tbuckley/cabot-search huggingface dataset:
Abstract 2461: Targeting eIF4A3 as a multifunctional translation initiation factor for breast cancer therapy
Authors: Jun Ling, Allen Huang, Ai Ohno, Joe Chen, Maria Cavataio
Journal: Cancer Research (2020)

Abstract eIF4A3 is a unique eukaryotic translation initiation factor (eIF) with broad functions in the whole process of RNA metabolism, including mRNA splicing via exon junction complex (EJC), mRNA nuclear export, translation, and RNA surveillance through nonsense-mediated RNA decay (NMD). These post-transcriptional processes are highly involved in cancer development. However, the roles of eIF4A3 in cancers have not addressed. In this study, by analyzing a breast cancer patient database, we identified that the up-regulation of eIF4A3 is correlated with poor survival of triple negative breast cancer (TNBC) patients. Overexpression of eIF4A3, along with other EJC components (Magoh, Y14 and CASC3), were observed in multiple TNBC cell lines as compared to human normal cells and mouse normal tissues. Knockdown of eIF4A3 by RNAi was found to strongly inhibit TNBC cell proliferation in vitro; down-regulation of endogenous eIF4A3 also suppressed tumor growth in a mouse model. Dominant negative eIF4A3 and an ATP-binding defective mutants inhibited TNBC cell growth in the clonogenic assay. Furthermore, TNBC cells were found to be more sensitive to eIF4A3-specific inhibitors than luminal A and B subtypes of breast cancer cells. Thus, our study elucidates a strong cancer-promoting activity of eIF4A3 in breast cancer growth at cellular and animal model levels, warranting a new strategy to target eIF4A3 for breast cancer therapy, especially for TNBC as the most difficult subtype to treat. Citation Format: Jun Ling, Allen Huang, Ai Ohno, Joe Chen, Maria Cavataio. Targeting eIF4A3 as a multifunctional translation initiation factor for breast cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2461.
Abstract 1423: A lncRNA <i>MEG9</i> protects vasculature from DNA damage
Authors: Cristina Espinosa-Diez, Eugenia Fraile-Bethencourt, Clayton Hudson, Rebecca Ruhl, Sudarshan Anand
Journal: Cancer Research (2020)

Abstract DNA damaging agents including ionizing radiation (IR) therapy are widely used in cancer patients. Previous studies have suggested that the tumor vasculature, specifically endothelial cell (ECs) dictate responses to IR. We recently showed how IR, among other DNA damaging agents, induced changes in microRNA programs and impacted tumor angiogenesis. Here, we describe how different DNA damaging agents affect long noncoding RNA (lncRNA) programs in vascular cells. Specifically, we identify lncRNA MEG9 (Maternally Expressed Gene 9 in humans, Mirg in mouse) as one of the most differentially expressed lncRNAs in angiogenic stimuli and stress responses. MEG9 is robustly induced by DNA damaging agents and suppressed by vascular growth factors. MEG9 is located in the DLK1-DIO3 imprinted cluster. Previous studies have shown how DLK1-DIO3 genes are associated with stem cell biology and with the pathogenesis of several diseases, such as cancer. Other studies have shown that microRNAs in this cluster are regulated by methylation. Consistent with this observation, we found that inhibition of DNA methylation either via 5-azacytidine or silencing of DNMT3b significantly upregulated de novo expression of MEG9. Gain and loss of function assays indicated an anti-apoptotic role of MEG9 via caspase 3/7 pathways in cultured ECs. Similarly, MEG9 inhibition decreased angiogenesis in a 3D sprouting angiogenesis assay. Interestingly, MEG9 inhibition in ECs accelerated fibrin formation suggesting a regulatory role for this lncRNA in thrombosis. Moreover, we observed that MEG9 inhibition affects vascular permeability in vitro and in vivo in bFGF-Matrigel plugs. Finally, systemic delivery of RNAi targeting Mirg (mouse MEG9) decreased tumor burden in a mouse model of triple negative mammary carcinoma. Our mechanistic studies indicated that MEG9 in ECs impacts pathways related to inflammation and thrombosis, both critical mediators of tumor responses to radiation. Taken together, our results show MEG9 as a novel DNA damage induced lncRNA with a protective role in the tumor vasculature functioning via multiple distinct mechanisms. Therefore, we propose that disruption of lncRNA MEG9 is a potent anti-angiogenic strategy that can synergize with DNA damaging agents. Citation Format: Cristina Espinosa-Diez, Eugenia Fraile-Bethencourt, Clayton Hudson, Rebecca Ruhl, Sudarshan Anand. A lncRNA MEG9 protects vasculature from DNA damage [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1423.
Abstract 5140: The expression and function of LAP2 and its interaction with Chmp1A in pancreatic cancer
Authors: Maiyon Park
Journal: Cancer Research (2020)

Abstract Introduction: Chromatin modifying protein 1A (Chmp1A) suppresses pancreatic cancer growth by the activation of ATM and p53. To understand the mechanisms underlying the function of Chmp1A in pancreatic cancer, Chmp1A associated proteins were identified using proteomic analysis. Lamina-associated polypeptide 2 (LAP2) protein isoforms were found to interact with Chmp1A. LAP2 has been shown to interact with Retinoblastoma (Rb) tumor suppressor and shown to be up-regulated in most proliferating cancer cells. However, the function of LAP2 in pancreatic cancer has been poorly understood. In this study, we propose that LAP2 protein functions as tumor suppressor by interacting with Chmp1A in pancreatic cancer. Experimental procedures: LAP2 transcripts were determined by RT-PCR and LAP2 proteins by WB and microscopic analysis in pancreatic cancer cells compared to normal pancreatic cells. We then tested the function of LAP2 by examining the effect of its overexpression on cancer cell growth. We also tested the interaction between Chmp1A and LAP2 by examining LAP2 expression in Chmp1A overexpressing or silenced cells and vice versa. Results: The level of LAP2 transcripts and proteins was increased in pancreatic cancer, compared to normal cells. Interestingly, LAP2 protein level was increased in cells derived from well, but not poorly differentiated pancreatic cancers. Immunostaining demonstrated an increased and altered cellular expression of LAP2, compared to normal. LAP2 expression was increased in Chmp1A overexpressing cells but decreased in Chmp1A silenced cells. In addition, Chmp1A expression was increased in LAP2 overexpressing cells. Summary: The expression of LAP2 isoforms were increased in tumor cells, compared to normal pancreatic cells. LAP2 overexpression study suggests its functions as tumor suppressor in pancreatic cancer. Immunocytochemical analysis suggests that the increased and altered expression of LAP2 might be important for its function in pancreatic cancer. Our data also indicates that there is comparable change in the expression between Chmp1A and LAP2 in pancreatic cancer cells. Citation Format: Maiyon Park. The expression and function of LAP2 and its interaction with Chmp1A in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5140.
Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies
Authors: Alexandra O. Sokolova, Brian H. Shirts, Eric Q. Konnick, Ginger J. Tsai, Bernardo H.L. Goulart, Bruce Montgomery, Colin C. Pritchard, Evan Y. Yu, Heather H. Cheng
Journal: Journal of the National Comprehensive Cancer Network (2020)

With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.
Abstract 2467: Interaction of CYP3A5 with AR-HSP90 complex regulating AR activation in prostate cancer cells
Authors: Priyatham Gorjala, Oscar Goodman, Ranjana Mitra
Journal: Cancer Research (2020)

Abstract Background: Previously we have demonstrated that CYP3A5 stimulates prostate cancer cell growth by promoting AR activation and downstream signaling. We further investigated the mechanism of CYP3A5's interaction with the AR-HSP90 complex known to regulate AR activation process. AR activation is tightly regulated and it involves several chaperons (HSP90, HSP70, HSP40, and HSP27), multiple cofactors and protein kinases. We hypothesize that stoichiometric CYP3A5 binding to the HSP90-AR complex can induce conformational changes in the chaperone complex, promoting AR nuclear migration and activation. Method: We used co-immunoprecipitation to identify the interaction of CYP3A5 with the components of the AR-HSP90 complex. Immunofluorescence studies were performed to identify the components of the AR-HSP90 complex that co-localize with CYP3A5. FRET analysis was used to confirm the interactions of CYP3A5 with the AR-HSP90 complex. Results: We performed co-immunoprecipitation (co-IP) experiments with extracts from flag-tagged CYP3A5 transfected LNCaP cells. Our data demonstrates that CYP3A5 co-immunoprecipitates with HSP90, AR, HSP70 and HSP40, all known components of the HSP90-AR complex. We further confirmed using reverse immunoprecipitation with AR/ HSP90 antibodies and agarose A/G beads that CYP3A5 is a part of the HSP90-AR mature complex. Empty vector transfected cell extract and IgG were used as controls for pull down and reverse IP respectively. Immunofluorescence studies demonstrated that HSP70 and HSP40 co-localized with CYP3A5 in the cytoplasm. Interestingly, the MDAPCa2b and LNCaP cells show co-localization of CYP3A5 and AR in the nucleus, in contrast to non-transformed RWPE1 cells where CYP3A5 remains in the cytoplasm. The nuclear presence of CYP3A5 is more pronounced in MDAPCa2b cells carrying the wild type CYP3A5. The FRET analysis further confirmed direct interaction between CYP3A5 and HSP40 a chaperon in the AR-HSP90 complex. Conclusions: Our data confirms that CYP3A5 directly interacts with the AR-HSP90 complex regulating AR activation process. Further understanding of this interaction can help establish CYP3A5-AR axis as a novel therapeutic target. Citation Format: Priyatham Gorjala, Oscar Goodman Jr., Ranjana Mitra. Interaction of CYP3A5 with AR-HSP90 complex regulating AR activation in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2467.
Abstract 3985: GDF15 expression level impacts the canonical pathways of the tumor microenvironment and ovarian tumors with wild-type p53 in response to chemotherapy
Authors: Daisy I. Izaguirre, Yvonne TM Tsang, Eucharist H. Kun, David M. Gershenson, Kwong-Kwok Wong
Journal: Cancer Research (2020)

Abstract Background The standard treatment for ovarian cancer is surgery, followed by chemotherapy with a platinum agent, such as cisplatin or carboplatin, and a taxane, such as paclitaxel. We previously observed that patients with ovarian cancer that was wild-type for p53 had a lower survival rate than did those with p53 mutations. A better understanding of the molecular changes that occur in epithelial ovarian cancer cells with wild-type p53 in response to cisplatin treatment could reveal a novel mechanism of chemoresistance. Therefore, we might be able to develop novel strategy to overcome chemoresistance. Methods Gene expression profiling was performed on the wild-type p53 ovarian cancer cell line A2780 to identify genes that are highly induced by cisplatin. Growth differentiation factor 15 (GDF15) was identified as being highly induced by cisplatin or carboplatin. This finding was validated in a panel of wild-type and mutant p53 ovarian cancer cell lines. Mouse orthotopic models were used to further investigate the induction of GDF15 by cisplatin in vivo and the effect of GDF15 knockdown (GDF15-KD) on tumor growth and cisplatin response. A novel analysis was performed of RNAseq data generated from tumors formed in cisplatin-treated orthotopic mouse models to understand the tumor and stromal cell signaling changes. Results The induction of GDF15 was demonstrated in vivo, and the serum level of GDF15 after cisplatin treatment was also found to be significantly up-regulated in an A2780 ovarian cancer orthotopic mouse model. More importantly, cisplatin treatment was more effective in shrinking the mouse tumors developed from GDF15-KD A2780 cell line than did control tumors. Histopathological and novel RNAseq analyses of mouse tumors revealed that GDF15-KD tumors had a lower stromal component than did control tumors after cisplatin treatment. GDF15-KD tumors also had a different repertoire of activated and inhibited canonical pathways in their stromal cell and cancer cell components than did control tumors in response to cisplatin treatment. Conclusions GDF15 expression in wild-type p53 ovarian cancer cells can modulate the canonical pathways in the tumor microenvironment in response to cisplatin and may be a mechanism of chemoresistance. Targeting GDF15 signaling could be a novel strategy to enhance the effectiveness of chemotherapy. Citation Format: Daisy I. Izaguirre, Yvonne TM Tsang, Eucharist H. Kun, David M. Gershenson, Kwong-Kwok Wong. GDF15 expression level impacts the canonical pathways of the tumor microenvironment and ovarian tumors with wild-type p53 in response to chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3985.
Abstract 2713: Elucidation of bone metastasis using a caudal artery injection mouse model and Akaluc-AkaLumine near-infrared bioluminescence technology
Authors: Takahiro Kuchimaru, Misa Minegishi, Shinae Kizaka-Kondoh
Journal: Cancer Research (2020)

Abstract Bone is one of the most common sites of metastasis for various primary tumors including breast, prostate and lung cancers. We have addressed molecular basis underlying bone metastasis using newly developed murine model of bone metastasis and near-infrared bioluminescence technologies. Our new murine model overcomes several limitations in the current standard model by intra-cardiac (IC) injection of cancer cells [1]. We found that the caudal artery is a new pathway to predominantly deliver cancer cells to the bone marrow of hind limbs in mice. Intra-caudal arterial (CA) injection is technically as easy as tail vein injection [2]. In addition, CA injection delivered cancer cells &amp;gt;10-fold more efficiently than IC injection. This accelerated the development of bone metastasis in hind limbs with wide variety of cell lines. We have combined the CA injection model with near-infrared bioluminescence imaging. Bioluminescence imaging (BLI) with firefly luciferases and its natural substrate D-luciferin has been indispensable to noninvasively monitor metastasis development in mice. To improve deep-tissue imaging, synthetic luciferin AkaLumine has successfully extended the wavelength of firefly bioluminescence to the near-infrared region where tissue is more transparent to light [3]. More recently, our collaborators created an engineered luciferase Akaluc that displays high catalytic activity in reaction with AkaLumine [4]. AkaLumine-Akaluc bioluminescence imaging (AkaBLI) is capable of noninvasive visualization of single cancer cells deep inside mice. Combining the CA injection model with AkaBLI technology is a powerful tool for elucidating the mechanism of bone metastasis in small animals. References [1] Kuchimaru et al. Nat Commun 2018, 9, 2918 [2] http://sites.google.com/view/takahirokuchimaru/protocol [3] Kuchimaru et al. Nat Commun 2016, 7, 11856 [4] Iwano et al. Science 2018, 359, 935 Citation Format: Takahiro Kuchimaru, Misa Minegishi, Shinae Kizaka-Kondoh. Elucidation of bone metastasis using a caudal artery injection mouse model and Akaluc-AkaLumine near-infrared bioluminescence technology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2713.
Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors
Authors: Xiaowei Wu, Mengdi Dai, Rongrong Cui, Yulan Wang, Chunpu Li, Xia Peng, Jihui Zhao, Bao Wang, Yang Dai, Dan Feng, Tianbiao Yang, Hualiang Jiang, Meiyu Geng, Jing Ai, Mingyue Zheng, Hong Liu
Journal: Acta Pharmaceutica Sinica B (2020)

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.
Abstract 4759: Nanoscale Huangjing extract from Mount Tai displays enzyme and biofuel enhancing activity: Potential in precision anti-cancer therapy
Authors: Aigerim Kabulova, Madina Razbekova, Yingqiu Xie, Adilet Dautov, Qian Wang, Haiyan Fan
Journal: Cancer Research (2020)

Abstract Chinese herb Huangjing has been well-known for its anti-cancer characters in xenograft models of cancers and traditional Chinese herbal classical books. However, the mechanisms are largely unknown. The processed Huangjing has the pharmacological function but fresh forms may have toxicity. Mount Tai is famous for its traditional culture and Chinese medicine resources with special environmental and nutritional potential for enrichment of herbal chemical competent. Our study aimed to test phosphatase activity of nanoparticles produced in the process of herb and to identify whether its anti-cancer properties is related to the phosphatase activity. Phosphatase has been known for its function in dephosphorylating of many drug targets therein to inhibit cancer cell growth. We recently reported engineered nanoparticles were proved to exhibit phosphatase activity and here we further demonstrated that nanoscale Huangjing herb from Mount Tai showed positive results on a few phosphatase substrates. The corresponding substrate specificity and kinetics of the reaction including the substrate concentration, pH, and temperature dependence were studied in detail. In addition, using a Biorad Biofeul kit, Huangjing was observed to catalyze p-nitrophenyl glucopyranoside to p-nitrophenol reaction. Our data suggest that Huangjing may cleave the covalent bond between beta glucose and nitrophenol suggesting the biofuel-like activity. We then performed experiments to test the effectiveness of Huangjing at nanoscale for inhibiting growth of cancer cells wherein, the growth of MDA-MB-231 and PC3 cells was greatly inhibited while normal cells are planning for comparison and investigation in mechanisms. The study has a significance in developing potential novel nanoscale drugs with phosphatase-like activity for treatment of certain cancers with combination of targeted kinase inhibitors based therapy or as a drug delivery machinery. Our preliminary results suggest a kinase synergistic based signaling. Thus, our data provided the potential concept of the combination of traditional Chinese medicine with modern chemotherapy. Citation Format: Aigerim Kabulova, Madina Razbekova, Yingqiu Xie, Adilet Dautov, Qian Wang, Haiyan Fan. Nanoscale Huangjing extract from Mount Tai displays enzyme and biofuel enhancing activity: Potential in precision anti-cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4759.
Abstract 4814: Circular RNA expression in oral squamous cell carcinoma
Authors: Hongyu Yang, Yufan Wang
Journal: Cancer Research (2020)

Abstract Objective: Circular RNA (circRNA) is a type of non-coding RNA molecule that affects the cellular regulatory network by sequestering microRNA (miRNA) like a sponge. This study was performed to identify differentially-expressed circRNA in oral squamous cell carcinomas (OSCCs). Methods: By using high-throughput transcriptome sequencing technology, we conducted a comprehensive study of circRNAs in human OSCC. The expression levels of circRNAs were determined by qRT-PCR and analyzed the correlations with clinicopathological characteristics in 42 patients. The circRNAs-miRNAs-mRNAs network was performed by bioinformatic integrated analysis. Results: By high-throughput sequencing, microarray circRNA expression profiles were acquired from patients with OSCCs (n = 8) and controls (n = 8), which totaled 1921 existing circRNA molecules and 10021 novel circRNA molecules. Most of the circular RNA is from exons and distributed in the No. 1 and 2 chromosomes. Eight up-regulated and down-regulated circRNA molecules were identified as differentially-expressed in OSCCs. Among this, the expression of circ_000334, circ_006740, and circ_006371 are significantly down-regulated in 42 pairs of samples. Conclusion: This study provides new insihgts into oncogenesis and development of OSCC, suggests novel therapeutic strategy for OSCC. Citation Format: Hongyu Yang, Yufan Wang. Circular RNA expression in oral squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4814.