tbuckley/cabot-search huggingface dataset:
Abstract 2731: Receptor for Hyaluronan Mediated Motility (RHAMM) promotes breast cancer progression
Authors: Claire Elizabeth Daughters, Todd P. Knutson, Colleen Forster, James McCarthy, Kaylee Schwertfeger, Andrew Nelson
Journal: Cancer Research (2020)

Abstract Breast cancer remains one of the leading causes of cancer-related death in women in the U.S. with over 40,000 deaths annually. Understanding mechanisms of breast cancer progression holds great clinical utility to individualize patient therapy and to increase our portfolio of effective treatments for the different subtypes of breast cancer. We performed a focused gene expression analysis of 120 patients across all relevant hormone receptor (HR) subtypes at our institution. Increased expression of hyaluronan mediated motility receptor (HMMR, aka RHAMM) was associated with higher Nottingham grade, lymph node metastasis, and higher stage (all p&amp;lt;0.01). RHAMM expression was higher in more aggressive HR subtypes (triple negative and HER2+). Unsupervised hierarchical clustering of the cohort with a 29 gene signature related to RHAMM biologic activity further supported these associations with breast cancer progression/aggressiveness. Using CRISPR/Cas9, stable RHAMM -/- MCF10DCIS cell lines were created; RHAMM deletion does not affect cell proliferation, but significantly reduces in vitro Matrigel invasion and soft agar colony formation. RHAMM knockout also diminishes invasive progression of the MCF10DCIS cells in vivo, using the mouse intraductal (MIND) xenograft model; 83% of control xenografts demonstrate tissue invasion by 6 weeks, while only 50% of RHAMM-/- xenografts show any invasive component (p=0.03). Our human and model system data indicate a role for RHAMM function in breast cancer invasion. On-going work will investigate the dependency of the invasive phenotype specifically on RHAMM-hyaluronan binding; this interaction can be pharmacologically disrupted and may represent a specific intervention to limit breast cancer invasion and potentially metastasis. Citation Format: Claire Elizabeth Daughters, Todd P. Knutson, Colleen Forster, James McCarthy, Kaylee Schwertfeger, Andrew Nelson. Receptor for Hyaluronan Mediated Motility (RHAMM) promotes breast cancer 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 2731.
Abstract 6071: Role of nitric oxide in the invasive pancreatic cancer cells
Authors: Mayumi Fujita, Veena Somasundaram, Debashree Basudhar Basudhar, Robert Y.s. Cheng, Lisa A. Ridnour, Kaori Imadome, Jae Hong No, Gaurav Bharadwaj, David A. Wink
Journal: Cancer Research (2020)

Abstract Pancreatic cancer is a metastatic tumor with an extremely low 5-year survival rate. Metastasis is a main cause of patient mortality as it is extremely difficult to treat. Thus, understanding the characteristics of cancer cell populations exhibiting the invasive phenotype is fundamental for developing novel strategies to counter metastasis and improve therapeutic efficacy. To characterize these invasive phenotypes, we compared the human PANC-1 parent cell line with PANC-1 cells (INV) that invaded through transwell inserts. INV cells exhibited increased invasiveness and higher resistance to Carbon-ion radiation compared to whole cultured, control PANC-1 cells (WCC). PANC-1 invasion was reduced by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. Cell invasion through extracellular membrane (ECM) involves complex regulation of cell adhesion and de-adhesion to ECM proteins. Suspended INV cells, as well as INV cells undergoing de-adhesion, showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, L-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and hampered spheroid formation ability, suggesting that NO can potentially influence PANC-1 aggressiveness. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK-independent mechanism promoted NOS/NO modulation of PANC-1 invasion. Furthermore, xenograft studies with INV and WCC in an NSG mouse model revealed a higher ability of INV in liver metastasis than WCC, and L-NAME diminished the metastasis observed in INV injected mice. In summary, these results implicate NO as a key mediator of therapeutic resistance to Carbon-ion radiation and metastasis of PANC-1 cells; inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells. Citation Format: Mayumi Fujita, Veena Somasundaram, Debashree Basudhar Basudhar, Robert Y.s. Cheng, Lisa A. Ridnour, Kaori Imadome, Jae Hong No, Gaurav Bharadwaj, David A. Wink. Role of nitric oxide in the invasive pancreatic 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 6071.
Abstract 1316: Molecular features of complete response to neoadjuvant anti-androgen therapy in high risk localized prostate cancer
Authors: Alok Tewari, Alexander T. Cheung, Jake Conway, Jihye Park, Stephanie Wankowicz, Rosina T. Lis, Zhenwei Zhang, Saud AlDubayan, Rana R. McKay, Mary-Ellen Taplin, Eliezer M. Van Allen
Journal: Cancer Research (2020)

Abstract Though often curable, high-risk localized prostate cancer has a significant chance of recurring either biochemically, locoregionally, or as distant metastatic disease. Efforts are ongoing to evaluate neoadjuvant strategies to reduce this risk of recurrence. Our recent clinical trial showed that intense androgen deprivation with enzalutamide, leuprolide, and abiraterone acetate with prednisone (ELAP) induced pathologic complete response or minimal residual disease (&amp;lt; 5mm) at prostatectomy in 30% of trial patients (exceptional responders). Though previous studies have identified the pathological and genomic heterogeneity of localized prostate cancer, the impact of this heterogeneity on treatment response is unknown. To address this, we performed multi-region whole-exome and whole transcriptome sequencing on tumor and normal prostate regions from 15 exceptional responders and 15 non-responders treated with intensive androgen deprivation prior to prostatectomy. Overall, we found heterogeneous somatic mutation patterns with strong evidence of intra-tumoral heterogeneity and no association between mutation frequency and response. However, when subsetting patients by treatment response, SPOP mutation and SPOPL copy number loss were only observed in exceptional responders, while TP53 mutations were only observed in the non-responders. We observed expression signature differences between exceptional responders and non-responders, with exceptional responders having an increase in Androgen Receptor related gene signatures. Though underpowered to identify statistically significant genomic correlates of response to neoadjuvant ADT, our findings may inform future studies to identify clinically relevant features of high-risk localized prostate cancers to stratify therapies to reduce the risk of disease recurrence. Citation Format: Alok Tewari, Alexander T. Cheung, Jake Conway, Jihye Park, Stephanie Wankowicz, Rosina T. Lis, Zhenwei Zhang, Saud AlDubayan, Rana R. McKay, Mary-Ellen Taplin, Eliezer M. Van Allen. Molecular features of complete response to neoadjuvant anti-androgen therapy in high risk localized prostate 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 1316.
Abstract 1241: Galectin-3 and the modulation of autophagy in the pancreatic cancer microenvironment
Authors: Antonio Felix, Silvio Consonni, Maira Pitta, Hernandes Carvalho, Michelly Pereira, Moacyr Rêgo
Journal: Cancer Research (2020)

Abstract Galectin-3, a member of the β-galactoside binding proteins family was found up- regulated in pancreatic cancer and may be affected by microenvironment factors, such as hypoxia and/or nutritional deprivation. In this study, we aimed to analyze the effects of hypoxia and nutritional deprivation on the Galectin-3 protein levels and the possible influence of this galectin on the autophagy of pancreatic cancer cells. Nutritional deprivation was performed through partial or total reduction of fetal bovine serum (FBS) or through complete removal of serum, glucose and amino acids. Hypoxia was established with 1% oxygen tension. Proteins Galectin-3, Beclin- 1 and LC3 were accessed through Western blot and immunofluorescence. Induction of LC3 stable production was performed through transfection of pEGFP-LC3 and evaluated by confocal microcopy. Degradative vacuole quantification was done by transmission electron microscopy and knockdown of Galectin-3 was performed using siRNA transfection. According to the analyzes, the most effective conditions for the induction of autophagy were partial FBS deprivation for PANC-1 (p = 0.0035) and complete FBS/amino acid/glucose deprivation for Mia PaCa 2 cells (p = 0.0362). PANC-1 cells presented higher levels of Galectin-3 when they were submitted to 24 hours of FBS deprivation and simultaneously FBS deprivation and hypoxia. Hypoxia alone caused increases in LC3 levels for Mia PaCa-2 and for PANC-1 cells. Knockdown of Galectin-3 caused decreases of LC3 levels in almost all experimental conditions for both pancreatic cell lines with exception of concomitant nutritional deprivation and hypoxia for PANC-1. These results show that the Galectin-3 and LC-3 protein are modulated by hypoxia and nutritional deprivation. Cells incubated under hypoxia presented higher levels of LC3, what arguments in favor of the pro-autophagic aspects of hypoxia. Moreover, inhibition of Galectin-3 causes reduction of LC3, which implies Galectin-3 as an important regulator of the autophagic process in pancreatic cancer cells. Key-words: Pancreatic Ductal Adenocarcinoma, LC3, Hypoxia, Nutritional deprivation. Citation Format: Antonio Felix, Silvio Consonni, Maira Pitta, Hernandes Carvalho, Michelly Pereira, Moacyr Rêgo. Galectin-3 and the modulation of autophagy in the pancreatic cancer microenvironment [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 1241.
Abstract 1597: The landscape of PD1-PD-L1 axis in the context of immune cells: Tumors versus stromal compartments
Authors: Xiaoqian Lin, Raed Sulaiman, Jennifer C. Aske, Paul Meyer, Luis RojasEspaillat, David Starks, Pradip De, Nandini Dey
Journal: Cancer Research (2020)

Abstract Introduction: Immune response, tolerance, suppression, and resistance are the result of a complex dynamic interaction comprising PD1-PD-L1 axis in the context of immune cells (ICs) involving tumor cells, and anti/pro-tumor immune-cells of the stromal compartment. Aim: Here we present the landscape of PD1-PD-L1 axis in the context of CD3, CD4, CD8, PD1, FOXP3, and IL12RB2 positive ICs in the tumor (T) and the tumor-adjacent normal (TAN) tissues from patients with ovarian cancers (OC), and lung cancers (LC). Methods: The study was approved by Avera IRB. Surgically resected paired T and TAN tissue samples (from patients with OC and LC) were used to identify CD3 (ab16669), CD4 (ab133616), CD8 (ab85792), FOXP3 ([236A/E7], PD1 (ab137132), IL12RB2 (NBP1-85983), CD68 (Dako. #M0876), CD163 (Cell Signaling #93498) in ICs and PD-L1 (Clone 22C3; Dako) in T cells &amp; tumor-associated macrophages (TAMs). Tonsil tissue was used for the IHC validation. Paired specimens were morphologically evaluated by H&amp;E stain &amp; Ki-67, cl-caspase 3. Anatomic pathological evaluation for the diagnosis of the disease was carried out by a Pathologist. Results: Expression of CD3, CD4, CD8, PD1, and FOXP3 was heterogeneous, with each tumor presenting an individual pattern of distribution of ICs. However in most tumor samples, the distribution of ICs was of tumor-cooperating phenotypes. PD-L1 expression in tumors did not correlate with any other ICs of the tumor-microenvironment. In TAN tissues from OC, PD1-PD-L1 staining was absent. While macrophages in TAN tissue from LC were moderately positive for PD-L1. In T tissue from OC and LC, PD1-PD-L1 staining was only present in the stroma, lymphocytes, and absent in the tumor compartments while PD-L1 staining was identified only in the macrophages. Tumoricidal cells were rarely observed within the tumor compartment of T tissues from OC. The tumors cells from LC was only positive for PD-L1. Conclusion: Using dual stain of PD1 and PD-L1, we present for the first time, the co-distribution pattern of PD1-PD-L1 axis in the context of the expression of CD3, CD4, CD8, FOXP3 T cells as well as CD68, and CD163 positive TAMs in the paired sample of a T tissue and its TAN tissue in LC and OC. The relationship between the PD1-PD-L1 axis and the expression of IL12 Receptor in the context of immune-landscape is being worked out and will be presented in the meeting. Citation Format: Xiaoqian Lin, Raed Sulaiman, Jennifer C. Aske, Paul Meyer, Luis RojasEspaillat, David Starks, Pradip De, Nandini Dey. The landscape of PD1-PD-L1 axis in the context of immune cells: Tumors versus stromal compartments [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 1597.
Abstract 534: Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format
Authors: Guidong Zhu, Jingdong Ye, Jichun Ma, Jingdong Qin, Yi Cai
Journal: Cancer Research (2020)

Abstract This research aimed to produce anti-claudin18.2 (CLDN 18.2)/anti-PD-L1 bispecific antibodies to enhance the therapeutic index and expand the responsive population of the parent anti-CLDN 18.2 and anti-PD-L1 antibodies through the mechanisms of tumor-specific distribution and synergistic tumor killing. CLDN 18.2 is highly expressed in several tumors but is minimally expressed in normal tissues and a chimeric IgG1 CLDN 18.2 antibody zolbetuximab significantly improved PFS and OS in gastric cancer patients in a CLDN 18.2-dependent manner on the background of EOX. However, the response rate was moderate (~10%), leaving room for further improvement. Anti-PD-L1 antibodies showed remarkable efficacy in lung cancer and melanoma but in various settings of gastric cancer they showed weaker benefits, which warrant optimization. We designed anti-claudin18.2/anti-PD-L1 bispecific antibodies in the SMARTOPTM format, where a single-chain diabody containing optimized CLDN 18.2 and PD-L1 binding variable domains is connected to the Fc domain by linkers that can be optimized by phage display libraries. The bispecific antibodies were selected by affinity at low pH values and slow off-rate to improve the therapeutic window by enhancing tumor retention and preserving or improving binding affinity in the low pH tumor microenvironment. Immunogenicity was optimized by mutating the surface residues and disulfide bonds were inserted to improve stability. A representative bispecific antibody SPX-301 showed comparable binding affinity to the CLDN 18.2 and PD-L1 antigens to the parent antibodies (SPX-101 and durvalumab, respectively). SPX-301 represents a novel anti-claudin18.2/anti-PD-L1 bispecific antibody in the SMARTOPTM format. The format demonstrated excellence retention of antigen binding affinity, high expression levels, minimal aggregation, and straightforward purification. The preclinical characterizations of SPX-301 will also be presented. Citation Format: Guidong Zhu, Jingdong Ye, Jichun Ma, Jingdong Qin, Yi Cai. Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format [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 534.
Abstract 6565: Impact of TIM-3 modulation on the sensitivity of anti-PD-1
Authors: Jian Zhu, Rebecca L. Zhu
Journal: Cancer Research (2020)

Abstract Concurrent inhibition of TIM-3 and PD-1 may have enhanced anti-tumor effects. In this study, computational models were established to identify factors involved in the interactions between these two immunotherapeutic targets. Abstracts published on TIM-3, PD-1, PD-L1, anti-PD-1/PD-L1 were downloaded from PubMed, and analyzed by natural language processing and text mining. Interactions among genes, compound/therapies, cell/animal models, pathway/disease, and clinical studies were retrieved from the text. Networks were constructed to simulate effects of TIM-3 inhibition on anti-PD-1. The TIM-3/anti-PD-1 network consists of 57 nodes, 175 interactions with 11,626 possible regulatory paths from TIM-3 to anti-PD-1. Overall, 6142 paths are associated with the agonistic interactions between TIM-3 inhibition and anti-PD-1, while 5484 are antagonistic. Factors associated with the enhancement of anti-PD-1 by TIM-3 inhibition include up-regulation of IL-2, IFN-gamma, Th1 cells/cytokines, CD8+ T cells or NK cells, and down-regulation of IL-10, NFkB-p65, COX2 or EMT. Treatments with either EGFR inhibitors (e.g. gefitinib), anti-CTLA-4, IL-2 agonist or radiation therapy may enhance the combination efficacy of TIM-3 and PD-1 inhibitors. On the other hand, CTLA-4, galectin-9, Wnt/beta-catenin or Tregs combined with TIM-3 over-expression may confer resistance to anti-PD-1. PD-L1 is a validated biomarker for anti-PD-1 response and its expression can be correlated with TIM-3. Similar text-mining approach was adopted to construct the TIM-3/PD-L1 network which consists of 65 nodes, 165 interactions and 1372 paths from TIM-3 to PD-L1. Up-regulation of either galectin-9, WNT/beta-catenin or Tregs by TIM-3 results in the induction of PD-L1. As the network analyses revealed, interactions between TIM-3 and PD-L1 are context dependent, and assessment of the effect of TIM-3 inhibition on anti-PD-1 requires profiling of multiple factors along the regulatory and signaling pathways. The TIM-3/PD-L1 and TIM-3/anti-PD-1 networks prove to be useful tools to facilitate the therapeutic development of TIM-3 and PD-1 inhibitors, especially for selecting patients with potential agonistic effects of this promising drug combination. Citation Format: Jian Zhu, Rebecca L. Zhu. Impact of TIM-3 modulation on the sensitivity of anti-PD-1 [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 6565.
Abstract 5970: Function and regulatory mechanism of GPM6A in hepatocellular carcinoma development and progression
Authors: Rui Zong Li, Gang Xu, Min Ji Zhu, Jian Wu, Jian Wu
Journal: Cancer Research (2020)

Abstract BACKGROUND: GPM6A is a glycoprotein found in endothelial cells and is considered to be a malignant lymphoma oncogene. However, the role of GPM6A in the development of hepatocellular carcinoma (HCC) is unknown. Through Affymetrix gene expression microarray and bioinformatics analysis, very low GPM6A expression was found in HCC tissue. The present study aims to explore the function and regulatory mechanism of GPM6A in HCC development and progression. METHODS: Levels of GPM6A expression was determined in various hepatoma cell lines and HCC specimens from different base disorders, and its role on cell proliferation was investigated in GPM6A stably over-expressing cell lines. Modulating effects of a specific miRNA were evaluated with miRNA mimetic transfection. RESULTS: Much lower GPM6A levels were found in HCC occuring in HBV-infection or nonalcoholic steatohepatitis. TCGA data confirmed that low GPM6A expression in HCC correlates with a poor overall survival and progression-free survival rate (p=0.018 and 0.004). Over-expression of GPM6A inhibited proliferation in SMMC-7721 and MHCC-97H cells by 31% and 30%, respectively (p&amp;lt;0.01), and led to decreased colony formation by 40%. Overexpression of GPM6A was found to significantly reduce wound healing and migration rates in these two cell types. miR-96-5p was expressed at 6 to 61-fold higher in HCC tissues than adjacent tissues (p&amp;lt;0.01); whereas GPM6A gene expression was at 3 to 55-fold lower (p&amp;lt;0.01) in a negative correlation between miR-96-5p levels and GPM6A levels in HCC specimens (r=-0.64, p&amp;lt;0.05). Further experiments demonstrated that miR-96-5p acted directly on the 3'UTR of the GPM6A gene, and transfection of miR-96-5p significantly decreased GPM6A mRNA expression by 50% in two hepatoma cell lines. Moreover, MiR-96-5p transfection promoted proliferation (66%, 59%, p&amp;lt;0.01), migration (10%, 9%, p&amp;lt;0.05) and invasion (557±66 vs. 226±19; 235±36 vs. 153±17, p&amp;lt;0.05-0.01) of SMMC-7721 and MHCC-97H hepatoma cells; whereas the function of oncogenic microRNA-96 was significantly inhibited in GPM6A-overexpressed hepatoma cells. CONCLUSIONS: GPM6A expression in HCC is commonly suppressed, and correlated to a poor prognosis. Its low expression in HCC tissues is most likely attributed to upregulated miR-96-5p, which may function as an oncolytic regulator through suppressed GMP6A that may block proliferation, cloning formation, migration and invasion of hepatoma cells. Citation Format: Rui Zong Li, Gang Xu, Min Ji Zhu, Jian Wu, Jian Wu. Function and regulatory mechanism of GPM6A in hepatocellular carcinoma development and 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 5970.