tbuckley/cabot-search huggingface dataset:
Abstract 5508: BCMA-CD3 bispecific antibodies: A modeling framework to characterize kinetics of bispecific antibody, T cell, cytokines, and serum M-protein
Authors: Chandrasekhar Udata, Dai Wei, Sibo Jiang, Alison Forgie, Andrea Hooper, Wenlian Qiao, Cynthia Musante, Donghua Yin
Journal: Cancer Research (2020)

Abstract The B-cell maturation antigen (BCMA) is an attractive target in multiple myeloma since it is more selectively expressed on myeloma cells. Meanwhile, T-cell-engaging bispecific antibodies (BsAbs) are an important class of antibody therapeutics in cancer therapy. BCMA-CD3 BsAbs simultaneously bind to CD3 on T cells and BCMA on tumor cells, activate T cells, and redirect T cells' cytotoxicity against tumor cells. BCMA is shed from the surface of plasma cells by gamma-secretase-mediated cleavage, leading to detectable, soluble BCMA (sBCMA) in circulation. Higher concentrations of sBCMA in patients with myeloma are associated with poorer clinical outcomes. Furthermore, sBCMA in circulation may act as a drug sink, especially when it is present in a relatively higher amount compared to the drug concentration, potentially attenuating the intended pharmacological mechanism and impacting pharmacokinetics and efficacious dose predictions. To address the complexities, we leveraged a quantitative systems model to characterize the kinetics of a model BsAb, T-cell, cytokines and serum M-protein upon BsAb treatment based on the literature data. This model incorporated T-cell activation, cytokine profiles as well as serum M-protein following various dosing regimens and baseline sBCMA levels. This model could assist in the design of clinical dosing strategies for BCMA-CD3 BsAb programs. Citation Format: Chandrasekhar Udata, Dai Wei, Sibo Jiang, Alison Forgie, Andrea Hooper, Wenlian Qiao, Cynthia Musante, Donghua Yin. BCMA-CD3 bispecific antibodies: A modeling framework to characterize kinetics of bispecific antibody, T cell, cytokines, and serum M-protein [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 5508.
Abstract 598: Integrated computational and experimental design of a monobody targeting PDL1
Authors: Reed E. Harrison, Chi-Wei Man, Yingxiao Wang
Journal: Cancer Research (2020)

Abstract Monobodies (Mb) are small, synthetic antibodies based on the human fibronectin type III domain that exhibit high thermodynamic stability without disulfide bonds. To explore suitability of these domains as cancer-targeting molecules, we apply computational and experimental methods to develop a Mb that targets programmed-death-ligand 1 (PDL1). As some tumors overexpress PDL1 to inhibit T-cell responses, a PDL1-binding Mb could be used to promote successful immunotherapy. More broadly, computational methods applied to developing a PDL1-binding Mb can also be applied to developing new Mbs that target cancer antigens. Starting from the G9 Mb (PDB: 1ttg), we grafted the CDR3 loop of a known PDL1-binder (PDB: 5jds) into the FG loop of the Mb. This design was displayed on the surface of yeast and shown to bind PDL1 better than the G9 Mb, though not as well as a high affinity variant of PD1, the cognate receptor of PDL1. Using molecular dynamics simulations, we evaluated structural features that are unlikely to contribute to PDL1-binding. Using this approach, we selected amino acid positions for site-saturated mutagenesis and constructed a yeast library displaying Mb isoforms. Through iterative rounds of selection, we identified a Mb isoform with further improved PDL1-binding. Citation Format: Reed E. Harrison, Chi-Wei Man, Yingxiao Wang. Integrated computational and experimental design of a monobody targeting PDL1 [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 598.
Abstract 2832: Multiplex fluorescent imaging of the metastatic melanoma microenvironment reveals spatially-dependent macrophage interactions modulating tumor-infiltrating T-cells
Authors: Victor G. Wang, Jan Martinek, Ananya Gulati, Hannah Boruchov, Kelly Ray, Karolina Palucka, Jeffrey H. Chuang
Journal: Cancer Research (2020)

Abstract Tumor-infiltrating lymphocytes (TIL) hold strong prognostic value in determining patient survival as well as response to immune checkpoint blockade across many tumor types, especially metastatic melanoma. Tumors often evolve mechanisms to prevent TIL access and/or function to allow for continued growth. One such mechanism is the recruitment and reprogramming of tumor-associated macrophages (TAM) which suppress TILs through a variety of pathways. The interactions between TAMs and TILs that result in a suppressive tumor microenvironment (TME) have been studied in vitro and with spatially-agnostic sequencing, leaving the location-specific contributions underexplored. Interrogating the TAM-TIL interactions in an intact TME will uncover novel mechanisms responsible for TAM function and may be key to reversing TIL immunosuppression, improving anti-tumor immune responses, survival, and potentially therapy response. We use histocytometry, a multiplex quantitative tissue imaging method capable of capturing whole-slide tumor sections, to explore the human metastatic melanoma TME in situ and resolve the spatial contributions of TAM-TIL interactions. We demonstrate a T-cell preference for physical contact with phagocytic TAMs in the tumor but non-phagocytic TAMs in the stroma. We further model immune synapses from histocytometry to probe the function underlying the TAM-TIL preference based on the directionality of signaling components. The model suggests T-cells in contact with macrophages in the tumor are communicating more frequently with the phagocytic TAMs as compared to their non-phagocytic counterparts, indicating that this interaction extends beyond a simple proximity preference. In addition, proliferating T-cells communicate more frequently with macrophages than non-proliferating T-cells but this effect limited to the intratumor space. Together we demonstrate the functional consequences of physical TAM-TIL interactions with unprecedented spatial resolution. This work unravels important TAM interactions that shape the TME which have not been previously appreciated, providing novel insight into the forces modifying T-cell function in the TME and revealing new TAM biology to explore further. Citation Format: Victor G. Wang, Jan Martinek, Ananya Gulati, Hannah Boruchov, Kelly Ray, Karolina Palucka, Jeffrey H. Chuang. Multiplex fluorescent imaging of the metastatic melanoma microenvironment reveals spatially-dependent macrophage interactions modulating tumor-infiltrating T-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 2832.
Abstract 6553: Plant power: Plant isolate dibenzyl trisulfide induces death of triple-negative breast cancer cells derived from an African American patient
Authors: Jonathan Wooten, Cristina Araújo, Shaniece Wauchope, Joyce Aja, Nicole Mavingire, Rupika Delgoda, Eileen Brantley
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC), characterized by tumors that lack estrogen receptor, progesterone receptor, and human epidermal growth receptor expression, represents one of the most aggressive subtypes of breast cancer. TNBC carries a poor prognosis due, in part, to a lack of clinically available targeted therapy. Novel therapeutic strategies to combat TNBC primarily involve the use of synthetic small molecules. However, the World Health Organization reports that there is increased use of natural remedies and traditional medicine to treat diseases. Our lab has investigated the chemotherapeutic and chemopreventive effects of a variety of plant isolates. Dibenzyl trisulfide (DTS) is derived from Petiveria alliacea, a perennial shrub that grows in tropical regions of the world. Previous investigations surrounding DTS are limited to anticancer actions in European American breast cancer cells. The purpose of this study was to evaluate the anticancer actions of DTS in CRL-2335 cells which are derived from an African American patient with TNBC. We found that DTS inhibited TNBC cell migration and proliferation using wound healing and colony forming assays. Furthermore, we found DTS induced apoptotic body formation and nuclear fragmentation using relief contrast and fluorescence microscopy respectively. Moreover, using the Annexin V/PI assay we found that DTS induced early apoptosis, which was partially attenuated in cells pretreated with pan-caspase inhibitor zVAD-fmk. Finally, quantitative polymerase chain reaction analyses revealed that DTS induced the expression of pro-apoptotic genes BAK1, LTA and GADD45A. Our data suggest that DTS effectively induces caspase-independent death of TNBC cells derived from an African American patient and represents a promising agent to treat more refractory forms of breast cancer. Citation Format: Jonathan Wooten, Cristina Araújo, Shaniece Wauchope, Joyce Aja, Nicole Mavingire, Rupika Delgoda, Eileen Brantley. Plant power: Plant isolate dibenzyl trisulfide induces death of triple-negative breast cancer cells derived from an African American patient [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 6553.
Abstract 4139: Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer
Authors: Kalin L. Wilson, Dana M. Brantley-Sieders
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis relative to other breast cancers. Due to its lack of expression of commonly targeted cell surface markers and hormone receptors, there is a dearth of precision treatment options for this malignancy, with chemotherapy and radiation therapy remaining the major mainstays of care. Our group has previously reported that the receptor tyrosine kinase EphA2 is enriched in the basal-like/triple-negative breast cancer subtype and that this expression is associated with reduced recurrence-free survival. Furthermore, genetic knockdown or inhibition of EphA2 with the small molecule ALW-II-41-27 (ALW) reduces cancer cell growth in vitro and in vivo. In these studies, we sought to investigate whether the antitumor properties of ALW can be augmented by addition of other compounds to further reduce cancer cell growth and induce apoptosis. To this end, TNBC lines MDA-MB-231, BT-549, HCC1395, and HCC1187 were seeded in 96-well plates and exposed to ALW alone or in combination with chemotherapeutic agents doxorubicin and paclitaxel, CDK inhibitor SCH-727965, and MCL-1 inhibitor S63845 and cell viability assessed by MTT assay at 48 hours. While there was no significant reduction in viability for cells treated with ALW plus chemotherapy and no consistent improvement with addition of S63845 across cell lines, the combination of ALW with SCH-727965 performed significantly better than either drug alone (p &amp;lt; 0.05) in HCC1395 and BT-549 cells. To evaluate drug synergy, cells of all lines above were exposed to variable concentrations of SCH-727965, ALW, and the combination in a fixed ratio of their respective IC50 values to generate dose response curves, and these data analyzed via CompuSyn software. Combination indices (CI) were &amp;lt;1 for the majority of conditions across all cell lines, supporting synergistic interaction. Effects were most pronounced in HCC1395 cells with average CI 0.82. Furthermore, TUNEL assays show that addition of SCH-727965 to ALW significantly increases the induction of apoptosis by HCC1395 and HCC1187 cells. These preclinical studies demonstrate that combination of ALW and SCH-727965 potently reduces TNBC cell growth and promotes cell death, representing promising early data on the effects of EphA2 inhibition as part of a combination targeted therapeutic approach for triple-negative breast cancer. Citation Format: Kalin L. Wilson, Dana M. Brantley-Sieders. Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast 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 4139.
Abstract 3313: iPSC-derived natural killer cells expressing EGFR-CAR against glioblastoma
Authors: Melissa Yu, Anthony G. Mansour, Kun-Yu Teng, Guoqiang Sun, Yanhong Shi, Michael A. Caligiuri
Journal: Cancer Research (2020)

Abstract Background: Natural Killer (NK) cells are a type of immune cells that belong to the innate immune system and executes a rapid immune reaction against cancer cells and viruses without prior activation. The huge success of chimeric antigen receptor (CAR)-T cells has motivated scientists to genetically modify human NK cells with CARs to further improve their tumor killing capacity. To engineer NK cells with a CAR, NK cells can be isolated from peripheral blood and umbilical cord blood. NK cells can also be derived from induced pluripotent stem cells (iPSCs) to produce a homogenous and standardized group of NK cells for the treatment of cancer. Here, we test the feasibility to engineer our EGFR-CAR construct into iPSC-derived hematopoietic stem cells (iPSC-HSC) to generate EGFR-CAR NK cells that will eradicate glioblastoma (GBM). Material and Methods: iPSCs-derived HSCs were differentiated into NK cells using co-culture with a feeder stroma of OP9-DL1 cells in the presence of human cytokines and NK cells were assessed by flow cytometry. Expanded NK cells (with K562 feeder cells expressing mb-IL-21 and 4-1BB) and HSCs from peripheral blood were efficiently transduced with a retroviral vector, carrying a CAR targeting EGFR. CAR expression was assessed by flow cytometry. After transduction, the CAR-NK cells were collected for cytotoxicity assay to test their efficacy. CAR-HSCs were differentiated into CAR-NK cells utilizing OP9-DL1 stroma cells. Results: Our results demonstrated that iPSCs can be fully differentiated into NK cells expressing typical NK cell surface markers including CD56, NKp46, CD16 and NKG2A, etc. In addition, HSCs can be engineered with EGFR-CAR without affecting their differentiation into CAR-NK cells. Our engineered EGFR-CAR NK cells showed an enhanced antitumor activity against GBM compared to NK cells without the EGFR-CAR. Conclusion: Collectively, our study suggests the feasibility of engineering CAR-EGFR NK cells from iPSCs for effective “off the shelf” immunotherapy. Our approach can be utilized to generate an unlimited number of CAR-NK cells to treat patients with cancer such as GBM in the clinical setting. Citation Format: Melissa Yu, Anthony G. Mansour, Kun-Yu Teng, Guoqiang Sun, Yanhong Shi, Michael A. Caligiuri. iPSC-derived natural killer cells expressing EGFR-CAR against glioblastoma [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 3313.
Abstract 5400: Pharmacogenomics in the primary and metastatic osteosarcoma: Gene expression profile associated with outcome
Authors: Alini Trujillo-Paolillo, Francine Tesser-Gamba, Antonio Sergio Petrilli, Maria Teresa Alves, Reynaldo Jesus Garcia-Filho, Renato Oliveira, Silvia Regina Toledo
Journal: Cancer Research (2020)

Abstract Purpose: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Drug resistance and unfavorable outcome are problems that still affect an important percentage of OS patients. Thus, the aim of the present study was to analyze the expression of genes related to pharmacogenomics in OS. Procedure: The expression of 32 target genes in 80 paired specimens (pre-chemotherapy primary tumors, post-chemotherapy primary tumors and pulmonary metastases), from 33 patients diagnosed with OS, were analyzed by the real-time PCR methodology. Five normal bone specimens were used as calibrators (control). The target genes are related to drug transport, drug detoxification, doxorubicin and folate pathway, DNA repair, cell cycle and apoptosis. Results: The higher ABCC3 gene expression in pre-chemotherapy primary tumors was associated with worse event-free survival (EFS) (p=0.048, HR=3.41). The higher TOP2A gene expression in post-chemotherapy primary tumors was associated with worse overall survival (OAS) and EFS (p=0.015, HR=5,37; p=0.006, HR=6.36; respectively). The lower MTHFR gene expression in pulmonary metastases was associated with worse OAS and EFS (p=0.027, HR=3.27; p=0.024, HR=3.1; respectively), as well as the lower BCL2L1 gene expression (p=0.018, HR=3.53; p=0.019, HR=3.29). Furthermore, lower expression of the RALBP1, ABCC2 and SOD1 genes in the pulmonary metastasis specimens were associated with worse EFS (p=0.022, HR=3.26; p=0.048, HR=3.16; p=0.027, HR=3.14; respectively). Moreover, the pulmonary metastases presented higher expression of the ABCC1 and ABCC4 genes (p=0.049; p =0.039; respectively) and lower expression of the ABCC10, ERCC2, MSH2, SLC22A1, SOD1 and TOP2A genes (p=0.049; p=0.043; p=0.043; p=0.017; p=0.048; p=0.005; respectively) than pre-chemotherapy primary tumors. Conclusion: Therefore, the pharmacogenomics profile may be useful as prognostic factors as well as therapeutic targets. Thus, our findings may, in the future, contribute to clinical management in the primary and metastatic OS. Citation Format: Alini Trujillo-Paolillo, Francine Tesser-Gamba, Antonio Sergio Petrilli, Maria Teresa Alves, Reynaldo Jesus Garcia-Filho, Renato Oliveira, Silvia Regina Toledo. Pharmacogenomics in the primary and metastatic osteosarcoma: Gene expression profile associated with outcome [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 5400.
Abstract 6588: Omics integration provides insight into esophageal cancer inhibitory mechanisms of a cranberry extract
Authors: Katherine M. Weh, Connor L. Howard, Bridget A. Tripp, Jennifer L. Clarke, Amy B. Howell, Laura A. Kresty
Journal: Cancer Research (2020)

Abstract Our laboratory studies chemoprevention of esophageal adenocarcinoma (EAC) through utilization of the rat esophagogastroduodenal anastomosis (EGDA) surgical model of reflux-induced EAC. Specifically, we evaluated mechanisms by which cranberry proanthocyanidins (C-PAC) inhibit reflux-induced EAC by utilizing multi-omics integrative approaches employing multiple program platforms. Herein, we investigated whether pathway-based integration could be used to examine cross-talk between genes, metabolites and the microbial profiles. For this analysis, we utilized transcriptomic and untargeted metabolomic data from rat esophagi of animals that received water or C-PAC in the drinking water alone or combined with reflux inducing EGDA surgery. Additionally, we isolated DNA from fecal pellets and performed 16S rRNA sequencing to assess gut microbiome composition and functionality. Each omics dataset was analyzed for significant pathway enrichment and network generation using Metacore, DAVID and Metabolync. PICRUSt was utilized to predict microbiota functionality. Analysis of transcriptomic and metabolomic data suggest that EGDA upregulates inflammatory, NF-kB, DNA damage, cell cycle and immune function pathways as well as metabolic pathways related to eicosanoids, amino acids and primary and secondary bile acids, while C-PAC mitigates these alterations. Preliminary microbiome data analysis also suggests that bacteria related to inflammation, metabolite transport and DNA damage are increased in abundance in EGDA, with a decrease in abundance following C-PAC treatment. Analysis of omics datasets can provide insightful relationships into the cross-talk between different processes regulated by transcription, metabolism and the microbiome. Single dataset and integrative analysis showed similarities in altered pathways for vehicle and C-PAC treated animals in the context of reflux. Integration is limited by the infancy of multi-omics analysis programs, as well as the limited amount of research involving prediction of bacterial function and integration of microbiome data with other omics datasets. Further research and development of these omics programs is needed to determine accuracy of predicted results as well as continued investigation of identified pathways. Citation Format: Katherine M. Weh, Connor L. Howard, Bridget A. Tripp, Jennifer L. Clarke, Amy B. Howell, Laura A. Kresty. Omics integration provides insight into esophageal cancer inhibitory mechanisms of a cranberry extract [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 6588.
Abstract 5949: Artesunate influences the transcripts for Eph receptors and ephrin ligands in breast cancer cells
Authors: Tanin Zadeh, Mariana Lucero, Raj Kandpal
Journal: Cancer Research (2020)

Abstract Purpose: Artesunate (ART), an anti-malarial drug, has been shown to induce apoptosis in breast cancer cells. The current study was conducted to explore the involvement of Eph receptor and ephrin ligand transcript levels in mediating apoptotic functions of ART in three phenotypically distinct breast cell lines. The specific involvement Eph receptors and ephrin ligands in apoptosis may potentially lead to novel approaches for therapeutic intervention of breast cancer. Methods: We cultured three cell lines that represent non-tumorigenic breast epithelium (MCF10A), non-invasive breast carcinoma (MCF7), and invasive triple negative breast carcinoma (MDA- MB-231) in the presence of varying concentrations of ART. Total RNA was isolated from untreated and ART-treated cell lines, and the relative abundance of Eph receptor and ephrin ligand transcripts was determined by qPCR. The changes in selected transcripts were confirmed by immunocytochemistry and western blot analysis. Results: Our study revealed that the transcripts corresponding to various Eph receptors and ephrin ligands are differentially expressed in a cell line specific manner in ART-treated cells. Specifically, EphA5 was upregulated and EphB4 was significantly downregulated in MCF10A cells. However, MDA-MB-231 cells were distinguished by upregulation of ephrinA2 and downregulation of EphA7, respectively. MCF7 also showed distinct response to ART treatment. Combinatorial alterations in transcript abundance for a subset of Eph receptors and ephrin ligands are likely to provide meaningful insights in the apoptotic effects of ART in breast cancer cells. Conclusions: A variety of experiments directly or indirectly support the role of Eph receptors and ephrin ligands in apoptosis of numerous cell types. To our knowledge, there have been no conclusive studies to implicate these molecules in ART-mediated cell death. We have demonstrated cell line-specific alterations in the levels of Eph/ephrin transcripts in cells primed for apoptosis by ART-treatment. Specifically, EphA5, EphA7, EphB4 and ephrin A2 appear to transduce apoptotic signals in ART-treated cells. These observations set the basis for pursuing additional mechanistic investigations to decipher novel mediators of apoptosis in breast cancer cells. Citation Format: Tanin Zadeh, Mariana Lucero, Raj Kandpal. Artesunate influences the transcripts for Eph receptors and ephrin ligands in breast 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 5949.