endoplasmic reticulum stress, making them susceptible to agents that increase proteotoxicity. Mechanistically, we find that in PUFA-enriched cancers, signaling from ECM sustains the AgNP sensitive phenotype by stimulating Akt activity and stabilizing cytoplasmic β-catenin. Transcriptionally active β-catenin increases expression of fibronectin and collagen, resulting in a positive feedback loop locking cells into the AgNP sensitive phenotype. Use of AgNPs to targeting vulnerabilities associated with ECM synthesis and signaling downstream of β-catenin is a novel approach to overcoming multiple EGFR-TKI resistance mechanisms. Ultimately, our goal is to elucidate the precise mechanism by which AgNPs overcome resistance to clinically available EGFR-TKIs. Identification of the specific drivers of sensitivity to AgNPs (and potentially other metal nanoparticles) will guide development of therapeutic metal nanoparticles, enable selection of cancer patients who will benefit most or are at greatest risk to nanomaterial exposure, and will spur innovation of other treatments that exploit the vulnerabilities we identify.
Citation Format: Christina Snyder, Monica Rohde, Ravi N. Singh. Exploiting vulnerabilities to nanoparticle induced lipid peroxidation and proteotoxicity to treat drug resistant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1745.