tbuckley/cabot-search huggingface dataset:
Abstract 1185: Impact of distance traveled to radiosurgery center on time to initiation of gamma knife treatment for brain metastases in a rural patient population
Authors: Azeem A. Rehman, Sarah Singh, David Arsanious, Paul Renz, Christopher P. Cifarelli
Journal: Cancer Research (2020)

Abstract The West Virginia University Gamma Knife center provides care for largely rural areas with patients that often travel 1-3 hours for treatment. Studies investigating whether distance to a tertiary cancer center results in meaningful delays in care are limited. This study examines patients treated with gamma knife for brain metastases to identify predictors of delay in care based on distance from the treatment center. Retrospective data for patients treated at the West Virginia University Gamma Knife center (2010-2017) for brain metastases with a primary diagnosis of lung or breast cancer was analyzed. Study variables included age, gender, primary histology, ECOG, KPS, RPA, interval time to initiation (TTI) of gamma knife treatment from diagnosis, and distance from home to the center. Statistical significance was determined by p&amp;lt;0.05. A total of 182 patients with a median age of 60 years (IQR: 53.5-69 years), median ECOG of 1 (Range: 0-3), median KPS of 80 (IQR: 70-100), and RPA of 2 were included. Median TTI of GK treatment was 21 days (IQR: 14-29 days) while median distance traveled to the facility was 45.8 miles (IQR: 24.5-86.7 miles). For patients residing within 45.8 miles, median TTI was 22 days (IQR: 15-33 days) compared with a median TTI of 20.5 days (IQR: 13.75-27 days) for patients living beyond 45.8 miles. There was no statistical difference between groups based on age, diagnosis, or distance to center with respect to TTI (p=0.28). Despite geographical disadvantages in a rural population, including distance traveled for treatment, no significant delay in TTI was identified in patients treated with gamma knife for brain metastases. Citation Format: Azeem A. Rehman, Sarah Singh, David Arsanious, Paul Renz, Christopher P. Cifarelli. Impact of distance traveled to radiosurgery center on time to initiation of gamma knife treatment for brain metastases in a rural patient population [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 1185.
Abstract 5641: CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager
Authors: Nizar El-Murr, Christophe Henry, Elisa Francesconi, Florence Attenot, Angela Virone-Oddos, Laurent Vidard, Lan Wu, Zhi-Yong Yang, Marielle Chiron
Journal: Cancer Research (2020)

Abstract SAR442257 (CD38/CD28xCD3) is a trispecific T cell engager designed for the treatment of multiple myeloma (MM). Its cytotoxic activity and anti-tumor efficacy is dependent on the expression of CD38 by malignant plasma cells and the recruitment and activation of T cells via CD3 and CD28. Here we show that MM cells also express CD28 on their membrane and investigate how this expression impacts the cytotoxic activity of the trispecific antibody. Using CRISPR, CD28 knock-out (KO) models were generated from two MM cell lines that have different receptor densities of CD38 and CD28: KMS-11 (CD38 ~3 000/cell; CD28 ~35 000/cell) and RPMI8226 (CD38 ~129 000/cell; CD28 ~84 000/cell). T-cell-mediated cytotoxicity was evaluated in vitro using either effector CD8+ T cells or total PBMC isolated from healthy donors. Binding of SAR442257 to tumor cells in the presence of saturating concentrations of anti-CD38 antibodies was evaluated by flow cytometry using APC-labeled SAR442257 and FITC-labeled anti-CD38 antibodies. In vitro killing assays showed that SAR442257 is active on both CD38 high and CD38 low MM cell lines (EC50 in the pM range for WT cell lines; Table 1). Following CD28 KO, SAR442257 remained active but displayed reduced cytotoxic activity as compared to WT CD38+ CD28+ cells. The reduced cytotoxic activity was noticeable in both CD38 low and CD38 high MM models suggesting that the expression of CD28 by MM cells contributes to the cytotoxic activity of the trispecific antibody. We further show that when other anti-CD38 antibodies are bound to CD38, binding of SAR442257 to tumor cells and T-cell mediated cytotoxicity are rescued by CD28 as evidenced by loss of binding and cytotoxic activity in CD28KO cells. Overall, these data show that SAR442257 is active on both CD38 high and low MM models and that CD28 expressed on MM tumor cells can be directly targeted by SAR442257, enhancing its cytotoxicity and allowing it to bind MM cells when CD38 is occupied by other anti-CD38 antibodies Table 1.T cell mediated killing assays. EC50rel, Relative EC50; CI, Confidence interval.EC50rel (pM) [±CI95%]KMS-11RPMI8226WTCD28KOWTCD28KOEffector CD8+ T cells4.1 [2.9 ; 5.9]30.2 [16.9 ; 54.0]0.2 [0.1 ; 0.3]0.5 [0.3 ; 0.8]Total PBMC26.0 [7.8 ; 87]&amp;gt;250032.0 [14.8 ; 69.2]304.0 [118.0 ; 787.0] Citation Format: Nizar El-Murr, Christophe Henry, Elisa Francesconi, Florence Attenot, Angela Virone-Oddos, Laurent Vidard, Lan Wu, Zhi-Yong Yang, Marielle Chiron. CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager [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 5641.
Abstract 4397: Pathway-based drug combinatory synergy prediction using gene expression and essentiality data
Authors: Jin Li, Xue Wu, Yang Huo, Enze Liu, Zhi Zeng, Lijun Cheng, Lang Li
Journal: Cancer Research (2020)

Abstract Background: Experiment based drug combinatory synergy discovery is limited in a moderate scale. Systems biology models can substantially widen the search space, and discover novel mechanisms. While most of systems pharmacology models were designed to optimize the predictive performance for the drug combination synergy, they were limited by their lack of mechanistic interpretations. The gene essentiality data generated from RNAi screening have not been integrated into the systems pharmacology model yet. Methods: Drug combinatory synergy data from NCI-ALMANAC was used in this research. Cancer cell line gene expression and essential score (RNAi screening from DepMap portal), drug targets and KEGG pathways were used in our systems pharmacology model. Two types of models were constructed. The first model predicts a drug combination's synergy using various pathways among various cell lines. The second model predicts various drug combinatory synergy in a cell line. Machine learning approaches, such as SVR, Ridge regression, Random forest and Logistic regulation were investigated in developing this model. Our predictive models were built upon 43 cell lines with both baseline gene expression and essential scores, 165 KEGG pathways, and 198 drug pairs who have at least synergistic drug combinatory effects in 3 or more cell lines. Results: In predicting drug combinatory synergy from both predictive models, the mean R square was merely 0.006 using individual gene expression or essentiality data. The mean R-square increased to 0.022 when using pathways. In drug combination specific predictive model (model 1), 64 and 62 drug combinations were related to more than 10 pathways which had enriched essential and expression genes, respectively. The correlation between expression enrich pathways and essential enriched pathways is only 0.04. In the cell line specific predictive model (model 2), drug combination synergy score from 14 cell lines can be predicted with more than 150 pathways, and 5 cell lines can be predicted with less than 10 pathways. Conclusion: Pathway-based models are more powerful than gene level-based models in predicting drug combination synergy. Gene expressions and essential genes provide much different information in predicting drug combination synergy. Drug combination synergy prediction and its related pathways are dramatically different among different cancer cell lines. Citation Format: Jin Li, Xue Wu, Yang Huo, Enze Liu, Zhi Zeng, Lijun Cheng, Lang Li. Pathway-based drug combinatory synergy prediction using gene expression and essentiality data [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 4397.
Abstract 4690: ARD1-mediated NRF2 acetylation promotes human colon cancer cell proliferation
Authors: Xizhu Fang, Yeon-Hwa Lee, Jie Zheng, Seong Hoon Kim, Jeong-Hoon Jang, Do-Hee Kim, Young-Joon Surh
Journal: Cancer Research (2020)

Abstract The transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2) is regarded as one of the main orchestrators of the cellular antioxidant and carcinogen-detoxifying response. NRF2 plays a pivotal role in protecting normal cells from carcinogenic insults, but it may also accelerate the proliferation and progression of cancer cells. Abnormally elevated expression or activation of NRF2 has been attributed to mutation, especially in the sequences involved in interaction with its negative regulator KEAP1. However, other mechanisms responsible for NRF2 overactivation/overexpression are less well understood. Arrest defective (ARD1), an N-terminal acetyltransferase that catalyzes N-terminal acetylation of target proteins, has lysine acetyltransferase activity and is involved in mediating various (patho)physiological processes, such as proliferation, apoptosis, autophagy, and differentiation. Aberrant overexpression of ARD1 is correlated with metastasis and poor prognosis in several types of cancer, suggesting that it may act as a tumor promoter. In the present study, we found that NRF2, acteyl-NRF2, and ARD1 were highly expressed in some human colon cancer cell lines (HCT-116, HCT-15, DLD1) and tissues obtained from colorectal cancer patients. Furthermore, overexpression of NRF2 and ARD1 was also verified by quantitative immunofluorescence analysis of colorectal tissue microarray. We noticed that silencing of NRF2 and ARD1 individually in human colon cancer cells (HCT-116) led to the decreases in viability, anchorage-independent growth, and migration capacity of HCT-116 cells. While there was no change in the protein level of ARD1 when NRF2 expression was knock down by siRNA, protein expression of Nrf2 and acteyl-NRF2 was markedly reduced by silencing of the ARD1 gene. This prompted us to explore the association between ARD1 and NRF2 in the human colon cancer cell proliferation and progression. Co-immunoprecipitation and immunocytochemical analyses showed that two proteins colocalized in the cytosol, and ARD1 directly bound to NRF2. Taken together, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer cells by acetylating and stabilizing this transcription factor. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea. Citation Format: Xizhu Fang, Yeon-Hwa Lee, Jie Zheng, Seong Hoon Kim, Jeong-Hoon Jang, Do-Hee Kim, Young-Joon Surh. ARD1-mediated NRF2 acetylation promotes human colon cancer cell proliferation [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 4690.
Abstract 2654: B cells produce IL-27 in breast cancer to upregulate PD-L1 expression and promote tumor progression
Authors: Hui Yan, Suryavathi Viswanadhapalli, Dariela Perez, Daniel Chupp, Maria Fernandez, Jingwei Wang, Shuai Wu, Carlos E. Rivera, Justin B. Moroney, Julia Taylor, John Im, Yiliao Luo, Junhao Liu, Sareddy Gangadhara, Tyler Curiel, Paolo Casali, Ratna Vadlamudi, Zhenming Xu
Journal: Cancer Research (2020)

Abstract B cells frequently infiltrate breast cancer (BCa) tumors, but their roles are inadequately understood. As shown by our analyses of the TCGA datasets and human BCa arrays, tumoral expression of B cell hallmark factors (e.g., CD20 and PAX5) coincides with those of the two subunits of pleiotropic cytokine IL-27, EBI3 and IL-27p28, whose expression is associated with poor prognosis in patients. In syngeneic mouse models, B cells promote BCa progression and do so by producing IL-27, but not IL-35 (IL-12/EBI3 heterodimer). Upon treatment by recombinant IL-27 or co-culturing with IL-27-producing B cells, BCa cells as well as targeted B lymphocytesactivate STAT1/STAT3 and upregulate immune checkpoint PD-L1 and chemokine receptor CXCR3, blocking of which synergistically arrest BCa cell proliferation in vitro and tumor growth in vivo, concomitant with reduction in PD-L1+B cells. Finally, B cell-specific deficiency in IL-27 receptor or PD-L1 inhibits BCa tumorigenesis, showing the dual functions of tumor-infiltrating B cells, i.e., IL-27 production for paracrinic PD-L1 upregulation. Citation Format: Hui Yan, Suryavathi Viswanadhapalli, Dariela Perez, Daniel Chupp, Maria Fernandez, Jingwei Wang, Shuai Wu, Carlos E. Rivera, Justin B. Moroney, Julia Taylor, John Im, Yiliao Luo, Junhao Liu, Sareddy Gangadhara, Tyler Curiel, Paolo Casali, Ratna Vadlamudi, Zhenming Xu. B cells produce IL-27 in breast cancer to upregulate PD-L1 expression and promote tumor progression [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 2654.
Correction to: YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma
Authors: Jiajie Hou, He Zhang, Jun Liu, Zhenjun Zhao, Jianye Wang, Zhike Lu, Bian Hu, Jiankui Zhou, Zhicong Zhao, Mingxuan Feng, Haiyan Zhang, Bin Shen, Xingxu Huang, Beicheng Sun, Mark J. Smyth, Chuan He, Qiang Xia
Journal: Molecular Cancer (2020)

An amendment to this paper has been published and can be accessed via the original article.
Statins as Anticancer Agents in the Era of Precision Medicine
Authors: Joseph Longo, Jenna E. van Leeuwen, Mohamad Elbaz, Emily Branchard, Linda Z. Penn
Journal: Clinical Cancer Research (2020)

Abstract Statins are widely prescribed cholesterol-lowering drugs that inhibit HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate metabolic pathway. Multiple lines of evidence indicate that certain cancers depend on the mevalonate pathway for growth and survival, and, therefore, are vulnerable to statin therapy. However, these immediately available, well-tolerated, and inexpensive drugs have yet to be successfully repurposed and integrated into cancer patient care. In this review, we highlight recent advances and outline important considerations for advancing statins to clinical trials in oncology.
Abstract 2266: SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma
Authors: Angela Virone-Oddos, Sahar Kassem, Béré Diallo, Alexandre Tang, Alain Fournier, Nizar El-Murr, Nadege Carrie-Constantin, Céline Nicolazzi, Isabelle Arnould, Hervé Avet-Loiseau, Sukhvinder S. Sidhu, Ludovic Martinet, Marielle Chiron
Journal: Cancer Research (2020)

Abstract CD38 is a cell surface glycoprotein highly expressed in multiple myeloma (MM) cells making it an attractive target for antibody–based therapy. Anti–CD38 treatment represents a major breakthrough in the treatment of relapsing and refractory multiple myeloma (RRMM) patients. However, a number of patients do not respond to anti–CD38 single agent therapy stressing the need for novel approaches. Here we describe SAR442085, a next generation anti–CD38 antibody, with higher affinity for the activating FcγRIIIa and FcγRIIa receptors expressed on effector cells as compared to the approved anti–CD38 antibody daratumumab, resulting in greater effector functions. SAR442085 targets CD38 with high affinity and is able to destroy CD38 expressing tumor cells in vitro through effector function mechanisms (ADCC and antibody dependent cellular phagocytosis, ADCP) as well as by direct apoptosis. SAR442085 exhibits better ADCC activity as compared to daratumumab with more than 8–fold EC50 improvement against RPMI–8226 MM cells. SAR442085 also inhibits CD38 enzymatic activity. Using primary bone marrow aspirates from MM patients, an increased ability of SAR442085 to engage CD16 was demonstrated, resulting in a higher level of NK cell activation and degranulation against primary plasma cells, as compared to daratumumab. In addition, SAR442085 demonstrated potent in vivo single–agent activity against murine tumor cells expressing human CD38, in a transgenic C57BL/6 mouse model humanized for all Fcγ receptors, with 90% mice survival at 10 and 1.25 mg/kg and up to 90 days median survival time. Overall, these data support the current evaluation of this next generation anti–CD38 antibody in phase I clinical trials in patients with relapsed/refractory MM. Citation Format: Angela Virone-Oddos, Sahar Kassem, Béré Diallo, Alexandre Tang, Alain Fournier, Nizar El-Murr, Nadege Carrie-Constantin, Céline Nicolazzi, Isabelle Arnould, Hervé Avet-Loiseau, Sukhvinder S. Sidhu, Ludovic Martinet, Marielle Chiron. SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma [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 2266.
Abstract 5618: Evaluating anti-IL-2Ra <i>in vivo</i> efficacy on humanized knock-in mice
Authors: Yanan Guo, Xiaofei Zhou, Youhong Su, Gary Ng, Chaoshe Guo
Journal: Cancer Research (2020)

Abstract Interleukin-2 receptor alpha chain (also called as CD25) is a 55 kD glycoprotein, also known as IL-2Ra, Ly-43, p55, or Tac. It is expressed on activated T and B cells, thymocyte subset, pre-B cells, and T regulatory cells. IL-2Ra and IL-2Rβ (CD122), together with the common gamma chain (IL2Rg)(CD132), form the high affinity signaling IL-2 receptor. Its affinity for IL2 and cellular function are tightly regulated and vary in different cell types. The high frequency of IL-2Ra on the surface of many different haematological tumor cells is now well established and, apart from its prognostic significance, IL-2Ra may be present on leukemic stem cells and enable oncogenic signaling pathways in leukemic cells. Additionally, high IL-2Ra expression in activated circulating immune cells and Tregs is a factor that has already been exploited by IL2 immunotherapies for treatment of tumors and autoimmune disease. The relative clinical safety and efficacy of administering anti- IL-2Ra radioimmunoconjugates and immunotoxins in various haematological tumor indications has been established and clinical trials of a novel IL-2Ra-directed antibody drug conjugate are underway. Biocytogen has generated IL-2Ra humanized mouse for both in vitro functional validation of signaling pathway and in vivo efficacy evaluation of IL-2Ra antibodies. The targeting strategy is that the genomic DNA covering exons 2~6 of mouse IL-2Ra gene which encode the extracellular domain are replaced by the counterpart of human IL-2Ra genomic DNA covering exons 2~6. Human IL-2Ra is mainly detectable on the T cells in spleen of the IL-2Ra humanized mice. The humanized mice are highly similar to the wild-type mice in basal leukocyte subpopulations, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. STAT-5 phosphorylation induced by mouse IL2 protein is blocked by anti-human IL-2Ra antibodies, suggesting that the functional pathways in IL-2Ra humanized mice work well. The colon cancer model established in IL-2Ra humanized mice is undergoing, anti-human IL-2Ra antibodies showed good efficacy in inhibiting tumor growth. Taken together, IL-2Ra humanized mice are a useful tool for in vivo efficacy evaluation of human IL-2Ra antibodies that can be advanced to human clinical trials. Citation Format: Yanan Guo, Xiaofei Zhou, Youhong Su, Gary Ng, Chaoshe Guo. Evaluating anti-IL-2Ra in vivo efficacy on humanized knock-in mice [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 5618.
Abstract 4375: Inhibition of triple negative breast cancer cell progression using estrogen related receptor alpha endogenous ligands
Authors: Faegheh Ghanbari, Sylvie Mader, Anie Philip
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is considered to be more metastatic, and has poorer prognosis and higher risk of recurrence than other subtypes of breast cancer. The death rate in patients with TNBC is twice that of ERα positive tumors mainly because there are fewer targeted therapies that treat TNBC patients [1]. Therefore, there is a need to discover new drug-targeted therapy for these patients. Several lines of evidence indicate that estrogen related receptors (ERRs), which belong to the orphan nuclear receptor superfamily, play a crucial role in breast cancer, with ERRα overexpression reportedly leading to adverse clinical outcomes in TNBC patients [2]. Despite intensive efforts, no endogenous ligand has been identified for ERRs so far. The discovery of ligands that bind these receptors may lead to novel strategies for the treatment of TNBC. In this study we show two endogenous ligands of ERRs: 1) estradienolone (ED), a novel endogenous steroid during pregnancy which acts as an inverse agonist of ERRs, 2) cholesterol as an agonist of ERRs. Our recent results show that ED acts as an inverse agonist of ERRα and ERRγ by directly interacting with these receptors, and inhibiting their transcriptional activity. We also demonstrate that ED has strong anti-mitogenic properties. ED inhibits the growth of both estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cells in a dose dependent manner, while of displaying a little effect on normal epithelial breast cells. In addition, we show that cholesterol binds directly and specifically to ERRα, it increases the transcriptional activity of ERRα in a peroxisome proliferator-activated receptor coactivator-1α (PGC-1) dependent manner. Our finding suggests that cholesterol enhances the interaction of ERRα and its coactivator PGC-1, and this leads to induce the expression of ERRα itself (an specific auto-induction) and the metabolic target genes of ERRα to fuel TNBC cells proliferation and migration. Moreover, our results demonstrates that the effect of cholesterol or lovastatin (a drug known to inhibit cholesterol synthesis) in triple negative breast cancer (MDA-MB 231) requires ERRα. These data suggest that both ED-ERR and cholesterol-ERR interactions may represent novel druggable signaling pathway in TNBC. Citation Format: Faegheh Ghanbari, Sylvie Mader, Anie Philip. Inhibition of triple negative breast cancer cell progression using estrogen related receptor alpha endogenous ligands [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 4375.
SAFETY AND EFFICACY OF PERCUTANEOUS MITRAL VALVE-IN-VALVE AND MITRAL VALVE-IN-RING PROCEDURES: SYSTEMATIC REVIEW AND POOLED ANALYSIS OF 30 DAY AND ONE YEAR OUTCOMES
Authors: Prasanna Sengodan, Yash Jobanputra, Kesavan Sankaramangalam, Ganesh Athappan, Wael Jaber, Jonathon White, Stephanie Mick, Jose Navia, Amar Krishnaswamy, E. Murat Tuzcu, Samir Kapadia
Journal: Journal of the American College of Cardiology (2018)