bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2032: Osteoblasts alter their protein expression profile in the presence of prostate cancer cells to facilitate their invasion
Authors: Todman Aaron J. , Ratnayake Wishrawana S. , Lajmi Luke , Breedy Sloan , Shourav Abiral H. , Bisht Kirpal , Acevedo-Duncan Mildred 
Published: March 2024

Abstract
Bone metastasis is the leading cause of death in prostate cancer patients, for which there is currently no effective treatment. Since the bone microenvironment plays an important role in this process, attention has been directed to the interactions between cancer cells and the bone microenvironment, including osteoblasts. Here, we investigated the mechanism of interactions between prostate cancer cells (DU-145 and PC-3) and osteoblast cell line hFOB.1.19. We are investigating the broader effects of four different nucleoside reverse transcriptase inhibitor (NRTI) analogs 5-fluoro-1-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (KBMD-E), 3-benzoyl-5-fluoro-1-((1S,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (KBMD-G), 1-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (KBMD-H) and 1-(5-hydroxymethyl)-2,5-dihydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (KBMD-S) along with aPKC specific inhibitors ICA-1S and ζ-Stat to develop as potential anti-cancer drugs. Our previous publications suggested that aPKC-ι and ζ are involved in prostate cancer progression and metastasis. Current data suggested that aPKC specific inhibitors along with KBMD compounds induced apoptosis and pyroptosis of DU-145 and PC-3 while having lesser effects on hFOB.1.19 cell line. Our data demonstrate that osteoblasts assist prostate cells to establish in the bone microenvironment by producing metastatic stimulating chemokines while upregulating responsible transcription factors such as c-Jun. In addition, our preliminary data suggested that PKC-ι and ζ are crucial for driving critical steps of the metastatic cascades of prostate cancer cells. Preliminary data suggested that all 6 compounds upregulated interleukin (IL)-18 and IL-1β while downregulating IL-8, IL-6 and CXCL-1. Upregulation of Caspase 8 with cleaved gasdermin D in prostate cells indicates an increase in pyroptosis. Our preliminary results suggest that all 6 compounds can be used to disrupt the main steps of prostate cancer bone metastasis which can be targeted to develop customized, tailored therapies for bone metastatic prostate cancer which merit further research.
Citation Format: Aaron J. Todman, Wishrawana S. Ratnayake, Luke Lajmi, Sloan Breedy, Abiral H. Shourav, Kirpal Bisht, Mildred Acevedo-Duncan. Osteoblasts alter their protein expression profile in the presence of prostate cancer cells to facilitate their invasion [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 2032.
Abstract 2038: Combination therapy leads to decreased viability in cardiomyblasts cells
Authors: Greenlee Ashley N. , Schwendeman Ethan J. , Smith Sakima A. 
Published: March 2024

Abstract
Anti-cancer therapies (ACT) have been extremely effective in improving survival in cancer patients; however, they have also been known to cause cardiovascular diseases (CVD) in the same patients. Published research shows that ACTs are toxic to cardiomyocytes through decreased viability. However, they have mainly focused on drugs that are phasing out of clinical practice while newly generated tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have rarely been studied, despite their increase in popularity for treating multiple cancers as monotherapies and combination therapies. Additionally, most of the concentrations tested tend to be higher than the concentration that directly interacts with cardiomyocytes, therefore overestimating its effects. The goal of this project is to elucidate whether newly generated TKIs and ICIs, both by itself and in combination, lead to decreased viability in cells. We tested three TKIs (Axitinib, Cabozantinib, and Lenvatinib) and two ICIs (Nivolumab and Pembrolizumab), both solely and together, on rat ventricular myoblasts (H9c2) cells using clinically relevant concentrations by calculating the unbound serum drug concentrations found in cancer patients. After 24 hours, we tested cell viability using the cell counting kit-8 (CCK-8) assay. After 24 hours, neither TKIs nor ICIs by themselves caused decreased viability compared to the control group. However, there were significant decreases in viability when treated with combination of the two, with more than 50% depletion in the Lenvatinib/Pembrolizumab group. Our study indicates although TKIs and ICIs by themselves do not effect viability, they have significant effects after 24 hours when the drugs are combined, even at clinically relevant concentrations. We plan to further characterize whether these drug combinations lead to cardiomyocyte death and through which pathway. Additionally, our lab has successfully differentiated and validated human-induced pluripotent ventricular myocytes (hiPSC-CMs) and testing whether these monotherapies and combination therapies effect viability and functionality on human-induced pluripotent ventricular myocytes (hiPSC-CMs) is currently in progress.
Citation Format: Ashley N. Greenlee, Ethan J. Schwendeman, Sakima A. Smith. Combination therapy leads to decreased viability in cardiomyblasts cells [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 2038.
Abstract 206: Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity
Authors: Visal Tanvi 
Published: March 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 207: Tumor suppressive role of NKX2-1 in advanced thyroid cancer progression
Authors: Shirai Yo-Taro , Kimura Shioko 
Published: March 2024

Abstract
NKX2-1 is a homeodomain transcription factor, known as a master regulator of thyroid development. NKX2-1 is also crucial for lung epithelium differentiation, and the involvement of NKX2-1 in lung carcinogenesis and cancer progression has been intensely investigated. However, the role of NKX2-1 in thyroid cancer progression remains elusive. The Cancer Genome Atlas (TCGA) dataset analysis demonstrated that papillary thyroid cancer (PTC) patients with low NKX2-1 mRNA expression had significantly poorer prognosis than those with a combination of intermediate and high mRNA expression of NKX2-1. Lentivirus-transduced tetracycline (Tet)-inducible system was used to achieve NKX2-1 overexpression in advanced follicular thyroid cancer (FTC) cell lines, FTC-238 and WRO, and an anaplastic thyroid cancer (ATC) cell line 8305C, in which NKX2-1 expression is barely/not detected. All these thyroid cancer cell lines showed significant suppression of cell proliferation with NKX2-1 overexpression. In addition, NKX2-1 overexpression inhibited migration of FTC-238 cells. The levels of mRNA and protein expression of mesenchymal markers, matrix metalloproteinase-2 (MMP-2) and fibronectin, were decreased by NKX2-1 overexpression in FTC-238 cells, suggesting a possibility that NKX2-1 partially inhibits epithelial-mesenchymal transition (EMT). SNAIL and SLUG are essential EMT transcription factors involved in metastasis in cancer progression. NKX2-1 mRNA expression was significantly lower in high SNAI1 (encoding SNAIL) expressing PTC in TCGA database. Indeed, suppression of SNAIL protein expression was found upon overexpression of NKX2-1 in FTC-238 cells which naturally express high level of SNAIL. These findings suggest that NKX2-1 may inhibit the migration of advanced thyroid cancer cells through SNAIL-induced EMT. Similarly, suppression of SLUG protein expression by overexpression of NKX2-1 was observed in WRO and 8305C cells which express high level of SLUG protein. Whether NKX2-1 overexpression inhibits migration and invasion of WRO and 8305C cells through SLUG-induced EMT is currently under examination. The Tet-inducible NKX2-1 expressing thyroid cancer cells will be used for in vivo evaluation of their metastatic ability using an immunocompromised mouse model. The findings so far suggest that NKX2-1 exerts a tumor suppressive activity in advanced thyroid cancers through suppression of cell proliferation, and cell migration presumably via suppression of EMT transcription factors.
Citation Format: Yo-Taro Shirai, Shioko Kimura. Tumor suppressive role of NKX2-1 in advanced thyroid cancer progression [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 207.
Abstract 2095: Peptide-based pivoting of p53 to target metastatic breast cancer
Authors: Putavet Diana , Baar Marjolein P. , Lehmann Johannes H. , Khalil Antoine , Shi Tao , Koorman Thijs , Dansen Tobias B. , Derksen Patrick WB , Teifel Michael , Madl Tobias , Sarlis Nicholas 
Published: March 2024

Abstract
The inability to target distant metastases limits the treatment of late-stage cancers. At least in part, this is due to the lack of optimal targeted therapies and treatment resistance to the remaining standard of care consisting of chemo-/radio- therapy. Here, we show that cancer cells that are irreparably damaged can withstand cell death through a process we define as “scarring”. In scarred cells, p53 is phosphorylated at Ser46 and Ser392 and localizes into progressive multifocal leukemia (PML) nuclear bodies. We have identified scarring in over a quarter of metastatic breast, colon, stomach and ovarian cancer. Thus, pivoting scarred p53 towards cell death in scarred cancer could establish a novel broad-range therapeutic opportunity against metastatic cancer. Targeting p53 with small molecules has proven challenging. We developed cell-penetrating peptides that selectively bind scarred p53. One of our lead compounds, CL04177 dissociates p53 from its PML scaffold leading to its a nuclear exclusion and initiation of the transcription-independent mitochondrial apoptosis. To examine the role of scarring as a therapeutic target, we focused on triple-negative breast cancer (TNBC). TNBC cells are marked by the expression of p53 and PML compared to other breast cancer subtypes. In cytotoxicity experiments, CL04177 specifically targeted TNBC over other breast cancer subtypes. Further investigation into how this compound can target metastatic cells revealed that scarred features are upregulated in metastasis-initiating cells of organoids when induced to invade in contact with collagen and that CL04177 can induce apoptosis specifically in these invading strands. In vivo, CL04177 showed favorable pharmacokinetics and -dynamics and a clear safety profile. Importantly, when dosed at 10-fold below its Maximally Tolerated Dose, CL04177 strongly reduced primary tumor mass and metastatic dissemination to the liver of TNBC cell line-derived orthotopic xenografts. This data indicates a new concept of scarred p53 in cancer progression and metastasis. Moreover, peptides that release scarring markers from nuclear structures can eliminate aggressive cancers in vitro and, most importantly, in vivo, e.g., in p53-mutated, metastatic TNBC. This ability introduces a conceptually new therapeutic option, especially for types of cancer for which there is a high unmet medical need.
Citation Format: Diana Putavet, Marjolein P. Baar, Johannes H. Lehmann, Antoine Khalil, Tao Shi, Thijs Koorman, Tobias B. Dansen, Patrick WB Derksen, Michael Teifel, Tobias Madl, Nicholas Sarlis. Peptide-based pivoting of p53 to target metastatic 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 2095.
Abstract 2101: Patient-derived cells (PDCs) and organoids (PDOs) as critical platforms for developing next therapeutic strategies for NSCLC
Authors: Park Sewon , Joo Yunjoo , Lee Ju-hyeon , Yun Mi Ran , Yu Mi Ra , Oh Seung Yeon , Lee Eun Ji , Kim Dong Kwon , Lee Seul , Lim Kyumin , Hong Min Hee , Lim Sun Min , Lee Jii Bum , Cho Byoung Chul 
Published: March 2024

Abstract
Purpose: Patient-derived cells (PDCs) and organoids (PDOs) are constructed from pleural effusions to mimic the biological features of patients. In cancer research, PDC/PDOs could be a critical tool because they can recapitulate tumor mutations. Since commercial cell lines have difficulty mimicking the heterogeneity of tumors, PDC/PDOs are widely used for predicting the preclinical drug efficacy. The aim of this study is to show that the PDC/PDOs can be used as effective tools for developing new therapeutic strategy on non-small cell lung cancer (NSCLC).
Experimental design: PDC/PDO models from malignant effusions were established as following. We succeeded the establishment with samples which are positive for malignancy in cytology tests and tumor colony formation. Mutations that cell harbors are confirmed by Sanger sequencing, Whole exome sequencing, or RNA-sequencing. Following the patient treatment history, we confirmed how does established patient derived model response to drugs that patient was treated.
Results: A total of 54 PDCs and 171 PDOs were established from NSCLC patients, including models harboring EGFR mutations, KRAS mutations, uncommon EGFR mutations. 8 models of PDC and 7 models of PDO harbor various mutations of resistance mechanisms to EGFR-TKIs (T790M, C797S/C797G, MET amplification). Also, 4 models of PDC and PDO harbor uncommon EGFR mutations (EGFR G719S, L861Q, G719C/S768I, G719S/S768I) and 12 models of PDO harbors KRAS mutation.
YUO-139 and YU-1092 are patient derived models that harbors uncommon EGFR mutation G719S and L861Q respectively. The models response to afatinib sensitively. IC50 of YUO-139 and YU-1092 to afatinib were 2.1 nM and 23.8 nM respectively. YUO-143 is a PDO model that harbors EGFR E19del/T790M/C797S which was derived from gefitinib and mavelertinib resistant patient revealed sensitivity to BLU-945 (IC50, 43 nM), a novel fourth-generation EGFR-TKI.
Conclusions: Patient derived models could be a critical tool for developing therapeutic strategies for NSCLC.
Citation Format: Sewon Park, Yunjoo Joo, Ju-hyeon Lee, Mi Ran Yun, Mi Ra Yu, Seung Yeon Oh, Eun Ji Lee, Dong Kwon Kim, Seul Lee, Kyumin Lim, Min Hee Hong, Sun Min Lim, Jii Bum Lee, Byoung Chul Cho. Patient-derived cells (PDCs) and organoids (PDOs) as critical platforms for developing next therapeutic strategies for NSCLC [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 2101.
Abstract 2126: Efficacy and underlying mechanisms of surufatinib in non-small cell lung cancer treatment
Authors: Zheng Yanfang , Shan Binjie , Wang Meng , Wu Xiaoran , Cai Rui , Niu Feiyu , Yuan Yan , Liu Lu , Zhu Xiongjie 
Published: March 2024

Abstract
Background: The prevalence and fatality of lung cancer, especially non-small cell lung cancer (NSCLC), highlight the urgency for efficacious therapies. Surufatinib, an inhibitor of tyrosine kinases like VEGF receptors (VEGFR) 1, 2, and 3, Fibroblast growth factor receptor 1 (FGFR1), and CSF-1R, shows potential in augmenting chemotherapy efficacy and reducing adverse effects. Preliminary clinical studies (NCT04922658) have indicated survival benefits for NSCLC patients treated with surufatinib. This investigation seeks to delineate the therapeutic efficacy of surufatinib, correlating clinical benefits with mechanistic insights.
Methods: To elucidate mechanisms, proliferation assays (CCK8), migration (scratch assay), and apoptosis (flow cytometry) were conducted in A549 and H1299 cell lines. Angiogenesis and macrophage polarization were examined via vascular junction points and mRNA expression profiling. In nude mice, subcutaneous tumors were induced and treated with the study drugs, with tumor growth and angiogenic markers assessed.
Results: In vitro, surufatinib potently inhibited angiogenesis and exerted a dose-dependent suppression of proliferation and colony formation in lung cancer A549 and PC9 cell lines. It also enhanced apoptosis and cell migration. Additionally, surufatinib shifted macrophage polarization towards an M1 phenotype while diminishing M2 macrophages, thereby, contributing to a more robust anti-tumor immune milieu. In vivo studies corroborated these findings, with surufatinib and vinorelbine combination therapy significantly curtailing tumor growth and reducing CD31 expression in tumor tissues, highlighting its potential for substantial therapeutic gains in NSCLC management.
Conclusion: Surufatinib achieved notable antitumor effect consistent with clinical findings in NSCLC, effectively inhibiting cellular proliferation and migration, attenuating angiogenesis, and enhancing apoptosis. Significantly, it also modulated macrophage polarization to favor an M1/M2 balance, thus activating the immune response. Therapeutic strategies with surufatinib have underscored augmented antineoplastic efficacy, meriting additional clinical investigations.
Citation Format: Yanfang Zheng, Binjie Shan, Meng Wang, Xiaoran Wu, Rui Cai, Feiyu Niu, Yan Yuan, Lu Liu, Xiongjie Zhu. Efficacy and underlying mechanisms of surufatinib in non-small cell lung cancer treatment [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 2126.
Abstract 2127: Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming
Authors: Wang Ningyu , Ma Hong , Mei Xiangping , Huang Ai , Xiao Yong , Yao Jing 
Published: March 2024

Abstract
Background: Biliary tract cancer (BTC) is notorious for its unfavorable clinical outcomes. Radiotherapy (RT) is a crucial component in BTC treatment. This study explores the radiosensitizing potential and mechanisms of Surufatinib (SF), an oral tyrosine kinase inhibitor, distinguished by its anti-angiogenic and immunomodulatory effects.
Methods: In a NOZ mouse xenograft model, tumor growth and expressions of Ki-67, CD31 were analyzed. NOZ and TFK1 BTC cells treated with SF and/or RT underwent assessments for viability, cycle, and apoptosis using CCK8, colony formation, and flow cytometry. Macrophage polarization in SF/RT-treated tumor cell-macrophage co-cultures was studied using Elisa, qRT-PCR, and flow cytometry.
Results: In vivo, SF impeded angiogenesis and bolsters the anti-tumor effect of radiotherapy. SF combined with RT significantly reduced subcutaneous tumor growth in nude mice, and diminished Ki-67 and CD31 expressions. In vitro, SF heightened cholangiocarcinoma cells' radio-sensitivity, causing DNA double-strand breaks and apoptosis. SF and radiotherapy combined notably increased γ-H2A expression and apoptosis levels (P&lt;0.05). SF induced inflammatory response changes, favoring M2 to M1 macrophage polarization. In a tumor cell-macrophage co-culture, the SF-radiotherapy group showed increased IL-6 and decreased TGF-β (P&lt;0.05), with upregulated M1 markers (IL-6, CXCL10) and downregulated M2 markers (TGF-β, CCL22, Arg-1) in macrophages (P&lt;0.05). Both in vivo and in vitro, SF significantly reduced CD206+ M2-type macrophages (P&lt;0.05).
Conclusion: Surufatinib alters the immune microenvironment in cholangiocarcinoma, reversing the immunosuppressive macrophage polarization induced by radiotherapy and reprogramming M2-type macrophages into M1-type, thereby enhancing the radiosensitivity of cholangiocarcinoma.
Citation Format: Ningyu Wang, Hong Ma, Xiangping Mei, Ai Huang, Yong Xiao, Jing Yao. Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming [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 2127.