bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2370: Tumor suppression potential of tRNA modification enzyme TruBs via let-7
Authors: Kurimoto Ryota , Tsutsumi Hiroki , Ikeuchi Saki , Asahara Hiroshi 
Published: July 2021

Abstract
MicroRNA (miRNAs) let-7 is firstly discovered and widely involved in various tumors. Let-7 suppresses mRNAs of many oncogenes, such as KRAS and MYC. This, let-7 is strongly and selectively regulated by Lin28A/B. The let-7-Lin28A/B relationship could explain the pathogenesis of many tumors. However, the control mechanism of let-7, which cannot be explained by Lin28A/B alone, is reported. Furthermore, the regulatory mechanism of microRNAs by RNA-binding proteins such as Lin28 remains unclear. We have reported that TruB1, one of the tRNA modifying enzymes, specifically regulates let-7 by whole RNA binding protein screen (Kurimoto et al., EMBO J (2020)39:e104708). In this study, we evaluated in detail the effect of this TruB1-let-7 axis on the tumor phenotype. In addition to TruB1, another tRNA modifying enzyme TruB2 and other candidate RNA binding proteins were evaluated for its let-7 regulatory mechanism and tumor suppressive potential. We evaluated the effects of these candidates on cell proliferation and stemness in MTT assay, sphere formation assay and Xenograft model with knock down (KD) or over expression (in A549, HeLa or THP-1 cells). To elucidate that the phenotype was associated with let-7, we also use RNAi for let-7 families. We also checked the let-7-candidate proteins binding by RIP and eCLIP (enhanced version of the crosslinking and immunoprecipitation) analysis. Clinical effectiveness was assessed by public database (GEO and TCGA). In results, overexpression of TruB1 and other several genes suppressed the tumor growth and sphere formation ability in vitro with let-7 elevation. Interestingly, these suppressions were also seen in TruB enzymatic null mutants in TruBs (as we have reported in recently (Kurimoto et al., EMBO J (2020)39:e104708)). However, only TruB1 KD and one other candidate (gene A) KD showed the tendency to increase the tumor growth in vitro or in Xenograft model. The eCLIP and RIP analysis showed direct binding of TruB1 and gene A to let-7, but not TruB2 and others. In public database, only TruB1 and gene A strongly inversely correlated with several tumors. There was no relationship in TruB2 and tumor. These data introduced the novel players TruB1 and gene A to regulate the specific miRNA biogenesis and its impact on tumor phenotypes. Our data highlighted the potential of RNA binding protein independing on its known activity.
Citation Format: Ryota Kurimoto, Hiroki Tsutsumi, Saki Ikeuchi, Hiroshi Asahara. Tumor suppression potential of tRNA modification enzyme TruBs via let-7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2370.
Abstract 2371: MicroRNA-99b-5p targets the mTOR/AR axis and induced autophagic cell death in prostate cancer cells
Authors: Niture Suryakant , Tricoli Lucas , Hayes Kala , Kumar Deepak 
Published: July 2021

Abstract
MicroRNAs are the small non-coding regulatory RNA molecules involved in a wide array of cellular and molecular processes. MicroRNAs negatively regulate gene expression via base-pairing with complementary sequences within mRNA molecules. In cancer, the dysregulation of miRNAs expression is associated with cancer development or suppression through the regulation of key gene expression followed by modulation of multiple cell signaling pathways. In the present study, we investigated the role of microRNA-99b-5p (miR-99b) on prostate cancer (PCa) cell survival, cell migration, and apoptosis. Overexpression of miR-99b in PCa cells inhibited cell proliferation, cell colony-forming capability, spheroid formation, and induced cell apoptosis. On the contrary, inactivation of miR-99b by miR-99b inhibitor promotes PCa cell proliferation, cell colony-forming capability, and cell migration. Mechanistically, miR-99b binds with the 3'UTR region of the mammalian target of the rapamycin (mTOR) gene and controls the expression of mTOR. Our preliminary data also suggest that miR-99b also inhibits androgen receptor (AR) activity in LNCaP cells and induced cell apoptosis. Further by inhibition of mTOR, miR-99b induced autophagy in PCa cells and autophagic cell death. Expression of miR-99b and inactivation of mTOR by rapamycin increased the sensitivity of PCa cells to anti-PCa drug docetaxel (DTX). Collectively the data suggest that miR-99b functions as a tumor suppressor in PCa cells, and therefore, miR-99b may be considered as novel biomarkers and therapeutic targets for PCa management in PCa patients.
Citation Format: Suryakant Niture, Lucas Tricoli, Kala Hayes, Deepak Kumar. MicroRNA-99b-5p targets the mTOR/AR axis and induced autophagic cell death in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2371.
Abstract 2373: Expression of exosomal let-7g in biofluids and outcome in colon cancer patient treated with anti-EGFR therapy
Authors: Hahne Jens C. , Lampis Andrea , Ghidini Michele , Ratti Margherita , Senti Chiara , Passalacqua Rodolfo , Cascione Luciano , Braconi Chiara , Sansom Owen , Fassan Matteo , Valeri Nicola 
Published: July 2021

Abstract
Introduction: Monoclonal antibodies against the Epidermal Growth Factor Receptor (EGFR) such as cetuximab or panitumumab are used for the treatment of metastatic colorectal cancer (mCRC) patients. Unfortunately, most patients develop resistance against these therapies within months. Several studies have shown that aberrations in the RAS pathway are responsible for resistance. However, even in metastases that are refractory to anti-EGFR treatment a significant fraction of RAS wild-type (wt) cells remain. These findings suggest a cross-talk between RAS mutant and wt cells in mediating resistance in the wt compartment.
Methods: Mouse and patient-derived organoids from mCRC as well as CRC cell lines were used to test the contribution of extracellular vesicles in mediating resistance in RAS wt cells. Using conditioned media, transfection experiments and liquid biopsies (plasma and urine) from patients differential expression of the let-7g microRNA was demonstrated in microvesicles from cetuximab sensitive and resistant cells. Changes in expression of let-7g were further analyzed by in-situ hybridization in tissues.
Results: Conditioned media from RAS mutant organoids rendered RAS wt organoids resistant against cetuximab treatment. Basal let-7g expression from pre-treatment plasma and urine samples of RAS wt patients correlated with clinical outcome and changes in let-7g circulating levels mirrored clinical behavior. In-situ hybridization in tissues confirmed changes in expression of the let-7g microRNA observed in plasma and urine samples.
Conclusions: Our data suggest that let-7g microRNA might function as a paracrine mediator of anti-EGFR resistance and might be exploited as a non-invasive biomarker of resistance to cetuximab treatment. Further work is ongoing to characterize the molecular mechanisms underpinning let-7g mediated effect on anti-EGFR sensitivity in RAS wt CRC cells.
Citation Format: Jens C. Hahne, Andrea Lampis, Michele Ghidini, Margherita Ratti, Chiara Senti, Rodolfo Passalacqua, Luciano Cascione, Chiara Braconi, Owen Sansom, Matteo Fassan, Nicola Valeri. Expression of exosomal let-7g in biofluids and outcome in colon cancer patient treated with anti-EGFR therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2373.
Abstract 2378: Circulating microRNAs and cytokines as prognostic biomarkers for doxorubicin-induced cardiac injury and for evaluating the beneficial effects of exercise
Authors: Jeyabal Prince , Kleinerman Eugenie S. 
Published: July 2021

Abstract
Introduction: Cardiotoxicity and late cardiomyopathies compromise survival in &gt;50% of childhood cancer survivors treated doxorubicin (Dox). Early intervention is important for initiating therapy to preserve heart function. There are no accepted biomarkers identifying which patients are at risk for developing cardiac problems and no interventions to inhibit the cardiac damage. Troponin has not proved useful for predicting Dox-induced cardiotoxicity and patient outcome. We developed a pediatric mouse cardiotoxicity model to define early biomarkers of Dox-induced cardiac injury, investigate the efficacy of an exercise intervention, and whether these biomarkers can be used as a non-invasive method to monitor exercise effectiveness.
Hypothesis: Circulating micro-RNAs are increased during Dox but not Dox + exercise therapy which correlate with cardiac damage. These can be used to monitor intervention effectiveness.
Methods: Mice were treat with Dox (2.5mg/kg 2x/wk for 2 wks), Dox + exercise (walking 45 min/day at 12 meter/min) or PBS. Cardiac function was evaluated by echocardiography 24 hrs after therapy. Blood was collect before and 6 and 24 hrs after therapy. Plasma cytokine levels, troponin and miRNAs (miRNA 1, 29b, 499) were quantified. We also obtained plasma samples from Dox-treated osteosarcoma patients.
Results: Decreased ejection fraction and fractional shortening were seen in Dox but not Dox + exercise-treated mice. There was an increase in miR-1 and miR-499 and the pro-inflammatory cytokines IL-1α, IL-1β and IL-6, in Dox-treated but not Dox + exercise-treated mice compared with PBS controls. Troponin levels were not elevated until 24 hrs following therapy. Increased miRNAs and cytokines in the Dox-treated patient plasma samples 24 hrs after therapy mimicked the results observed in mice.
Conclusion: These data indicate that miRNA499, miRNA1, IL-1α, IL-1β and IL-6 are early biomarkers of Dox-induced cardiac injury which predict cardiac functional changes and can be used to evaluate intervention efficacy during combined therapy. Following these biomarkers may also assist in identifying patients at risk for cardiac late effects and also enable intervention modification as needed.
Citation Format: Prince Jeyabal, Eugenie S. Kleinerman. Circulating microRNAs and cytokines as prognostic biomarkers for doxorubicin-induced cardiac injury and for evaluating the beneficial effects of exercise [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2378.
Abstract 2380: MiR29b may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells
Authors: Kimura Yuki , Ohzawa Hideyuki , Kaneko Yuki , Futoh Yurie , Tamura Kohei , Takahashi Kazuya , Saito Akira , Tojo Mineyuki , Kumagai Yuko , Miyato Hideyo , Sata Naohiro , Kitayama Joji 
Published: July 2021

Abstract
Background: Mesothelial cells play tumor-promoting roles in the development of peritoneal metastasis (PM) through mesothelial-mesenchymal transition (MMT). MiR-29 family is well known as tumor suppressor.
Methods: MiR-29b mimics and negative control miRNA were transfected by lipofection method. Proliferation and migration of human gastric cancer cell lines, MKN45 and NUGC-4, were examined with MTT assay and transwell assay, respectively. MMT of human peritoneal mesothelial cells (HPMCs) was induced 10 ng/ml of TGF-β. Proliferation and migration of HPMCs were examined with the same methods, and MMT was evaluated with immunofluorescence staining for epithelial, mesothelial and mesenchymal markers. To evaluate the effect of miR-29b in vivo, we developed a highly metastatic subclone YTN16P2 from a murine gastric cancer cell line, YTN16, with in vivo selection, and inoculated the YTN16P2 in peritoneal cavity of syngenic C57BL/6 mice. MiR-29b mimics or negative control miRNA with atelocollagen were intraperitoneally (ip) injected every 3 days from tumor implantation. The mice were sacrificed at 14 days after tumor implantation, and formation of peritoneal metastasis were evaluated.
Results: Transfection of miR-29b mimics significantly decreased the proliferation of MKN45 and NUGC-4 by 20-60% (p&lt;0.01) as compared with negative control miRNA. Migration was inhibited more strongly by 90% (p&lt;0.001). After 48 hr-culture with TGF-β, HPMCs apparently changed the morphology from round to spindle shape. The expression level of E-cadherin and Calretinin in HPMCs was decreased while vimentin tended to be upregulated by TGF-β. However, transfection of miR-29b mimics significantly suppressed the morphological changes and reduced the expression levels of vimentin with restored expression of E-cadherin and Calretinin, suggesting the inhibition of MMT in HPMCs. MiR-29b also decreased the proliferation and migration of HPMCs by 20% (p&lt;0.05) and 90% (p&lt;0.001) as compared with negative control miRNA. Finally, mice treated with miR-29b developed less PM nodules than those treaded with negative control miRNA and only atelocollagen.
Conclusion: MiR-29b efficiently suppresses MMT. Replacement of the miR-29b in peritoneal cavity might be used for the treatment of PM partially via the effects on mesothelial cell.
Citation Format: Yuki Kimura, Hideyuki Ohzawa, Yuki Kaneko, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Yuko Kumagai, Hideyo Miyato, Naohiro Sata, Joji Kitayama. MiR29b may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2380.
Abstract 2398: Disruption of mitochondrial metabolism by ClpP activation in triple negative breast cancer
Authors: Fennell Emily M. , Aponte-Collazo Lucas J. , Rushing Blake R. , Li Yuan-Yuan , Pathmasiri Wimal , Wynn Joshua D. , Graves Paul R. , Holmuhamedov Ekhson L. , Herring Laura E. , Iwanowicz Edwin J. , Graves Lee M. 
Published: July 2021

Abstract
ONC201 is a novel anticancer compound currently in over 20 clinical trials for multiple different cancers, including triple negative breast cancer (TNBC). We recently demonstrated that ONC201 and the more potent TR compounds selectively activate the mitochondrial protease ClpP. While previous studies demonstrated substantial effects on mitochondrial metabolism, the consequences of ClpP activation on cancer cell metabolism are yet to be defined. To investigate this, we performed an unbiased metabolomics and proteomics analysis comparing the effects of ONC201 and TR-57 on the TNBC metabolome and proteome. Consistent with these compounds targeting the mitochondria, our studies identified multiple mitochondrial metabolites and enzymes that were impacted by ClpP activation, such as TCA cycle intermediates and enzymes, heat shock proteins and mitochondrial ribosomal proteins. In addition to previously reported elements of the integrated stress response (ATF4, CHOP), we identified several proteins that were upregulated as part of the mitochondrial-nuclear signaling process. qRT-PCR was used to determine the impact of ONC201 or TR-57 treatment on transcript levels of proteomic hits. Importantly, the effects of ONC201 and the TR compounds on these proteins and cell growth were abolished in ClpP null cells. In summary, our studies further demonstrate that loss of metabolic function in mitochondria contributes to the anticancer activity of these ClpP activator compounds.
Citation Format: Emily M. Fennell, Lucas J. Aponte-Collazo, Blake R. Rushing, Yuan-Yuan Li, Wimal Pathmasiri, Joshua D. Wynn, Paul R. Graves, Ekhson L. Holmuhamedov, Laura E. Herring, Edwin J. Iwanowicz, Lee M. Graves. Disruption of mitochondrial metabolism by ClpP activation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2398.
Abstract 2423: Discovery of ZN-e4, an irreversible EGFR-TKI with potent anti-tumor activity in EGFR mutant non-small-cell lung cancer
Authors: Li Jiali , Abraham Sunny , Ma Jianhui , Huang Peter Q. , Bunker Kevin D. , Doñate Fernando , Samatar Ahmed A. 
Published: July 2021

Abstract
Small molecule tyrosine kinase inhibitors against the epidermal growth factor (EGFR) have made significant impact in the treatment of advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Although the first and second-generation EGFR inhibitors have remarkably improved survival in advanced EGFR mutant NSCLC patients, most of the patients develop acquired resistance. The gatekeeper mutation (T790M) is the most common acquired resistance mechanism to the first and second-generation EGFR inhibitors. To overcome the T790M acquired resistance, third-generation EGFR inhibitors, such as osimertinib, were developed. However, additional mutant selective EGFR inhibitors with improved toxicity profile are still needed as osimertinib treatment produced incidence of adverse events, such as diarrhea and skin rush. Here, we describe the identification and characterization of ZN-e4, an orally bioavailable, selective, irreversible third generation EGFR inhibitor. ZN-e4 selectively inhibited the kinase activity of several mutated forms of EGFR, including L858R, T790M/L858R, and Exon19 del in biochemical assay. In cell-based assays, ZN-e4 demonstrated a 20-40-fold selectivity ratio for mutant EGFR forms over the wild-type form thus minimizing the potential for on target toxicity. ZN-e4 potently inhibited the proliferation of NSCLC cell lines harboring EGFR activating and T790M mutation and induced tumor regression in small and large tumors with activating EGFR mutations in preclinical human NSCLC xenograft models. Taken together, our data suggest that ZN-e4 is a potent and selective third generation EGFR inhibitor. Currently, ZN-e4 is in a Phase I clinical trial in patients with EGFR mutant NSCLC showing clinical activity and encouraging toxicity profile.
Citation Format: Jiali Li, Sunny Abraham, Jianhui Ma, Peter Q. Huang, Kevin D. Bunker, Fernando Doñate, Ahmed A. Samatar. Discovery of ZN-e4, an irreversible EGFR-TKI with potent anti-tumor activity in EGFR mutant non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2423.
Abstract 2451: A novel single domain antibody targeting TIGIT for cancer use in combination therapies
Authors: Hua Botong , Yang Ming , Xue Jie , Dong Chen , Mao Yi-Ting , Li Ou , Cheung Eric , Issafras Hassan , Xu Wenfeng , Jiang Weidong 
Published: July 2021

Abstract
T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as another popular checkpoint receptor that negatively regulates T-cell functions. TIGIT is upregulated by immune cells, such as activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment. Beyond CTLA4 and PD1, TIGIT therapies recently demonstrated great combo potential in the clinic along with well-tolerated toxicity profile. Here we present HLX53, a novel single domain antibody (sdAb) targeting TIGIT with differentiated format, binding epitope, and functional activity. HLX53 binds to TIGIT and blocks CD155 and CD112 with sub-nanomolar affinity. In mixed lymphocyte reaction assay (MLR), HLX53 significantly increased IL2 secretion compared to Tiragolumab and Vibostolimab analogues. HLX53's IL2 induction seems to require an adequate bridging effect between T-cell and antigen-presenting cell via Fc-FcγR engagement, further promoting the maturation of antigen-specific T-cell. In vivo, HLX53 exhibits a better tumor inhibition than Tiragolumab analogue and shows synergy in combination with anti-PD-L1 antibody in MC38 model. In addition to its unique epitope/MOA, HLX53 being a sdAb has a shorter half-life and thus potentially a better tumor penetration and a differentiated PK/PD profile. Understanding pharmacokinetic and pharmacodynamic relationships enables a dosing regimen providing adequate target coverage and superior tumor eradication.
Citation Format: Botong Hua, Ming Yang, Jie Xue, Chen Dong, Yi-Ting Mao, Ou Li, Eric Cheung, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A novel single domain antibody targeting TIGIT for cancer use in combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2451.
Abstract 2462: A combination of IL7Rα and NRAS mutations up-regulates Bcl-2 and cMyc levels leading to formation of T-cell acute lymphoblastic leukemia
Authors: Winer Hila , Rodrigues Gisele , Li Wenqing , Hixon Julie , Durum Scott K. 
Published: July 2021

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia derived from T-cell precursors. With current treatments, survival rate is high, but the treatments are highly toxic with severe side effects. In addition, relapse is relatively common in T-ALL and is exceptionally difficult to salvage with hematopoietic stem cell transplant which is essentially the only treatment. Thus, a better understanding of T-ALL etiology and subtypes is required to develop the warranted improved therapies. Individual mutations in IL7Rα and RAS pathways have been previously shown to be prevalent in T-ALL and especially in relapsed patients. However, it is not fully understood how these mutations are involved in disease origin and progression. In addition, we have previously shown that mutations in either IL7Rα or NRAS alone are not sufficient to induce T-ALL. Nevertheless, a combination of both causes severe T-ALL in mice which can be ameliorated by IL7Rα and NRAS signaling inhibition. To better understand how this combination can be utilized to understand disease etiology, we have tested for combinations of mutations that resulted in varying expression levels of the mutated proteins. Our results revealed that a specific ratio between IL7Rα and NRAS expression is necessary to generate T-ALL in mice. Transplanting transduced lymphocyte progenitors into RAG-/- immune-deficient mice allowed us to find an optimal order of the two oncogenes in a polycistronic vector that leads to severe T-ALL. A comparison of transplants from several arrangements of oncogenes in the vector enabled us to screen for potential regulatory pathways that are important for disease progression in vivo by analyzing the cancer cells' transcriptome and proteome. We found that the disease is characterized by a significant increase in IL7Rα-mediated BCL-2 expression, and an increase in c-Myc protein levels, via NRAS signaling. Our results are confirmed by induction of a similar phenotype with a combination of overexpressed WT c-Myc and mutant IL7Rα, which caused severe leukemia as early as 16 days post-transplant. Taken together, we developed a robust model to study T-ALL in mice, shed light on novel pathways of oncogenesis and discovered new targets for intervention that could lead to better therapeutic development.
Citation Format: Hila Winer, Gisele Rodrigues, Wenqing Li, Julie Hixon, Scott K. Durum. A combination of IL7Rα and NRAS mutations up-regulates Bcl-2 and cMyc levels leading to formation of T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2462.