tbuckley/cabot-search huggingface dataset:
Abstract 3364: Preclinical evaluation of BiTE®immune therapy targeting MUC17 or CLDN18.2 for gastric cancer
Authors: Julie M. Bailis, Petra Lutterbuese, Oliver Thomas, Kathrin Locher, John Harrold, Michael Boyle, Joachim Wahl, Shyun Li, Alexander Sternjak, Anja Henn, Christoph Dahlhoff, Virginie Naegele, Benno Rattel, Tobias Raum, Angela Coxon
Journal: Cancer Research (2020)

Abstract Advanced gastric cancer remains a disease of high unmet medical need. In the United States, most patients present with symptomatic, incurable disease and prognosis is poor, with a 5-year survival rate of less than 10%. BiTE® (bispecific T cell engager) immune therapy activates a patient's own T cells to kill tumor cells and has the potential to overcome common mechanisms of therapy resistance. We generated fully human, half-life extended (HLE) BiTE® molecules against the tumor antigens MUC17 and CLDN18.2 for the treatment of gastric cancer. The mucin MUC17 is a protein normally found in the mucosal layer of intestinal epithelial cells that is delocalized and expressed in 45% of gastric tumors. The claudin CLDN18.2 is a protein normally found in the cellular tight junctions of gastric mucosa and intestinal epithelium that is delocalized and expressed in &amp;gt;60% of gastric tumors. AMG 199 (MUC17 HLE BiTE®) and AMG 910 (CLDN18.2 HLE BiTE®) show potent cytotoxic activity against gastric cancer cell lines that express MUC17 or CLDN18.2, respectively, in vitro, and promote significant tumor growth inhibition against established gastric tumor xenograft models in vivo. In preclinical non-human primate (NHP) toxicology studies, both molecules show evidence for BiTE® target engagement, including T cell activation and proliferation, but demonstrate different effects on target-expressing tissue. Weekly administration of AMG 199 is well tolerated in NHP with minimal findings in MUC17-expressing normal tissues. In contrast, treatment with AMG 910 led to direct cell killing of CLDN18.2-expressing gastric mucosal cells in NHP, a finding which was fully reversible once treatment was stopped. AMG 199 and AMG 910 may offer the potential to improve outcomes in advanced gastric patients worldwide. Citation Format: Julie M. Bailis, Petra Lutterbuese, Oliver Thomas, Kathrin Locher, John Harrold, Michael Boyle, Joachim Wahl, Shyun Li, Alexander Sternjak, Anja Henn, Christoph Dahlhoff, Virginie Naegele, Benno Rattel, Tobias Raum, Angela Coxon. Preclinical evaluation of BiTE®immune therapy targeting MUC17 or CLDN18.2 for gastric 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 3364.
Abstract 336: Organotypic co-cultures as a novel 3D model for head and neck squamous cell carcinoma
Authors: Julia C. Thierauf, Luca Engelmann, Natalia Koerich Laureano, Hans-Jürgen Stark, Elena-Sophie Prigge, Dominik Horn, Kolja Freier, Niels Grabe, Philippe Federspil, Peter K. Plinkert, Magnus von Knebel Doeberitz, Jochen Hess, Annette Affolter
Journal: Cancer Research (2020)

Abstract Background. Head and neck squamous cell carcinomas (HNSCC) are histologically and molecularly heterogeneous tumors and frequently develop resistance mechanisms against treatment. Reliable patient-derived 3D tumor models are urgently needed to further study the complex pathogenesis of these tumors and how to overcome treatment failure. Methods. We developed a 3D organotypic co-culture (OTC) model for HNSCCs that maintains the architecture and cell composition of the patients' tumor. A dermal equivalent, composed of healthy, human-derived fibroblasts embedded into viscose fibers, grows in an insert for approximately 10 days in culture and serves as a scaffold for the patient sample. After outgrowth of fibroblast within the dermal equivalent, we cultivated vital HNSCC tumor explants from 13 patients (non-HPV driven, n=7; HPV-driven HNSCC, n=6) by carefully placing them on top of the scaffold. Fractionated irradiation (IR) was applied to 5 samples. To evaluate tumor proliferation and areas of apoptosis, we performed immunohistochemistry and immunofluorescence with antibodies against ki-67, cleaved caspase-3, pan-cytokeratin (PanCK), p16INK4a, and vimentin. Results. All 3D OTC models of non-HPV driven samples encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of primary and 3D-OTC models were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth and invasion patterns. Radioresistant and clonally expanding tumor cells were enriched in 3D-OTC models after fractionated IR. HPV DNA was detectable in both primary and OTC (day 14) of HPV-driven tumors; However, p16INK4a expression levels were varying. Conclusion. Our 3D-dimensional organotypic co-culture model for HNSCC supports cancer cell survival and proliferation in their original microenvironment. The model enables investigation of invasive cancer growth as well as clonal expansion of resistant cancer cells upon treatment. In the future, the introduced model might serve as a platform to perform sensitivity testing upon treatment to predict the patients' individual response to therapy. Citation Format: Julia C. Thierauf, Luca Engelmann, Natalia Koerich Laureano, Hans-Jürgen Stark, Elena-Sophie Prigge, Dominik Horn, Kolja Freier, Niels Grabe, Philippe Federspil, Peter K. Plinkert, Magnus von Knebel Doeberitz, Jochen Hess, Annette Affolter. Organotypic co-cultures as a novel 3D model for head and neck 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 336.
Abstract 1924: Genetic analysis of responses to eribulin <i>versus</i> vinorelbine and paclitaxel in 100 cancer cell lines from the cancer cell line Encyclopedia (CCLE)
Authors: Pallavi Sachdev, Roy Ronen, Janusz Dutkowski, Bruce A. Littlefield
Journal: Cancer Research (2020)

Abstract Background: Eribulin mesylate, a synthetic analog of the marine sponge natural product halichondrin B, is a microtubule dynamics inhibitor that acts via both cytotoxic antimitotic mechanisms as well as non-cytotoxic effects on tumor vasculature, tumor phenotype and the tumor microenvironment. Eribulin is approved in the US for treatment of certain patients with advanced breast cancer or liposarcoma. Here we examined in vitro antiproliferative responses to eribulin versus vinorelbine and paclitaxel in 100 human cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE), followed by analysis of CCLE baseline gene expression data with the goal of assessing overlapping and non-overlapping pathways and genes associated with drug response and resistance. Methods: In vitro proliferation assays were conducted on 100 CCLE cell lines. Cancer types represented by ≥5 cell lines include breast, lung, blood, colorectum, ovary, pancreas, skin and kidney. Comparative systems-level analyses of genes, networks and pathways associated with drug response and/or resistance were performed to identify gene and pathway-level determinants of drug response that were either unique to eribulin or shared with vinorelbine and/or paclitaxel. Results: We evaluated genes and molecular pathways driving sensitivity to eribulin versus vinorelbine and paclitaxel in a panel of 100 CCLE cell lines and identified key molecular determinants of response and resistance unique to eribulin. Pathway expression analysis revealed key pathways significantly associated with response to eribulin, including those associated with oxidative stress-induced senescence, histone deacetylation, DNA methylation and Notch signaling. The oxidative stress-induced senescence pathway was significantly enriched for genes whose pretreatment/basal mRNA expression levels were positively associated with response to eribulin but not vinorelbine or paclitaxel. Expression levels of various tubulin isoforms were also identified as positively correlated with eribulin response. Higher and lower pretreatment expression of E-cadherin and N-cadherin, respectively, were also found in cell lines sensitive to eribulin treatment. Conclusion: Pretreatment gene expression analysis demonstrated key gene sets and molecular pathways that may drive response and resistance to eribulin and may differentiate this drug from vinorelbine and paclitaxel. Detailed analysis will be presented at the meeting. Citation Format: Pallavi Sachdev, Roy Ronen, Janusz Dutkowski, Bruce A. Littlefield. Genetic analysis of responses to eribulin versus vinorelbine and paclitaxel in 100 cancer cell lines from the cancer cell line Encyclopedia (CCLE) [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 1924.
Abstract 4363: A-FABP and estrogens are independently involved in the development of breast cancer
Authors: Bing Li, Jiaqing Hao, Xiaofang Yan, Maiying Kong, Edward Sauter
Journal: Cancer Research (2020)

Abstract Background: We previously reported that postmenopausal obese women exhibit increased levels of circulating adipocyte fatty acid binding protein (A-FABP), which is associated with breast cancer (BC) development. In postmenopause, increased estrogen levels are associated with increased BC risk. Hypothesis: Estrogens (estrone: E1, estradiol: E2 and estriol: E3) are associated with A-FABP in the setting of obesity and obesity-related BC development. Methods: Immunoassays for E1, E2, E3, and A-FABP were performed using serum samples from women with and without BC. Results: Statistical analysis was conducted using the Mann-Whitney test and multiple linear regression models. Considering all subjects, E1 and E2 but not E3 levels were significantly higher in pre- than in postmenopause among both non-obese and obese individuals (p&amp;lt;0001). E3 (p&amp;lt;0.01) and E1 (p&amp;lt;0.05) levels were higher in non-obese than in obese women. A-FABP levels were significantly higher in obese postmenopausal women with and without BC, but not in premenopausal women, regardless of BC status. When stratified by BC status, E2 levels were significantly higher, while E1 and E3 levels were significantly lower in postmenopausal healthy obese than non-obese women. These body mass index (BMI) based differences were not observed among women with BC. E3 levels were higher in obese pre (p=0.003) and postmenopausal (p=0.001) women with BC than those without. A-FABP levels were significantly higher in postmenopausal obese healthy women and women with BC. A-FABP was not highly associated with E1, E2 or E3. Impact: 1) A-FABP expression is increased in postmenopausal obese women with and without BC; 2) E1 and E2 expression is higher in pre- than postmenopausal women, regardless of BMI; 3) E1 and E3 levels are higher in lean than obese individuals, regardless of menopausal status; 4) the influence of obesity on E1, E2 and E3 expression in postmenopause is lost in women with BC, 5) E3 is increased in obese vs. non-obese women with BC, and 6) A-FABP and estrogens are independently involved in the development of BC. Citation Format: Bing Li, Jiaqing Hao, Xiaofang Yan, Maiying Kong, Edward Sauter. A-FABP and estrogens are independently involved in the development of 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 4363.
Abstract 6535: A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties
Authors: James Harper, Andrew Leinster, Nicola Rath, Shannon Burke, Kathy Mulgrew, Hong Jin, Robert W. Wilkinson
Journal: Cancer Research (2020)

Abstract Oncolytic viruses offer the potential to be transformative in the treatment of cancers through their ability to selectively infect, replicate in and kill tumors whilst able to potently activate the immune system. Their activity can be further augmented through the addition of transgenes leading to tumor selective gene expression. Our proprietary Newcastle Disease virus (NDV) backbone has previously been demonstrated to have broad oncolytic activity whilst inducing potent anti tumor immune effects in preclinical models. We set out to test whether the incorporation of an IL-12 transgene into the NDV backbone could result in transgene dependent enhancement in anti tumor efficacy. In vitro, the addition of IL-12 into the NDV genome did not alter NDV infectivity in tumor or non-cancer cells compared to the backbone virus and infection of cancer cells resulted in the production of bioactive IL-12. In an immune-deficient xenograft model, a single systemic administration of NDVhuIL-12 resulted in tumor selective replication and local IL-12 production within the tumor microenvironment (TME). In syngeneic tumor models, local tumoral administration of NDVmuIL-12 resulted in the generation of an elevated and more durable type II interferon response compared to NDV-GMCSF; though similar pharmacokinetic profiles were observed. This difference in cytokine response correlated with superior single agent efficacy of NDVmuIL-12 compared to NDV alone in the B16F10 model. Furthermore, NDVmuIL-12 demonstrated anti tumor efficacy in several NDV refractory models, suggesting tumor expression of IL-12 was necessary to drive anti tumor activity in some circumstances. Across all models tested significant changes in the tumor immune microenvironment, previously associated with enhanced anti tumor immunity were observed in NDVmuIL-12 tumours compared to backbone virus alone. There is an abundance of pre-clinical data demonstrating that IL-12 can exert potent anti tumor activity, but its clinical application has been hindered through its toxicity when administered systemically. These data provide evidence that recombinant NDV could be utilised to deliver IL-12 to the TME when administered systemically and that the addition of IL-12 potentiates the anti tumor activity of NDV. Citation Format: James Harper, Andrew Leinster, Nicola Rath, Shannon Burke, Kathy Mulgrew, Hong Jin, Robert W. Wilkinson. A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties [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 6535.
Abstract 2476: Role of retinoblastoma gene in maintenance of osteoblast function and communication
Authors: Elisha Pendleton, Anthony Ketner, Thomas Bodenstine, Nalini Chandar
Journal: Cancer Research (2020)

Abstract Retinoblastoma gene (Rb1) loss of function mutations is commonly seen in osteosarcomas resulting in poorly differentiated tumors. In addition to cell cycle regulation, Rb1 function has been shown to be important in cell fate determination. It is known that loss of Rb1 function in mesenchymal stem cells inhibits osteoblast differentiation and predisposes them towards adipocytic lineage. Recent studies have suggested a role for Rb1 in cell adhesion but mechanistic details are missing. As cadherin 11 (Cad11) and gap junctional protein connexin43 (Cx43), play important roles in adhesion and communication in osteoblasts, we studied these proteins in MC3T3-E1 mouse calvaria osteoblast cell line. We compared osteoblasts with reduced Rb1 expression to vector-transfected osteoblasts to assess the relationship between Rb1, Cad11, and Cx43. Decreased RNA and protein expression of Cad11 were noted during differentiation of Rb1 deficient osteoblasts when compared to controls. Gap junctional intercellular communication was also studied and found to be reduced with Rb1 loss. Rb1 deficient cells had a higher steady-state level of adipocyte transcription factors and adipocyte markers when compared to control. Interestingly no changes were observed in Cx43 mRNA or protein expression when comparing the two lines. Immunofluorescence analysis demonstrated that a decrease in Cad11 may have affected its co-localization with Cx43. This, in turn, may have affected the proper formation of intercellular channels and thereby communication. These observations suggest that loss of Rb1 affects adhesion and communication in osteoblasts resulting in the expression of an adipocyte phenotype. Citation Format: Elisha Pendleton, Anthony Ketner, Thomas Bodenstine, Nalini Chandar. Role of retinoblastoma gene in maintenance of osteoblast function and communication [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 2476.
Abstract 3516: Commercial gene expression tests for prostate cancer outcome risk in men of West African ancestry
Authors: Sandra M. Gaston, Rick A. Kittles, Radka Stoyanova, Teresa M. Giret, Saba A. Ansari, Sanoj Punnen, Alan Pollack
Journal: Cancer Research (2020)

Abstract Both incidence and mortality data show that the burden of prostate cancer (PrCa) is greater for African Americans (AA) than for European Americans (EAs), with AAs about 1.7 times more likely to be diagnosed with PrCa than EAs and about 2.4 times more likely to die of this disease. Molecular testing of prostate cancer tissue is increasingly being incorporated into patient management. Current National Comprehensive Cancer Network (NCCN) guidelines recommend three commercially available gene expression based tests for PrCa prognosis: Decipher (GenomeDX), Oncotype GPS (Genomic Health) and Prolaris (Myriad). All three of these tests were developed in predominantly EA patient populations and subsequent studies in AA patients have not included ancestry genotyping to assess genetic admixture. In a pilot study we used the Genomics Resource Information Database (GRID) to compare the research versions of these three commercial gene expression tests for PrCa outcome risk in 157 cancer positive biopsy cores from 55 patients. We also performed ancestry genotyping to estimate each patients European, West African and Native American Ancestry. The overall distribution of scores predicting average, higher than average and lower than average outcome risk differed for the three tests, with higher risk scores in 17%, 7% and 27% and lower risk scores in 69%, 73% and 43% of the cores for the Decipher, GPS and Prolaris tests, respectively. Interestingly, 25%, 37%, and 16% of 56 Cores with high risk pathology (grade group 3-5) were classified as low risk by the Decipher, GPS and Prolaris tests, respectively. In the 21 cores from men with &amp;gt; 70% WA ancestry, 100%, 80% and 30% of cores with intermediate and high risk pathology (grade group 2-5) were paradoxically classified as low risk by the research Decipher, GPS and Prolaris tests, respectively. These preliminary results are consistent with the evidence recently published by Creed et al (2019) suggesting that the currently available commercial genomic tests may underestimate prostate cancer outcome risk in AAs. Ancestry genotyping may be useful in rescaling genomic prostate cancer outcome risk tests that were developed in predominantly EA cohorts for use in AA patients. Reference: Creed JH et al. Cancer Epidemiol Biomarkers Prev, published online 2019. Citation Format: Sandra M. Gaston, Rick A. Kittles, Radka Stoyanova, Teresa M. Giret, Saba A. Ansari, Sanoj Punnen, Alan Pollack. Commercial gene expression tests for prostate cancer outcome risk in men of West African ancestry [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 3516.
Abstract 1020: Anti-oxidant amino acid L-ergothioneine exhibits immunomodulatory effect by regulating immunosuppressive cytokine production of tumor cells
Authors: Kazunori Kato, Katsuhiro Kuroki, Yui Shimizu
Journal: Cancer Research (2020)

Abstract Ergothioneine (ERG) is a natural antioxidant nutrient containing in edible golden oyster mushroom, Pleurotus cornucopiae (Tamogitake). In previous AACR meeting, we reported that administration of ERG rich water extracts of p. cornucopiae to tumor-bearing mice could suppress the growth of subcutaneous tumors and reduce the number of regulatory T cells (Treg) in lymph node and spleen. However, the molecular events inducing antitumor and immunomodulatory effects are still unknown. Our aim is to identify the mechanism of ERG in tumor cells which secrete various immunomodulatory cytokines. We cocultured human tumor cell lines with ERG and tested cytokine concentration in culture supernatants and expression of immune checkpoint molecules on tumors. ERG could significantly inhibit the production of VEGF, CCL2 and TGF-β1 which are important in not only angiogenesis and tumor invasion but also Treg induction. Importantly, ERG also reduced the expression of some immune checkpoint molecules on tumor cells and prolonged the survival of IL-2-activated lymphocytes in vitro. Overall, ERG rich water extract of p. citrinopileatus might inhibit the induction of Treg in tumor-bearing host via suppression of VEGF and TGF-β1, indicating a novel immunomodulatory antioxidant nutrient in mushrooms Citation Format: Kazunori Kato, Katsuhiro Kuroki, Yui Shimizu. Anti-oxidant amino acid L-ergothioneine exhibits immunomodulatory effect by regulating immunosuppressive cytokine production of tumor 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 1020.