bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5443: Modulating plasticity in aggressive variant prostate cancers
Authors: Soundararajan Rama , den Hollander Petra , Shepherd Peter , Navone Nora , Lorenzini Daniele , Laberiano-Fernandez Caddie , Lu Wei , Zhou Jianling , Liu Jingjing , Zhang Jianhua , Solis-Soto Luisa Maren , Mani Sendurai A. , Aparicio Ana 
Published: September 2020

Abstract
Aggressive Variant Prostate Cancers (AVPC) are a clinically and molecularly distinct subset of prostate cancers with a poor prognosis characterized by androgen-indifference, platinum-sensitivity and combined defects in Tp53, RB1 and PTEN, for which novel therapeutic approaches are urgently needed. Defects observed in these tumor suppressor pathways have been linked to lineage plasticity in genetically engineered mouse models. We hypothesized that this plasticity can be identified in human tumor samples, and can be modulated to serve as the foundation for effective combination therapies for the AVPC subset. We previously defined a gene expression signature derived from mouse embryonic day 6.5 that is representative of extensive cellular plasticity (PMID:26123483). We determined the plasticity scores in 12 patient-derived xenograft (PDX) models representative of the spectrum of prostate cancer biology (using available RNA sequencing profiles), and in 26 macrodissected tumor biopsies obtained from patients who received platinum-based chemotherapy for aggressive prostate cancer (using ALMAC Affymetrix gene expression microarray). As expected, the AVPC PDX models exhibited high plasticity scores as did 11 (42.3%) of the patient samples, associated with patient progression free- and overall survival. We next treated a well characterized AVPC PDX model (144-4) with the anti-EMT drug (p38MAPK inhibitor) SB203580 at 10mg/kg, and observed a decrease in stem-cell and EMT factors associated with plasticity. These data confirm the association between plasticity and AVPC in human tumor samples, and suggest that changes in plasticity can be measured in tumor samples to determine the value of its modulation in clinical trials.
Acknowledgments: ALMAC Diagnostics Services, UK, and UTMDACC ATGC Core Lab (CCSG-CA016672-ATGC) for RNA sequencing services; UTMDACC Prostate Cancer SPORE (RS, SAM, AA), UTMDACC IRG (RS), and the UTMDACC Prostate Cancer Moonshot Program (AA) for financial support.
Citation Format: Rama Soundararajan, Petra den Hollander, Peter Shepherd, Nora Navone, Daniele Lorenzini, Caddie Laberiano-Fernandez, Wei Lu, Jianling Zhou, Jingjing Liu, Jianhua Zhang, Luisa Maren Solis-Soto, Sendurai A. Mani, Ana Aparicio. Modulating plasticity in aggressive variant prostate cancers [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 5443.
Abstract 5444: Clinical significance of tetraspanin CD63 in human ESCC
Authors: Matsumoto Yasunori , Kano Masayuki , Murakami Kentaro , Endo Satoshi , Toyozumi Takeshi , Shiraishi Tadashi , Kamata Toshiki , Ryuzaki Takahiro , Kinoshita Kazuya , Hirasawa Soichiro , Matsubara Hisahiro 
Published: September 2020

Abstract
Background: ESCC(Esophageal Squamous Cell Carcinoma) is highly aggressive due to its tendency to metastasize to the lymph nodes and organs. Our laboratory previously reported that the exosome amount in the peripheral blood could predict the prognosis of ESCC patients. CD63 is a tetraspanin family protein and is often used as a marker of exosome.CD63 highly express in early stage melanoma and thought to be a suppressive factor against EMT (epithelial-to-mesenchymal transition) in melanoma. On the other hand, some report confirmed CD63 as a prometastatic factor via regulating E cadherin expression. The function of CD63 are still controversial. We herein assessed CD63 expression and clinicopathological findings in ESCCpatient, and assessed molecular roles of CD63 in ESCC cell lines.
Materials and methods: The relationship between the CD63 expression in the resected ESCC specimen (from 1997 to 2006, n=86) and clinicathological features were assessed using immunohistochemical staining. Human ESCC cell lines (TE2,TE15) were used as high CD63 expression cell lines for in vitro analysis. CD63 was knockdown using siRNA, and CD63 down regulate was confirmed by western blot and PCR. The influence on the cell behavior and gene expressions were assessed by cell proliferation assay, mRNA microarray, and GSEA(Gene Set Enrichment Analysis).
Results: There were no statistically significant correlation between the CD63 expression and age, sex, tumor depth (T), lymph node metastasis (N), distant organ metastasis (M), differentiation of tumor, lymphatic vessel invasion (ly), venous invasion (v), the type of progression. As for the prognosis, the high CD63 expression patients have significantly poorer prognosis than the low expression of CD63 patients. (P=0.047, log rank test). In vitro study, cell proliferation assay showed down expression of CD63 reduce cell proliferation. Knock down of CD63 downregulates HER2 expression and influence on other ERBB signaling pathways.
Conclusions: High CD63 expression predicts poor prognosis in human ESCC. The molecular function of CD63 could have relationship to ERBB signaling pathways in human ESCC cells.
Citation Format: Yasunori Matsumoto, Masayuki Kano, Kentaro Murakami, Satoshi Endo, Takeshi Toyozumi, Tadashi Shiraishi, Toshiki Kamata, Takahiro Ryuzaki, Kazuya Kinoshita, Soichiro Hirasawa, Hisahiro Matsubara. Clinical significance of tetraspanin CD63 in human ESCC [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 5444.
Abstract 5452: Neuroendocrine negative RB1 WT SCLC and LCNEC
Authors: Sonkin Dmitriy , Thomas Anish , Teicher Beverly A. 
Published: September 2020

Abstract
Background: Based on genomics data generated in last few years about 15% of tumors diagnosed as large cell neuroendocrine carcinomas (LCNEC) are actually neuroendocrine negative. Interestingly, approximately similar percentage of small cell lung cancers (SCLC) are also neuroendocrine negative, historically known as SCLC variant and are enriched for RB1 WT tumors. Here we compare the morphological, genomic and other features of neuroendocrine negative RB1 WT SCLC and LCNEC.
Methods: To comprehensively compare neuroendocrine RB1 WT SCLC and LCNEC, we examined morphological, genomic and other features of these rare lung cancer subtypes using publicly available data. From a genomics perspective, we payed special attention to key oncogenic genetic alterations and expression pattern of transcription factors known to play critical role in SCLC and LCNEC.
Results/Conclusions: The expression pattern of transcription factors ASCL1, POU2F3, NEUROD1, YAP1 in LCNEC has number of similarities to expression pattern of these transcription factors in SCLC. Neuroendocrine negative/low RB1 WT SCLC and neuroendocrine negative/low, RB1 WT, KEAP1 WT, STK11 WT LCNEC have similar genomics and morphological characteristics and might be in fact the same entity. Based on differences in distribution of different lung cell types at different anatomical locations such as: peripheral, midzone or central, collecting information on lung tumor location along with genomic information and neuroendocrine markers staining could be important for better understanding of rare lung tumor subtypes. Clinical trial NCT04010357 is going to investigate efficacy of CDK4/6 inhibitor abemaciclib in RB1WT SCLC. Based on our observations patients with neuroendocrine negative/low RB1 WT, KEAP1 WT, STK11 WT LCNEC subtype might be also candidates for clinical trial-based treatment with CDK4/6 inhibitors.
Citation Format: Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher. Neuroendocrine negative RB1 WT SCLC and LCNEC [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 5452.
Abstract 5457: Structural and functional assessment of mutations identified in different breast cancer genes
Authors: Mishra Neha , Khan Mudassar Ali , Kuligina Ekaterina S. , Hasan Syed , Varma Ashok K. 
Published: September 2020

Abstract
Atomic protein structure helps in understanding the functions associated with protein molecule. Therefore, it is very important to correlate the structural information from the biological functions of proteins for translational research. So far, BRCA1 and BRCA2 (Breast Cancer Susceptibility genes 1 and 2) genes have been extensively studied genes for hereditary breast and ovarian cancers. BRCA1 comprises 1863 amino acids and is involved in the tumour suppressor function. It also plays an important role in cell cycle checkpoint control and DNA damage repair process. Germ-line mutations discovered in BRCA1 and BRCA2 genes are distributed all over gene coding regions. BRCA1 encompasses different functional domains like RING-domain at N- terminus, DNA binding domain at the centre and tandem repeats of BRCT at C-terminus. RING-domain of BRCA1 interacts with BARD1, BAP1 whereas C-terminal region of BRCA1 interacts with BACH1, CtIP, Abraxas and controls the cell -cycle checkpoint through the protein-protein interactions. Germ-line mutations identified from the larger cohort of patients is available in different databases. However, unreported mutations are also regularly detected in clinical settings. We have evaluated the folding pattern of mutations discovered in different domains of BRCA1 and BRCA2 using in-silico, in-vitro and biophysical approaches. Furthermore, studies of protein-protein interactions (PPIs) with the binding partners of BRCA1 such as RAP80, MERIT40, and ABRAXAS have been explored using isothermal titration calorimetry. The slight differences between wild-type and mutant proteins of BRCA1 and BRCA2 have been observed. The data obtained from Circular- Dichroism, protein-protein interactions and structural analysis confirm that an alterations in protein folding pattern although not able to serve as a sole tool for mutation pathogenicity assessment, could provide valuable information to aid the classification of uncertain, potentially disease-causing, variants in the human cancer-relevant genes. Grant number: DST (Grant DST/INT/RUS/RSF/11), Russian foundation for Basic research (grant number 19-515-25001)
Citation Format: Neha Mishra, Mudassar Ali Khan, Ekaterina S. Kuligina, Syed Hasan, Ashok K. Varma. Structural and functional assessment of mutations identified in different breast cancer genes [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 5457.
Abstract 5475: Evaluation of feature selection methods used for cluster analysis in identification of novel cancer subtypes
Authors: Vidman Linda , Källberg David , Rydén Patrik 
Published: September 2020

Abstract
Background: RNA-seq data from tumor samples can be used to identify novel cancer subtypes using cluster analysis. The number of features is often large compared to the number of samples and different clusters can appear in different subsets of the feature space. Feature selection techniques are therefore commonly used to reduce the dimension and remove redundant and irrelevant features before performing cluster analysis. An abundance of feature selection methods have been proposed in the literature, but it is unclear how the ability to identify novel subtypes of cancer using cluster analysis is affected by choice of feature selection method.
Method: We evaluated 13 feature selection methods on four publicly available cancer data sets from The Cancer Genome Atlas. RNA-seq data and associated clinical data were retrieved from Broad institute GDAC Firehose. Overlap and characterization of the highest ranked features (i.e. genes) were studied for top 100, 1000 and 3000 genes. Performance was measured by comparing known cancer subtypes to partitions obtained using hierarchical clustering with Euclidean distance and Ward´s linkage, based on the selected features. The result was compared to both a random selection (negative control) and a supervised approach (positive control) using adjusted Rand index.
Results: The relative performance of the feature selection methods varied heavily depending on number of included genes and the data set used. Based on all data, gene selection using the Dip-test statistic and the Bimodality index generated the overall highest clustering performance. The overlap of selected genes between the Bimodality index, the Dip-test and the supervised approach was relatively low. The Dip-test and Bimodality index tended to favor genes with relatively low expression values.
Conclusions: The choice of feature selection method can have a huge impact on the ability to identify cancer subtypes using cluster analysis, and the relative performance is highly dependent on the data. Low overlap of selected genes between the highest ranked methods suggests that the methods identify genes that contain complementary information, and that it might be beneficial to combine two or more feature selection methods.
Citation Format: Linda Vidman, David Källberg, Patrik Rydén. Evaluation of feature selection methods used for cluster analysis in identification of novel cancer subtypes [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 5475.
Abstract 5508: BCMA-CD3 bispecific antibodies: A modeling framework to characterize kinetics of bispecific antibody, T cell, cytokines, and serum M-protein
Authors: Udata Chandrasekhar , Wei Dai , Jiang Sibo , Forgie Alison , Hooper Andrea , Qiao Wenlian , Musante Cynthia , Yin Donghua 
Published: September 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 5509: Breaking the paradox breakers - RAF inhibitor mechanisms
Authors: Mendiratta Gaurav , McFall Thomas , Stites Edward 
Published: September 2020

Abstract
A number of ATP competitive inhibitors of RAF onco-protein have been successful in tumors with RAF V600 mutations but have failed for more common cases with upstream mutations. Instead, a paradoxical activation (PA) of downstream signaling is observed in response to these inhibitors when RAF is not the driver mutation. A detailed understanding of processes that potentiate PA would help in minimizing side effects, choosing appropriate mono- or combination treatments and guide future drug development. Several mechanisms of PA have been proposed in the past, such as negative co-operativity to additional drug binding and RAF dimer stabilization. However, the evidence for these mechanisms is indirect and does not explain PA for all the different types of drugs.
In our work, we created a mathematical model of RAF activation solely based on canonical RAF signal regulatory processes to show how autoinhibition provides a general mechanism of PA. We also used this model to show that 14-3-3 proteins could further potentiate PA by stabilizing autoinhibited RAF. Based on the computational work, we predicted that transfecting 14-3-3 proteins would potentiate PA even with drugs which are otherwise expected to provide minimal or no PA. Our experiments with these drugs in SKMEL2 melanoma cells and SW48 colon cancer cells validated our predictions thereby providing support for our general model of PA.
Citation Format: Gaurav Mendiratta, Thomas McFall, Edward Stites. Breaking the paradox breakers - RAF inhibitor mechanisms [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 5509.
Abstract 5574: In vivo model development for immune cell-based therapeutics
Authors: McMichael Elizabeth , Jetley Utsav , Rudulier Christopher , Borah Minasri , Ganci Nicole , Ragothaman Vandhana , Balwani Ishina , Frain Amanda , Pajanirassa Priya , Miki Yuko , Jones Jeffrey , Luster Troy , Keenan Marie , Martinez Terina , Zhang Yong , Schultes Birgit 
Published: September 2020

Abstract
The implementation of various mouse models is critical to asses safety, efficacy, and short- and long-term persistence of therapeutic modalities, especially for cell-based therapies. To increase our repertoire of viable humanized murine models, we developed two in vivo models by taking advantage of Taconic's immunodeficient mice, one monitoring graft versus host disease (GvHD) and the other addressing human natural killer (NK) cell cytotoxicity. We utilized NOG mice to develop a model of GvHD, by transplanting human PBMCs at varying doses and monitoring mice for changes in body weight over time. We determined a dose of injected PBMCs that allowed for GvHD to occur yet provided a window of opportunity for potential therapies to slow progression. When human natural T regulatory cells (nTregs) were co-injected with PBMCs in NOG mice, there was prolonged survival and a less rapid loss of body weight as compared to PBMCs alone. To create an NK cytotoxicity model, we transplanted human primary NK cells into NOG-hIL15 mice, which are NOG mice that constitutively produce human IL-15. We showed successful engraftment and proliferation of NK cells, with peak engraftment occurring 4-5 weeks post injection, and that these human primary NK cells were able to persist without signs of xenogeneic GvHD. Utilizing K562 tumor cells that express luciferase, we found these engrafted NK cells have fast and potent cytotoxic activity using IVIS imaging, resulting in elimination of tumor cells as compared to non-engrafted mice. Our results collectively suggest that the two in vivo models developed here will be valuable tools for investigating the clinical benefit of immune cell-based therapeutics.
Citation Format: Elizabeth McMichael, Utsav Jetley, Christopher Rudulier, Minasri Borah, Nicole Ganci, Vandhana Ragothaman, Ishina Balwani, Amanda Frain, Priya Pajanirassa, Yuko Miki, Jeffrey Jones, Troy Luster, Marie Keenan, Terina Martinez, Yong Zhang, Birgit Schultes. In vivo model development for immune cell-based therapeutics [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 5574.
Abstract 558: M6123, a selective FGFR1 antagonist, demonstrates anti-tumor activity as monotherapy and in combination with chemotherapy in mesothelioma models
Authors: Esdar Christina , Ross Edith , Sanderson Michael , Zimmermann Astrid 
Published: September 2020

Abstract
Malignant pleural mesothelioma is an aggressive, asbestos-related cancer most commonly arising from the mesothelial cells lining the pleural cavity surrounding the lung. Despite the poor prognosis and increasing incidence of this disease, the combination of pemetrexed with cisplatin currently remains the only available treatment option to patients. Molecular characterization of mesothelioma tumors indicates a potential dependency on autocrine FGF-FGFR signaling. Based on this information, the therapeutic activity of M6123, a potent and selective, monovalent antagonist of FGFR1, was investigated in preclinical mesothelioma models in vitro and in vivo. In a panel of mesothelioma cell lines, M6123 mediated cellular growth reduction was clearly correlated with the level of endogenous FGF2 ligand. M6123 monotherapy significantly inhibited FGFR1 signal transduction and tumor growth in a cell line derived mesothelioma model. Furthermore, combination benefit was observed for M6123 with standard of care (SoC) chemotherapy. In a panel of nine mesothelioma patient derived xenograft (PDX) models, 66% (6/9) were sensitive to the combination of M6123 plus pemetrexed/cisplatin compared to 33% (3/9) for chemotherapy alone. The expression of a focused set of FGF-FGFR pathway genes was examined in PDX models to elucidate potential predictive biomarkers of sensitivity to M6123. Sprouty homolog 2 (SPRY2), a negative regulator of FGFR1 signaling, was upregulated in non-sensitive PDX models, whilst positive regulators of FGFR1 signaling including the ligand FGF5, the coreceptor FGFRL1 (FGFR5) and the downstream transcription factor ELK3 were elevated in sensitive models. In summary, M6123 showed favorable anti-tumor activity in preclinical models of mesothelioma, in particular in combination with standard of care chemotherapy. Further preclinical testing is warranted to confirm a predictive biomarker signature for selection of mesothelioma patients that may benefit from addition of M6123.
Citation Format: Christina Esdar, Edith Ross, Michael Sanderson, Astrid Zimmermann. M6123, a selective FGFR1 antagonist, demonstrates anti-tumor activity as monotherapy and in combination with chemotherapy in mesothelioma models [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 558.