tbuckley/cabot-search huggingface dataset:
Ocular Adverse Effects of Infigratinib, a New Fibroblast Growth Factor Receptor Tyrosine Kinase Inhibitor
Authors: M. Teresa Magone, Iris R. Hartley, Edmond Fitzgibbon, Rachel Bishop, Mike Arango, Susan Moran, Roo Vold, Jaydira del Rivero, Karen Pozo, Jamie Streit, Kelly L. Roszko, Michael T. Collins, Rachel I. Gafni
Journal: Ophthalmology (2020)
Abstract B35: Characterization of exosomes extracted from primary tumor samples of HPV+/- oropharyngeal cancer
Authors: Vivian F. Wu, Xiang Guo Dai, Michael Chopp
Journal: Clinical Cancer Research (2020)

Abstract Objective: To determine if distinctions in exosomal cargo contribute to differences in EMT between HPV-related and HPV-unrelated oropharyngeal disease and can provide a signature for prediction of tumor aggressiveness and metastatic potential. Subjects and Methods: Specimen from patients with HPV+/- OPSCC were collected according to an IRB-approved protocol including primary tumor, lymph node metastasis, distant metastasis, and serum when available. Exosomes isolated from HPV+ and HPV- tumors were analyzed with miARma-seq and proteomics. These same exosomes were cocultured with well-characterized HPV+ and HPV- cell lines as well as fibroblasts and normal keratinocytes. Tumor aggressiveness, EMT, and potential for metastasis were measured utilizing wound healing scratch assays and transwell invasion assay techniques based on the Boyden Chamber migration assay. Confirmation of epithelial to mesenchymal transition was evaluated by Western blot and qPCR using a panel of well-established EMT markers (e-cadherin, n-cadherin, vimentin, snail, slug, twist, ZEB1/2). Results: Tumors from HPV+ patients demonstrate exosomal content enriched in EMT markers compared to HPV-negative patient cultures. Exosomes extracted from primary tumor and lymph node metastasis of the same patient demonstrate differential expression of markers of EMT. Exosomes extracted from lymph node and cocultured with fibroblasts demonstrate increased invasion and migration. Conclusions: Exosomes can be extracted from primary patient tumor cultures of both primary tumor and lymph node metastasis. These exosomes demonstrate differential expression of markers of EMT. Exosomal contents can be exploited for biomarker discovery to aide in prognostication. Citation Format: Vivian F. Wu, Xiang Guo Dai, Michael Chopp. Characterization of exosomes extracted from primary tumor samples of HPV+/- oropharyngeal cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B35.
Abstract 992: IL-6/STAT3-mediated inflammatory signaling results in dysregulated fibroblast growth factor receptor activation and tumor cell signaling in human pancreatic adenocarcinoma
Authors: Karol Nawalaniec, Yuxiang Wang, Romana Moench, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by delayed diagnosis and the lowest five-year survival amongst all cancer sites. PDAC development and progression are attributed to chronic inflammation and associated tissue repair mechanisms which contribute to high density tumor formation and chemoresistance. PDAC-associated inflammation is, in part, owed to high levels of interleukin 6 (IL-6) and its activated pathways including JAK/STAT3. In Addition, Fibroblast growth factor (FGF) signaling pathways are known to be dysregulated in cancer and have been implicated in various malignancies including PDAC. As such, we sought to explore the association between IL-6-induced inflammatory signaling and FGF signaling activation. To observe this effect as it pertains to carcinogenesis and cancer progression we used four human cell lines ranging from healthy pancreatic ductal epithelial (HPDE) cells to various grade (G) PDAC cells. Cells were treated with IL-6 at a concentration of 100 ng/mL for 24 hours. The results showed increased phosphorylation of STAT3 in BxPC-3 (G2) and PANC-1 (G3) cells with no change noted in HPDE and SW1990 (G2, metastatic) cells. IL-6 stimulation likewise resulted in markedly increased phosphorylation of the fibroblast growth factor receptor substrate 2-alpha (FRS2-α) and its downstream component Erk1/2 in BxPC3 cells, indicating activation of FGF signaling through the MAPK/Erk pathway in our low grade PDAC cell model. In conclusion, the results demonstrate a potential link between IL-6 induced inflammatory signaling and dysregulation of FGF signaling in human PDAC. Activated STAT3 signaling seems to be involved in this process. Existing cancer therapies aimed at controlling growth factor signaling broadly target vascular endothelial or epithelial growth factor receptors (VEGF/EGFR) with marginal efficacy and adverse side effects in PDAC. Identifying the pivotal link between inflammatory signaling and dysregulation of fibroblast growth factor signaling will allow for the development of more precisely targeted and effective cancer therapy in pancreatic cancer. This may minimize clinically observed exaggerated fibrotic events within the tumor and may hence result in higher vulnerability for established chemotoxic therapies in the tumor cells. Citation Format: Karol Nawalaniec, Yuxiang Wang, Romana Moench, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. IL-6/STAT3-mediated inflammatory signaling results in dysregulated fibroblast growth factor receptor activation and tumor cell signaling in human pancreatic adenocarcinoma [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 992.
The kinetics of viral load and antibodies to SARS-CoV-2
Authors: Jiufeng Sun, Xi Tang, Ru Bai, Chumin Liang, Lilian Zeng, Huifang Lin, Runyu Yuan, Pingping Zhou, Xuhe Huang, Qianlin Xiong, Jinju Peng, Fengfu Cui, Bixia Ke, Juan Su, Zhe Liu, Jing Lu, Junzhang Tian, Ruilin Sun, Changwen Ke
Journal: Clinical Microbiology and Infection (2020)
Abstract 3366: <i>In vivo</i> efficacy of a PD-L1 targeted, antigen seeding engineered toxin body
Authors: Hilario J. Ramos, Brigitte Brieschke, Sara LeMar, Joseph D. Dekker, Aimee Iberg, Garrett L. Robinson, Asis Sarkar, Banmeet Anand, Melissa M. Singh, Jay Zhao, Jack P. Higgins, Erin K. Willert
Journal: Cancer Research (2020)

Abstract Engineered toxin bodies (ETBs) comprised of a proprietarily engineered Shiga-like Toxin A subunit (SLTA) genetically fused to antibody-like binding domains work through novel mechanisms of action and can force internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Our PD-L1 targeted ETB, MT-6402, includes antigen seeding technology (AST), and additionally delivers a viral antigen for presentation in complex with MHC-I to resident viral-specific cytotoxic T lymphocytes (CTLs). The fusion protein provides a powerful, dual mechanism of action to specifically target and destroy PD-L1 positive tumor and inhibitory immune cells. In vitro testing of human tumor cell lines has demonstrated that cell surface PD-L1 expression is required for activity of the PD-L1 targeted ETBs. MT-6402 demonstrated effective depletion of PD-L1 expressing cells across a panel of immortalized cancer cell lines from multiple origins, including lung, skin, breast, and ovary. In a co-culture assay of PD-L1 target cells and antigen specific T-cells, PD-L1 targeted MT-6402 delivers a viral antigen to the target cells and can activate cytokine secretion and T-cell mediated killing. Additionally, MT-6402 treatment of human peripheral blood mononuclear cells (PBMCs) leads to selective depletion of PD-L1 positive cells (IFN-γ stimulated monocytes) in the absence of depletion of PD-L1 low/negative lymphocytes. Murine models, including patient derived xenografts, have demonstrated that the PD-L1 targeted ETBs are efficacious in vivo. Additional in vivo tumor models to further describe the effect of MT-6402 are being explored. Exploratory studies in a primate model have shown that MT-6402 can be tolerated at levels shown to induce T cell activation (type 1 cytokines). MT-6402 delivers a powerful and unique dual mechanism of action. The combination of a PD-L1 specific direct cell kill and redirection of a robust effector T cell response to the tumor has potential benefit in solid tumor indications, including in the relapsed setting, when disease has progressed after checkpoint and/or other therapies. Citation Format: Hilario J. Ramos, Brigitte Brieschke, Sara LeMar, Joseph D. Dekker, Aimee Iberg, Garrett L. Robinson, Asis Sarkar, Banmeet Anand, Melissa M. Singh, Jay Zhao, Jack P. Higgins, Erin K. Willert. In vivo efficacy of a PD-L1 targeted, antigen seeding engineered toxin body [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 3366.
Early temporary with the AT1 blocker Losartan (L), in high dose or associated with Mycophenolate Mofetil (MMF), limits future injury in the remnant kidney
Authors: Clarice Kazue Fujihara, Claudia R. Sena, Luciana F. Carvalho, Glaucia R. Antunes, Denise M. A. C. Malheiros, Roberto Zatz
Journal: Journal of the American Society of Nephrology (2002)
Abstract 3714: Role of miR-29a in pancreatic stellate cell mediated stromal remodeling in pancreatic ductal adenocarcinoma
Authors: Shatovisha Dey, Sheng Liu, Tricia D. Factora, Solaema Taleb, Primavera Riverahernandez, Lata Udari, Xiaoling Zhong, Jun Wan, Janaiah Kota
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of malignancy with nearly equal incidence and mortality rates in patients. The disease is characterized by dense desmoplastic tumor-associated stroma, which prevents effective therapeutic delivery to the tumor core and confers resistance to chemotherapy. The central effectors of such characteristic stroma in PDAC are the pancreatic stellate cells (PSCs), which are activated by autocrine and paracrine signaling of the tumor cells and deposit excessive amounts of extracellular matrix (ECM) proteins- the major component of the stroma. This interaction of the PSCs with the cancer cells greatly promote tumor progression and metastasis. In our previous work, we demonstrated that microRNA (miRNA) 29a plays a key role in PSC-mediated stromal reaction, and that the loss of the molecule in PSCs accelerates ECM protein accumulation and cancer growth. To understand the mechanistic regulation of miR-29a in PDAC stroma, we performed RNA-seq analysis with human PSCs (hPSCs), which identified 197 genes that differentially expressed with miR-29a overexpression at a false discovery rate less than 0.05. This included 19 downregulated and one upregulated direct miR-29a targets. Of these, expression of six key targets with the highest fold changes, namely, ADAMTS2, IGF1, E2F7, LAMC1, CLDN1 and ITGA6 by miR-29a were validated at the protein level in hPSCs. In addition, canonical pathways associated with the target genes and their network interactions were assessed, which identified the association of the key targets with pathways such as collagen synthesis, insulin signaling, TGF-β and PI3K/Akt pathways. ADAMTS2, E2F7, LAMC1 and CLDN1 expressions were significantly upregulated in PDAC patient pancreas compared to that in healthy individuals. Together, the current study presents a comprehensive understanding of miR-29a mediation in stromal remodeling, and elucidates associated pathways in regulating PSCs' function in PDAC desmoplasia and pancreatic carcinogenesis. Citation Format: Shatovisha Dey, Sheng Liu, Tricia D. Factora, Solaema Taleb, Primavera Riverahernandez, Lata Udari, Xiaoling Zhong, Jun Wan, Janaiah Kota. Role of miR-29a in pancreatic stellate cell mediated stromal remodeling in pancreatic ductal adenocarcinoma [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 3714.
Abstract 4861: Loss of YAP1 activates Wnt/beta-Catenin signaling in prostate cancer
Authors: Siyuan Cheng, Shu Yang, Nestor Prieto-Dominguez, Zachary M. Connelly, Yingli Shi, Xiuping Yu
Journal: Cancer Research (2020)

Abstract Prostate cancer (PCa) is the most common non-cutaneous cancer among American men. In 2019, 174,650 new patients will be diagnosed from this disease. Most patients with localized PCa could be treated successfully. However, when PCa develops into castrate-resistant prostate cancer (CRPCa), the five-year survival rate drops below 30%. Neuroendocrine prostate cancer (NEPCa) is an aggressive subtype of PCa observed in 20%-30% CRPCa patients. Understanding how NEPCa progressed from prostate adenocarcinoma could reveal novel therapeutic targets. Previous studies indicate that activation of Wnt/beta-Catenin signaling promotes the progression to CRPCa with an increased NE differentiation. Additionally, animal studies suggest that Wnt/beta-Catenin signaling is active in NEPCa. Here we explored the mechanisms that promote Wnt/beta-Catenin signaling in NEPCa. Using TRAMP mice, which develop NEPCa after castration, we assessed the expression of Wnt-related genes and found that after androgen deprivation, the expression of Wnt7A is increased in prostate derived from both wild type and TRAMP mice but the expression of DKK1, a Wnt inhibitor, is decreased in wild type prostate but not in TRAMP prostate. The elevated expression of Wnt7a in combination with the lack of induction of Dkk1 in TRAMP tumors provides a mechanism to activate Wnt/beta-Catenin signaling in these tumors. Furthermore, we found the expression of YES-associated Protein (YAP1), a key transcriptional coactivator of Hippo pathway, is lost in NEPCa, in contrast to the elevated expression of YAP1 in high-grade prostate adenocarcinoma. YAP1 knockdown activated Wnt/beta-Catenin activity in PCa PC3 and 22Rv1 cells, indicating that the loss of YAP1 expression provides another mechanism to activate Wnt/beta-Catenin signaling, promoting NEPCa phenotype in PCa cells. Funding: This study is supported by: FWCC/Foundation Legacy Funds, DOD New Investigator Award, The Office of Research SEED awards, NIH R01 AND R03. Citation Format: Siyuan Cheng, Shu Yang, Nestor Prieto-Dominguez, Zachary M. Connelly, Yingli Shi, Xiuping Yu. Loss of YAP1 activates Wnt/beta-Catenin signaling in prostate 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 4861.
Abstract 5849: Association between annexin-A6 expression and metabolic vulnerabilities of TNBC cells and their response to EGFR-tyrosine kinase inhibitors
Authors: Stephen D. Williams, Amos M. Sakwe
Journal: Cancer Research (2020)

Abstract PURPOSE: Triple-negative breast cancer (TNBC), and the basal-like TNBC subtype, accounts for ~20% of all breast cancer (BC) cases, and is particularly prevalent in younger patients of African-American and Hispanic descent. The importance of annexin A6 (AnxA6) as a tumor suppressor in various cancers has been widely investigated, but the mechanisms by which AnxA6-induced basal-like triple negative breast cancer progression remain largely unknown. Physiological changes such as hypoxia, metabolic acidosis, and oxidative stress in the tumor microenvironment (TME) during cancer progression endow cancer cells with malignant properties, ultimately leading to metastatic dissemination that remains the major cause of death in cancer patients. By linking the altered expression status of AnxA6, with changes in metabolic output of the tumor cells and the efficacy of the otherwise ineffective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), these metabolic vulnerabilities can be targeted to attenuate the growth and/or motility of this hard-to-treat breast cancer subtype. DESIGN METHODS: AnxA6-high (BT-549) and AnxA6-low (MDA-468) TNBC cell lines were cultured in hypoxic conditions (94%N2; 1%O2; 5%CO2; 37°C) using a Bactrox Hypoxia Chamber (Terra Universal Inc., Fullerton, CA). TNBC cells were treated with EGFR-TKI Lapatinib (Biovision Inc., Milpitas, CA). RESULTS: We demonstrate that exposure of AnxA6-high (BT-549) and AnxA6-low (MDA-468) TNBC cell lines to acute hypoxia (1% O2; ≤24 hrs.) is associated with down-regulation of AnxA6 while chronic hypoxia (1% O2; &amp;gt;24 hrs.) led to a consistent up-regulation of AnxA6. AnxA6, FABP4, and HIF-1α downstream genes GLUT1 and PGK-1, mRNA levels were upregulated in chronic hypoxic conditions. AnxA6 metabolic studies reveal that contrary to AnxA6-high, down regulation of AnxA6 in TNBC cells increased lactate production, glucose consumption, and ATP-synthesis and lipid metabolism under hypoxia. In addition, chronic hypoxia sensitized TNBC cells to EGFR-TKIs. CONCLUSION: These data suggest that the transition from AnxA6-high to AnxA6-low may be dependent on hypoxia in the TME and consequently, TNBC cell survival and resistance to EGFR-targeted therapies. Supported by NIH/NIGMS 1SC1CA211030 (AMS) Citation Format: Stephen D. Williams, Amos M. Sakwe. Association between annexin-A6 expression and metabolic vulnerabilities of TNBC cells and their response to EGFR-tyrosine kinase inhibitors [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 5849.
Abstract 5592: MOSPD2 a novel target for bi-specific antibody mediated solid tumor cells immune death
Authors: Yaniv Salem, Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Itzhak Mendel, Eyal Breitbart
Journal: Cancer Research (2020)

Abstract Introduction: We have previously identified motile sperm domain-containing protein 2 (MOSPD2) as key regulator of monocyte motility. While MOSPD2 is normally expressed by myeloid cells with low/undetectable levels in healthy tissues, high expression of MOSPD2 is detected in multiple solid tumors and cancer cell lines. MOSPD2 expression was highly elevated in invasive and metastatic breast cancer but not in in-situ tumors, and our data indicate that it is essential for breast cancer cell metastasis in vitro and in-vivo. Based on its abundant-and specific solid tumor expression profile, MOSPD2 may serve as a target for immune-mediated targeting of tumor cells. Experimental procedure: We have developed CD3xMOSPD2 bi-specific IgG antibodies (BsAb) for killing of MOSPD2+ cancer cells. Binding of the BsAbs to cancer cells and T-cells was validated by flow cytometry. For efficacy, cancer cell lines were co-cultured with effector CD8 T-cells in the presence of CD3xMOSPD2 BsAb or a control IgG. Cancer cell survival and T-cell activation was determined by flow-cytometry and ELISA for IFN-gamma. Results: Flow-cytometry confirmed surface binding of BsAbs to cancer cell lines and CD8 T-cells. Employing CD3xMOSPD2 IgG BsAb on cancer cell lines induced T-cell activation and yielded profound death of target tumor cells. Conclusions: CD3xMOSPD2 bi-specific antibodies potentially offer a new immuno-oncology therapeutic tool for treatment of various MOSPD2-positive solid tumors. Citation Format: Yaniv Salem, Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Itzhak Mendel, Eyal Breitbart. MOSPD2 a novel target for bi-specific antibody mediated solid tumor cells immune death [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 5592.
Abstract 1829: Olaparib antiproliferative effect in pancreatic cancer and correlation with the response to other anticancer agents
Authors: Elisabetta Leo, Giuditta Illuzzi, Sabrina Bentouati
Journal: Cancer Research (2020)

Abstract AstraZeneca obtained positive results from POLO, the first Phase III randomised, double-blind study that evaluated the efficacy of the PARP inhibitor (PARPi) olaparib, for maintenance monotherapy in patients with gBRCA mutated metastatic pancreatic cancer whose disease has not progressed on first-line platinum-based chemotherapy. To support the application of olaparib for the proposed indication in these patients, a series of in vitro pharmacological tests were performed and will be here presented. 1. In a panel of pancreatic cancer cell lines, a striking correlation was observed between the responses to platinum and to olaparib. This indicates that it is predictable that olaparib will show efficacy in treatment of platinum-sensitive pancreatic cancer, as it has been previously demonstrated in other cancer indications. 2. Tests in isogenic cell line pairs and non-tumour cell lines revealed that platinum treatments lead to cytotoxic effects that are only ~10-20-fold more selective for BRCAm versus BRCAwt and non-tumour models; in contrast, olaparib is able to selectively kill BRCAm cells, with ~500-1000-fold sensitivity versus the BRCAwt cells. 3. In the panel of pancreatic cancer cells, the sensitivity to other DNA damaging agents used as standard of care, such as irinotecan (and, to some extent, 5FU, other key components of FOLFIRINOX as well as gemcitabine), correlated with sensitivity to olaparib. In contrast, no correlation was observed with paclitaxel (mitotic inhibitor), or with other agents. 4. The antiproliferative effects to olaparib treatments in the cancer cell panel were compared to that of other 5 clinical PARPi. High correlations were observed in the responses to all the PARPi except for veliparib, which inhibits the catalytic activity of PARP but does not act as PARP-trapper, confirming that the efficacy of PARPi in monotherapy depends on their ability to stabilise the interaction between PARP and the DNA. Citation Format: Elisabetta Leo, Giuditta Illuzzi, Sabrina Bentouati. Olaparib antiproliferative effect in pancreatic cancer and correlation with the response to other anticancer agents [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 1829.