bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5186: Human stem cell humanized mouse model for in vivo evaluation of bispecific antibody efficacy and drug-induced cytokine release
Authors: Yao Li-Chin , Cai Danying , Aliperta Roberta , Colthart Allison , Meier Werner , Cheng Mingshan , Keck James G. 
Published: September 2020

Abstract
Bispecific antibodies have shown several promising advantages over monoclonal antibodies and are emerging as one of the growing cancer immunotherapies. Preclinical in vivo models to assess efficacy and cytokine release associated with immune cell engagement are needed. We have developed a human stem cell (HSC) humanized mouse model for testing efficacy and for quantifying cytokine release in response to bispecific antibody treatment. Here we evaluated an EGFR bispecific T cell engager (BiTE), using EGFR-positive MDA-MB-231 orthotopic breast cancer model in CD34+ HSC humanized NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG™) mice. BiTE treatment for 2 weeks resulted in complete tumor regression when dosing was initiated at an average tumor volume of around 100 mm3. In addition, BiTE treatment for 4 weeks effectively inhibited the tumor growth when dosing mice bearing larger tumors of around 400mm3 in volume. Sixteen hours after the first two doses as compared to PBS control, human cytokines IFN-γ, IL-6, and IL-10 were elevated. Cytokine levels then returned to the baselines following continuous dosing. We observed a similar time course and levels of cytokine release between these two BiTE-treated groups with different tumor sizes. T cell activation in the peripheral blood after the last dose was assessed by flow cytometry analysis. In the BiTE-treated group, T cell percentage decreased, as compared to the PBS control. Both CD4+ and CD8+ T cell subsets showed an increased frequency of CD69+ cells after BiTE treatment. Evaluation of drug efficacy and cytokine release in response to BiTE treatment using PBMC-humanized NSG™ mice with and without MDA-MB-231 tumors are underway and results will be discussed.
Citation Format: Li-Chin Yao, Danying Cai, Roberta Aliperta, Allison Colthart, Werner Meier, Mingshan Cheng, James G. Keck. Human stem cell humanized mouse model for in vivo evaluation of bispecific antibody efficacy and drug-induced cytokine release [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 5186.
Abstract 5251: Reproducible, MoA-reflecting reporter-based bioassays to enable drug development of biosimilars and biobetters
Authors: Edenson Steven , Moravec Richard , Li Dun , Wilkinson Jennifer , Fan Frank , Cong Mei 
Published: September 2020

Abstract
Cytokines and growth factors are small immunomodulatory proteins secreted by a wide variety of cells including fibroblasts, endothelial and stromal cells, whose role is to regulate surrounding cells in an autocrine, paracrine or endocrine fashion. Immunocytokines represent a promising class of activators of the immune system, with the potential to be used alone or in combination with other therapeutic modalities. Many are currently FDA approved therapy agents (e.g. IFN, IL-2 and Epo), while others are targets for approved biological blocking therapies to treat a variety of diseases. Examples of cytokine blocking agents include basiliximab (IL-2R), tocilizumab and sarilumabad (IL-6R), siltuximab (IL-6), ustekinumab and its biosimilars (IL-12/IL-23 p40), secukinumab (IL-17A), bevasizumab (VEGF), and denosumab (RANKL). Many more are in development and trials as biosimilars and biobetters. IL-2 and IL-15 are still clinically important cytokines as researchers look to improve potency, patient tolerance and response by developing new molecules with sustained and targeted activities. We have developed luciferase reporter bioassays which individually can be used for the quantitation of a variety of cytokines and growth factors including IL-2, IL-6, IL-10, IL-12, IL-15, IL-17, IL-23, BCMA, TGF-b, VEGF and RANKL using respective mechanism of action pathways. The bioassay format is based on thaw-and use cells, eliminating the need to establish and pre-culture cytokine responsive cell lines which provides the benefits of convenience, reproducibility, and transferability. We demonstrate these assays measure cytokine response and inhibition with blocking drugs or potency changes from stressed samples. In summary, these reporter-based bioassays provides valuable tools for the development, stability testing, and potency determination in the manufacture of cytokine biosimilars and biobetters.
Citation Format: Steven Edenson, Richard Moravec, Dun Li, Jennifer Wilkinson, Frank Fan, Mei Cong. Reproducible, MoA-reflecting reporter-based bioassays to enable drug development of biosimilars and biobetters [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 5251.
Abstract 5254: Combined in vitro TTFields and paclitaxel reduce proliferation and clonogenicity in non-small cell lung cancer (NSCLC) cells from a patient previously treated with standard-of-care
Authors: Michelhaugh Sharon K. , Mittal Sandeep 
Published: September 2020

Abstract
TTFields therapy in conjunction with chemotherapy has been FDA approved as a first line treatment regimen for patients with unresectable malignant pleural mesothelioma. Clinical trials are underway to test the efficacy of TTFields in patients with progressive NSCLC or NSCLC brain metastases following standard-of-care or radiosurgery, respectively. Our study utilized tumor cells extracted from a NSCLC metastatic brain tumor from a patient previously treated with standard-of-care chemoradiation prior to progression to brain metastasis. These patient-derived NSCLC cells were subjected to TTFields application with and without paclitaxel to determine if the combination of TTFields with paclitaxel would be more effective than either treatment alone. Written informed consent was obtained from the patient, who was 60 years-old and female. She received concurrent carboplatin/paclitaxel and radiotherapy to the upper lobe of her left lung prior to discovery and resection of a solitary brain lesion. Cells isolated from the metastatic brain tumor were cultured for 3 passages prior to plating on coverslips (4 × 104 each) in DMEM/F12 media with 10% fetal bovine serum. TTFields were applied at ~1.6 V/cm at 150 kHz. Paclitaxel was added to the media to a final concentration of 5 nM. Cells were treated for 14 days. At the end of the treatment period, some coverslips of cells were lysed and assayed for lactate dehydrogenase (LDH) to represent cell number (n=5) and another set of coverslips of cells were harvested and replated in triplicate for the clonogenic assay (n=3). Groups were compared with one-way ANOVA. Data shown in table are mean ± SD. For the LDH assay, ANOVA p&lt;0.0001. For the clonogenic assay, ANOVA p=0.0003. Overall, the combination of TTFields with paclitaxel produced additive reductions in cell proliferation (75%) and reduced the clonogenic potential (95%) compared to untreated controls. The additive effects of TTFields and paclitaxel suggest that they target different cell populations within a heterogeneous tumor, and that lung cancer patients previously treated with standard-of-care may benefit from TTFields therapy.
Proliferation and clonogenic assay results from combined TTFields and paclitaxelAssayControlPaclitaxel (5 nM)TTFieldsTTFields ± Paclitaxel (5 nM)Proliferation (LDH assay)1.83±0.090.81±0.041.34±0.150.46±0.21Clonogenicity (cell counts)26641±46258697±161717399±59981598±598
Citation Format: Sharon K. Michelhaugh, Sandeep Mittal. Combined in vitro TTFields and paclitaxel reduce proliferation and clonogenicity in non-small cell lung cancer (NSCLC) cells from a patient previously treated with standard-of-care [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 5254.
Abstract 5255: The SAGE Direct TestTM: A reliable way of functional profiling to predict the most effective treatment for cancer patients
Authors: Mishra Dhruva , Moy Jennifer , Apfel Chris 
Published: September 2020

Abstract
Cancer is a genetic disease with increasing heterogeneity during disease progression. However, despite the widespread use of genomic testing, a recent publication estimated that only 5% of cancer patients in the US benefit from genome-driven targeted therapies, largely because “actionable mutations” are rare.[1] Thus, SageMedic has developed the SAGE Direct Test™, leading the next generation of functional precision medicine to accurately predict the most effective treatment for virtually all cancer patients without limitations of genomic sequencing or having to identify a specific pathway. Our SAGE Direct Test™ consists of four critical steps, i.e., tissue processing, creation of 3D microtumors, live/dead cell imaging, and metabolic profiling. Using our proprietary technology, we can create hundreds of 3D microtumors from a core needle biopsy sample that recapitulate the in vivo tumor heterogeneity and microenvironment of the tumor biopsy. After these microtumors have been treated with a panel of drugs, we quantify the number of live and dead cells in those microtumors using our proprietary technology and scalable automatic stage confocal imaging (Molecular Devices). The advantage of our SAGE Direct Platform™ is the ability to multiplex our image-based results with the metabolic profile of our 3D microtumors, which cross validates our image-based readout. Our SAGE Direct Test™ has been optimized with ATCC cell lines and further validated with patient-derived tumor cells from lung, ovarian, and colon cancer tumor samples. Validation of high-quality confocal imaging samples followed by quantitative metabolic analysis suggests accurate quantification of viable cells, as reflected in a positive correlation between imaging quantitation and metabolic analysis (correlation coefficient r=0.84, p&lt;0.01). In summary, SageMedic has developed the SAGE Direct Test™, a simple, highly sensitive, robust, and straightforward functional profiling assay with significant clinical relevance, as it can model the natural physiological conditions of tumors.
[1] Marquart et al. Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology. JAMA Oncology 2018 Aug 1;4(8):1093-1098
Citation Format: Dhruva Mishra, Jennifer Moy, Chris Apfel. The SAGE Direct TestTM: A reliable way of functional profiling to predict the most effective treatment for cancer patients [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 5255.
Abstract 5256: Toward biomarkers discovery: Profiling triple-negative breast cancer cells by cell-SELEX
Authors: Camorani Simona , Leonetti Francesco , Collina Francesca , Cantile Monica , Botti Gerardo , Zannetti Antonella , Fedele Monica , Cerchia Laura 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) is a high heterogeneous group of tumors with a distinctly aggressive nature and high rates of relapse. So far, the lack of any known targetable proteins has not allowed a specific anti-tumor treatment, thus the identification of novel agents for specific TNBC recognition and treatment is desperately needed. Nucleic acids aptamers are emerging as the most promising candidates for targeting tumor cells. They are also termed "chemical antibodies" because their form unique tertiary structures, which allow specific binding to their target molecules. Recently, by cell-SELEX integrated to advanced Next Generation Sequencing and bioinformatics, we isolated a panel of six nuclease-resistant RNA aptamers able to bind at high affinity to TNBC cells, discriminating them from both normal cells and non-TNBC breast cancer cells, and interfere with their growth as mammospheres. Also, they diversify TNBC histological specimens in a tissue microarray without recognizing samples from both ER+, PR+, HER2+ breast cancers and normal adjacent tissues. Here, short versions of the aptamers have been generated, by truncating their length from 84 nt up to nearly 30 nt, which preserve efficacious targeting and anti-tumor properties as the parental moieties. In order to identify the targets of the above aptamers, which might be important surface cancer biomarkers crucial for the malignant phenotype, different biochemical approaches are harnessed that include aptamer-mediated affinity purification coupled to Mass Spectrometry and/or antibody array for human soluble receptors. Binding analyses on recombinant proteins, cells or tissues are used to verify the putative targets. Results obtained so far indicate that the target of one of the six aptamers is a secreted protein tightly and specifically associated to TNBC cell surface and with a poor prognosis. This protein identification and the functional role of its targeting by the aptamer will be shown here in detail.
The proposed cell-targeting aptamer strategy could provide an important new avenue for selective TNBC therapy.
Citation Format: Simona Camorani, Francesco Leonetti, Francesca Collina, Monica Cantile, Gerardo Botti, Antonella Zannetti, Monica Fedele, Laura Cerchia. Toward biomarkers discovery: Profiling triple-negative breast cancer cells by cell-SELEX [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 5256.
Abstract 5266: Continuous trifluridine treatment in colorectal cancer cell lines- investigating its potential
Authors: Tsunekuni Kenta , Matsuoka Kazuaki , Kobunai Takashi , Takechi Teiji , Eguchi Hidetoshi , Mori Masaki , Doki Yuichiro , Ishii Hideshi 
Published: September 2020

Abstract
Background: Trifluridine (FTD) is a key component of the novel, orally-administered, antitumor drug trifluridine/tipiracil, and is approved for treatment of patients with metastatic colorectal and gastric/GEJ cancers refractory to standard chemotherapy. FTD, an antineoplastic thymidine analogue, is incorporated into the genomic DNA of tumor cells, thereby triggering cell death. An international, double-blind, placebo-controlled Phase III study confirmed the efficacy of trifluridine/tipiracil in patients previously treated with standard chemotherapy. However, the clinical benefit of trifluridine/tipiracil in the first-line metastatic setting still remains unknown. Therefore, we analyzed the sensitivity for FTD, 5-FU, L-OHP, and SN-38 in parental and three FTD long-term treated cell lines.
Methods: Three human colorectal cancer cell lines (DLD-1, HCT-116, and RKO) and their respective FTD long-term treated cell lines (treated by step-wise increase in concentrations of FTD starting at 1 µM and ending at 400 µM over a 5 month period) were used. Sensitivity assays using crystal violet staining for FTD, 5-FU, L-OHP, and SN-38 and wound healing assay to assess the migration capacity were performed in these cell lines. Further, mRNA was purified and the resulting microarray was utilized to analyze expression profiles.
Results: Continuous FTD long-term treated cell lines were resistant to FTD. In the sensitivity assays, the IC50 values in all three continuously FTD treated cell lines increased by &gt;22-fold for FTD, by &lt;2-fold for 5-FU and L-OHP, and by &lt;9-fold for SN-38 (2 to 8.2-fold in three cell lines) compared to those in parental cell lines. We found that FTD long-treated cells had weaker migration ability than parental cells in all three cell lines. Additionally, HIF1A related glycolytic mRNA was downregulated in FTD long-treated cell lines compared to that in parental cell lines.
Conclusions: Although long-term treatment with FTD induced resistance in colorectal cancer cell lines, no cross-resistance to other drugs (5-FU, L-OHP) and partial resistance to SN-38 that are used in standard chemotherapy was observed. Therefore, FTD is expected to be effective even after treatment with standard chemotherapy. Although FTD/TPI is currently used in the later line, it is suggested from this basic study that FTD/TPI may be applicable to take to the front line therapy.
Citation Format: Kenta Tsunekuni, Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi, Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki, Hideshi Ishii. Continuous trifluridine treatment in colorectal cancer cell lines- investigating its potential [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 5266.
Abstract 5313: TT-00420, a novel multiple kinase inhibitor to treat TNBC
Authors: Peng Peng , Li Guoyu , Qiang Xiaoyan , Tian Yuwei , Yu Qi , Marangoni Elisabetta , Wu Frank 
Published: September 2020

Abstract
TT-00420, a clinical stage spectrum-selective multiple kinase inhibitor, has been shown to be very efficacious against TNBC cell lines and in vivo models in our previous study. TT-00420 simultaneously inhibits Aurora A/B, RTKs involved in angiogenesis, JAK kinase family as well as CSF1R in kinase profiling assay. In breast cancer cell panel screening, TT-00420 specifically inhibits the proliferation across different subtypes of TNBC, while leaving ER/PR+ and Her2+ cells intact. Incubation of TNBC cell line HCC1806 with TT-00420 results in dose-dependent down-regulation of EGFR, TWIST1, SNAI2, FOSL1, and MYC, a cluster of genes collectively known as “Achilles cluster” essential for TNBC cell growth and proliferation. TT-00420 exhibits great in vivo efficacy in a panel of TNBC PDX models. In the mechanism study, we reveal that the inhibition of Aurora A or B lays the cornerstone of pan-TNBC inhibition capability of TT-00420, and the inhibition of angiogenesis pathway or JAK family or EGFR contributes to potency and activity of TT-00420 against TNBC at various degrees. Treatment of a mouse syngeneic TNBC model with TT-00420 normalizes the vessel conditions in tumors, which is consistent with TT-00420's capability to enhance the anti-tumor immune response both alone or combined with PD-1 blockade. Taken together, TT-00420 represents a novel synergistic inhibitory mechanism to treat TNBC.
Citation Format: Peng Peng, Guoyu Li, Xiaoyan Qiang, Yuwei Tian, Qi Yu, Elisabetta Marangoni, Frank Wu. TT-00420, a novel multiple kinase inhibitor to treat TNBC [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 5313.
Abstract 5315: BPI-28592, a next-generation TRK kinase inhibitor that potently inhibits primary and resistant NTRK mutations
Authors: Fu Bang , Yan Dan , Liu Lingling , Guo Jing , Huang Jisheng , Ma Tianyi , Li Yinlong , Ren Wei , Chen Jie , Liu Xiangyong , Lan Hong , Ding Lieming , Wang Jiabing 
Published: September 2020

Abstract
Oncogenic NTRK gene fusions occur at very low frequency in common cancers but high frequency in rare tumors including childhood malignances. The 1st-generation TRK inhibitors, e.g., larotectinib and entrectinib, have been used successfully to treat cancers carrying the NTRK fusions with excellent response rate and long duration. Nonetheless, duration of response may eventually be limited by acquired resistance mutations, such as TRKA-G595R or TRKC-G623R. We aimed at identifying a 2nd-generation inhibitor which can cover the primary TRK fusions and overcome the common resistant mutants induced by the 1st -generation TRK inhibitors. Using structural modeling to guide rational drug design, we discovered BPI-28592 as a 2nd-generation TRK inhibitor with desired potency and good drug-like properties. BPI-28592 is of a novel structure and possessed sub-nanomolar potency against a variety of primary TRK fusions. Importantly, the molecule exhibits low nanomolar inhibitory activity against acquired mutants commonly identified in patients who are refractory to 1st-generation TRK inhibitors, including TRKA-G595R TRKA-F589L, TRKA-G667C, and TRKC-G623R, etc. BPI-28592 showed a highly selective profile in a Kinome scan of 468 individual kinases. In cell-based assays, BPI-28592 dose-dependently inhibited proliferation of primary as well as resistant TRK mutant cell lines, blocked TRK protein phosphorylation and downstream signaling. Furthermore, BPI-29592 demonstrated in vivo efficacy in xenograft models derived from primary and resistant TRK mutant cells. BPI-28592 exhibited a profile of high oral exposure across multiple pre-clinical species, favorable ADME properties, and wide therapeutic window in pre-clinical toxicology studies. In conclusion, we discovered BPI-28592 as a novel, potent and selective next-generation TRK kinase inhibitor. The molecule has completed IND-enabling studies and is planned to enter Phase 1 clinical development in early 2020.
Citation Format: Bang Fu, Dan Yan, Lingling Liu, Jing Guo, Jisheng Huang, Tianyi Ma, Yinlong Li, Wei Ren, Jie Chen, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-28592, a next-generation TRK kinase inhibitor that potently inhibits primary and resistant NTRK mutations [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 5315.