tbuckley/cabot-search huggingface dataset:
Abstract 1624: Lrig1 is an Egfr-dependent tumor suppressor in mouse duodenal and colonic neoplasia
Authors: Robert J. Coffey, Hiro Niitsu, Yuanyuan Lu, Won Jae Huh, Jeffrey L. Franklin
Journal: Cancer Research (2020)

Abstract Leucine-rich repeats and immunoglobulin-like domain 1 (Lrig1) is a pan-ErbB negative regulator. Lrig1 null mice develop spontaneous duodenal adenomas by 3-4 months of age but they exhibit no overt colonic pathology (AE Powell Cell 149:146-158, 2012). To examine a possible tumor suppressor role for Lrig1 in colonic neoplasia, we utilized Lrig1CreERT2 and Lrig1Apple mice in which a tamoxifen-inducible Cre recombinase or an Apple fluorescent reporter were inserted into the translational start site of endogenous Lrig1, thus creating Lrig1 null mice. Colonic tumors were generated by administration of AOM/DSS to Lrig1CreERT2/CreERT2 mice and by administration of tamoxifen (TAM) to Lrig1CreERT2/Apple;Apcflox/+ mice to induce loss of one Apc allele. Compared to littermate control mice, there was a significant increase in colonic tumor number in both Lrig1 null cohorts (p=0.016 and p=0.007, respectively). We previously reported Egfr was the most upregulated ErbB family member in Lrig1 null duodenal tumors (Y Wang Am J Path 185:1123-1134, 2015). To directly implicate Egfr in both Lrig1 null duodenal and colonic tumors, we administered TAM at 6 weeks of age to Lrig1CreERT2/CreERT2;Egfrflox/flox mice. At 6 months of age, all oil-injected mice developed tumors, whereas tumors were not detected in 8/21 (38.1%) of TAM-injected mice; the tumor volume in TAM-injected mice was reduced to 7.78 mm3 (73.5%) compared to (10.58 mm3) in the oil-injected group as measured by MRI scanning (p&amp;lt;0.05). In the AOM/DSS colonic tumor model, administration of TAM at 6 weeks of age to Lrig1CreERT2/CreERT2;Egfrflox/flox mice resulted in a significant decrease in tumor number (p=0.021) but not size compared to oil-injected mice. These results indicate that Lrig1 is an Egfr-dependent tumor suppressor in both mouse duodenal and colonic neoplasia. Citation Format: Robert J. Coffey, Hiro Niitsu, Yuanyuan Lu, Won Jae Huh, Jeffrey L. Franklin. Lrig1 is an Egfr-dependent tumor suppressor in mouse duodenal and colonic neoplasia [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 1624.
Abstract 3816: Elucidating the potential role of membrane complement regulatory proteins (CD46, CD55, CD59) in tumorigenesis of cervical cancer
Authors: Xuetang Mo, Thomas Ho-Yin Leung, Michelle Kwan-Yee Siu, Hextan Yuen-Sheung Ngan
Journal: Cancer Research (2020)

Abstract Introduction: Cervical cancer is a common genital tract cancer. Although abundant screening and vaccination are beneficial for reducing the disease burden, the molecular mechanism underlying tumorigenicity and aggressiveness are not fully understood. Human papillomavirus (HPV) E6 protein was found to be responsible in the development of cervical cancer. Membrane complement regulatory proteins (mCRP), such as CD46, CD55, CD59, control complement activation on the surface of tumour cells and suggested to be important in contributing tumorigenesis in various types of cancers. In our recent study, we have reported that HPV E6 protein enriches the expression of CD55 in cervical cancer cells, which would further promote radio-resistance and cancer aggressiveness. In the present study, we would characterize the functional role of other two mCRPs CD46 and CD59 in contributing cervical carcinogenesis. We would further examine if triple knockout of CD46, CD55, CD59 would have synergistic effect on blockage of tumorigenesis in cervical cancer. Material and method: Flow cytometry was performed to analyse the expression level of CD46, CD55 and CD59 in cervical cell lines C33A, C4-1, CaSki, SiHa, and a HPV18-E6-overexpressing stable clone (18E6-5, origin C33A cells). In order to investigate the effect on the blockage of those mCRPs, 18E6-5 clone with high CD46, CD55 and CD59 expression were chosen for in vitro functional study using and CRISPR/Cas9 knockout. Results and discussion: The percentage of CD46(+), CD55(+) and CD59(+) cells were high in C4-1, CaSki, SiHa and 18E6-5 lines. The C33A cells demonstrate a low CD55(+) subpopulation while high CD46(+) and CD59(+) subpopulations. We found that single knockout of CD46 or CD59 supressed cell proliferation, sphere-forming, anchorage-independent cell growth capability, and sensitized cells to radiation treatment. In addition, triple knockout of CD46, CD55, CD59 remarkably inhibited those effects comparing with the effects of single and double knockout. Conclusion: Silencing of CD46, CD55, CD59 expression abolished the tumorigenic, radio-resistant and aggressive effects in cervical cancer cells, with triple knockout displayed the highest blockage effects. Those mCRPs would be responsible for tumorigenicity, radio-resistance and cancer aggressiveness in cervical cancer. Citation Format: Xuetang Mo, Thomas Ho-Yin Leung, Michelle Kwan-Yee Siu, Hextan Yuen-Sheung Ngan. Elucidating the potential role of membrane complement regulatory proteins (CD46, CD55, CD59) in tumorigenesis of cervical 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 3816.
Highly improved aqueous lubrication of polymer surface by noncovalently bonding hyaluronic acid-based hydration layer for endotracheal intubation
Authors: Yan-Pu Li, Wei Liu, Ya-Hui Liu, Yue Ren, Zhi-Guo Wang, Baisong Zhao, Shishu Huang, Jia-Zhuang Xu, Zhong-Ming Li
Journal: Biomaterials (2020)
Abstract 3269: Ablation of Cbl-b gene function leads to increased activation and resistance to immunosuppression in human primary T lymphocytes
Authors: Eric Parmantier, Georges Kalouche, Clara Soulard, Christophe Lanneau, Sophie Boisrobert-Blais, Céline Nicolazzi, Cécile Orsini
Journal: Cancer Research (2020)

Abstract Purpose: The role of Cbl-b as an essential modulator of T cell activation has been widely documented, particularly in mouse studies. To substantiate the effects of Cbl-b ablation in human T cells, gene editing conditions were optimized, and gene KO efficiency was evaluated along with T cell response to stimulatory antibodies. Experimental design: Non-preactivated human primary T cells obtained from several donors were electroporated with the CRISPR/Cas9-gRNA ribonucleoprotein complex targeting CBLB gene or controls. Cells were then activated in presence of anti-CD3 and anti-CD28 antibodies with or without the immunosuppressive factors PGE2 or TGFβ. Gene editing efficiency was measured using targeted NGS technology and cytokine release (IL2, IFNγ, TNFα), membrane activation markers (CD25, CD69) and cell proliferation were evaluated at various timepoints. Results: Initial studies showed moderate gene editing efficiencies with on average 45% and 25% of out-of-frame mutations using 2 gRNAs targeting different regions of CBLB gene and were correlated with increased IL-2 release. By optimizing gene editing experimental conditions, out-of-frame mutations in CBLB gene reached more than 70% and were associated with higher levels of secreted IL2, IFNγ and TNFα early after T cell stimulation and increased CD25 membrane expression at later timepoints, compared to controls. Furthermore, CBLB gene-edited T cells were less susceptible to PGE2- and TGFβ-mediated inhibition of cell proliferation. Conclusion: The efficient gene editing in human non-preactivated T cells, through the delivery of the CRISPR/Cas9-gRNA ribonucleoprotein complex, confirms that Cbl-b acts as a negative regulator of T cell activation and further validates its role in transducing immunosuppressive environmental cues. Citation Format: Eric Parmantier, Georges Kalouche, Clara Soulard, Christophe Lanneau, Sophie Boisrobert-Blais, Céline Nicolazzi, Cécile Orsini. Ablation of Cbl-b gene function leads to increased activation and resistance to immunosuppression in human primary T lymphocytes [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 3269.
Abstract 6055: Discovery of epitope-selective anti-CD25 targeting therapeutic antibodies for effective Treg cell depletion in cancer using a novel AI/ML based platform
Authors: Phung Gip, Bing Li, Angeles Estelles, Hanako Daino-Laizure, Oleg Gurinovich, Piotr Zalicki, Kevin Hauser, Alex Taguchi, Christian Barrett, Andrew Morin, Jordan Willis, Mohan Srinivasan, Isaac Bright, Matt Greving
Journal: Cancer Research (2020)

Abstract Therapeutic antibodies have contributed significantly to better clinical outcomes across multiple tumor types. However, there is still unmet clinical need in cancers with an immunosuppressive and stroma rich tumor microenvironment (TME). One key limitation in early antibody discovery is immunodominance - an evolutionary bias toward specific epitopes that steer antibody selection away from potentially high-efficacy epitopes. Our integrated computational and laboratory approach to antibody discovery enabled us to build focused epitope embodiments of structural epitopes. These epitope embodiments, called Meso-scale Engineered Molecules (MEMs), are used in antibody selection to steer hits toward intended epitopes. CD25 (IL2Rα) is highly expressed on regulatory T-cells (Tregs) that drive immunosuppression in the TME. Depletion of Tregs can restore anti-tumor T effector (Teff) function in the TME, by increasing the Teff/Treg ratio, especially when combined with checkpoint-inhibitors. Using our epitope-selective antibody discovery platform, we built MEMs that embody eight CD25 structural epitopes outside the CD25:IL-2 interface. Through in vitro selection, several high-affinity (median KD = 25 nM) anti-CD25 antibodies from each of the eight intended CD25 epitopes were identified and confirmed to be on epitope by cross-blocking assays and in-epitope alanine mutations. Several conventional- and epitope-selective anti-CD25 clones were converted to human IgG1 and tested in in vitro assays. As a result, these antibodies bound specifically to CD25+ cells, preserve IL-2 signaling via pSTAT5 assays and elicited potent ADCC activity using human effector cells, superior to benchmark antibodies. These studies show that our integrated computational and laboratory platform improves the antibody discovery process, producing clones with biological function and improved therapeutic efficacy. Citation Format: Phung Gip, Bing Li, Angeles Estelles, Hanako Daino-Laizure, Oleg Gurinovich, Piotr Zalicki, Kevin Hauser, Alex Taguchi, Christian Barrett, Andrew Morin, Jordan Willis, Mohan Srinivasan, Isaac Bright, Matt Greving. Discovery of epitope-selective anti-CD25 targeting therapeutic antibodies for effective Treg cell depletion in cancer using a novel AI/ML based platform [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 6055.
Abstract 1740: Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption and cisplatin sensitization in non-small cell lung cancer
Authors: Christopher M. Baehr, Lu Zhang, Kit Lam
Journal: Cancer Research (2020)

Abstract In the United States, non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality. Traditional chemotherapies are toxic, and drug-resistance development is common. Recently, several drug candidates were shown to selectively induce lysosomal membrane permeabilization in aggressive tumors. One of these agents, chloroquine and its derivatives, has been shown to sensitize NSCLCs to cisplatin in human clinical trials. This has led to the interest in lysosome dysregulation as a cancer therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low lysosomal specificity and low potency. Here, we report on the development of a transformable nanomaterial which may be triggered to induce the mechanical lysosomal membrane permeabilization in vitro and in mouse xenograft models. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and due to lysosomal pH shift switch conformation to nanofibrils, leading to mechanical disruption of the lysosome, cisplatin sensitization and cell death. We show that the nanomaterial is cytotoxic to NSCLC cells in the low-micromolar range, but is able to sensitize NSCLC cells to cisplatin in the nanomolar range. Moreover, we demonstrate promising antitumor effect in mouse xenograft models with limited toxicity. This is the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy. Citation Format: Christopher M. Baehr, Lu Zhang, Kit Lam. Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption and cisplatin sensitization in non-small cell lung 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 1740.
Abstract 2894: XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma
Authors: Shawn Fessler, Anouk Dirksen, Scott D. Collins, Ling Xu, Winnie Lee, Jason Wang, Ron Eydelloth, Elena Ter-Ovanesyen, Jeffrey Zurita, Elizabeth Ditty, Barrett Nehilla, Susan Clardy, Susan Clardy, Tyler Carter, Kenneth Avocetien, Mark Nazzaro, Nam Le, Kalli C. Catcott, Alex Uttard, Bingfan Du, Chen-Ni Chin, Rebecca Mosher, Kelly Slocum, Liuliang Qin, David Lee, Dorin Toader, Marc Damelin, Timothy B. Lowinger
Journal: Cancer Research (2020)

Abstract The Dolasynthen platform incorporates the highly potent anti-mitotic agent auristatin F-HPA (AF-HPA), with its associated DolaLock mechanism of controlled bystander effect, and enables the synthesis of antibody-drug conjugates (ADCs) with precise control of the drug-to-antibody ratio (DAR) and site-specific bioconjugation. XMT-1592 is a novel ADC comprised of an anti-NaPi2b antibody and Dolasynthen, conjugated in a site-specific manner to yield DAR 6. NaPi2b, also known as SLC34A2, is a transmembrane sodium-phosphate transporter that is broadly expressed on tumor cells in ovarian carcinoma, NSCLC lung adenocarcinoma and other tumor types. Recent studies have shown that NaPi2b expression is enriched in the EGFR and KRAS mutant subtypes of lung adenocarcinoma. Binding studies showed a specific, high-affinity interaction of XMT-1592 with NaPi2b that was not affected by conjugated Dolasynthen. XMT-1592 elicited potent and specific in vitro cytotoxicity against NaPi2b-expressing ovarian carcinoma cells. XMT-1592 exhibited potent and specific in vivo activity in NaPi2b-expressing tumor xenografts derived from ovarian carcinoma or lung adenocarcinoma. Consistent with the targeted delivery benefits of the ADC approach, XMT-1592 yielded high and sustained concentrations of AF-HPA to tumors but not normal tissues. To evaluate the benefits of site-specific bioconjugation of Dolasynthen, we conducted in vitro and in vivo comparisons of XMT-1592 to a stochastically conjugated version of the ADC. XMT-1592 had improved in vivo activity, pharmacokinetics, and clinical pathology relative to its stochastic counterpart. Taken together, these results support XMT-1592 as a development candidate for the treatment of NaPi2b-expressing tumors. Citation Format: Shawn Fessler, Anouk Dirksen, Scott D. Collins, Ling Xu, Winnie Lee, Jason Wang, Ron Eydelloth, Elena Ter-Ovanesyen, Jeffrey Zurita, Elizabeth Ditty, Barrett Nehilla, Susan Clardy, Susan Clardy, Tyler Carter, Kenneth Avocetien, Mark Nazzaro, Nam Le, Kalli C. Catcott, Alex Uttard, Bingfan Du, Chen-Ni Chin, Rebecca Mosher, Kelly Slocum, Liuliang Qin, David Lee, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma [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 2894.
Abstract 1133: Risk effect of primary prevention strategy with aspirin on lung cancer incidence depends on high-level use, bodyweight and age: A U.S. adults evidence
Authors: Xuesi Dong
Journal: Cancer Research (2020)

Abstract Chemoprevention of cancer with aspirin is of particular interest as a primary prevention strategy, which was still in controversial. Using 101,462 individual participants' data from a U.S. adult's cohort, Cox regression model was used to detect the aspirin dosage effect on lung cancer risk. We calculated the effects of irregular use, low-dose use, and high-dose use of aspirin on lung cancer risk in population stratified by bodyweight and age. High-dose use of aspirin raised up 28% risk of lung cancer compared to no use (HR = 1.28, 95%CI = [1.14-1.45], P = 3.37×10-5). Meanwhile, the risk effect of high-dose aspirin significantly decreased with bodyweight increasing, indicating an antagonistic interaction (HRinteraction = 0.96, 95%CI = [0.94-0.99], P = 1.26×10-2). Furthermore, for these participants prone to lung cancer with bodyweight less than 80 kg, high-dose aspirin usage showed an elevated risk if their age less than 76 (HRage≤76 = 1.47, 95%CI = [1.25-1.73], P = 3.81×10-6), but did not exhibit risk effect in elders (HRage&amp;gt;76 = 1.13, 95%CI = [0.46-2.69], P = 0.80). The three-way interaction among dose of aspirin, bodyweight and age indicated that these vulnerable people (age ≤76 years and bodyweight &amp;lt;80 kg) with high lung cancer risk should be cautious to use high-dose aspirin for lung cancer chemoprevention. Citation Format: Xuesi Dong. Risk effect of primary prevention strategy with aspirin on lung cancer incidence depends on high-level use, bodyweight and age: A U.S. adults evidence [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 1133.
Abstract 2380: A novel role for PACS-1 in suppression of oncogenic replication stress in cancer cells
Authors: Chinnadurai Mani, Kaushlendra Tripathi, David W. Clark, Gary Thomas, Komaraiah Palle
Journal: Cancer Research (2020)

Abstract PACS-1 is a protein involved in trafficking, especially transport of proteins like furin and Mannose-6-phosphate into the trans-golgi network. Intriguingly, our studies identified dynamic translocation of PACS-1 during cell division and its association with chromatin in tumor cells. Downregulation of PACS-1 in cancer cell lines attenuated cell growth, induced replication stress mediated DNA damage response (DDR), such as ATM/ATR-mediated checkpoint activation, and formation RPA, FANCD2 and pH2AX foci. Consistent with these observations, live-cell imaging revealed increased nuclear translocation of PACS-1 during S-phase and until the complete cell division. These results point to a novel role for PACS-1 during normal replication or in the suppression of oncogenic replication in tumor cells. However, a direct role for PACS-1 in cancer development or progression is not clear. Analysis of the cancer genome atlas (TCGA) data revealed occurrence of PACS-1 amplifications, mutations and deletions in cancers of different tissues. PACS-1 depletion leads to proteasome-mediated degradation of HDAC2 and HDAC3, compromised chromatin maturation, leads to replication stress and genomic instability. Intriguingly, stable overexpression of PACS-1 in MDA-MB-231 cells enhanced malignant behavior of tumor cells in their ability to form soft agar colonies and matrigel invasion compared to the cells that are expressing vector control. PACS-1 downregulation promotes replication stress in tumor cells suggesting that its upregulation in tumors may be important for replication stress recovery in cancer cells and for an efficient response to chemotherapy induced DNA damage. Furthermore, Prognoscan analysis indicated that PACS-1 expression levels correlates with poor survival in multiple studies, including breast, ovarian and lung cancers, suggesting a role for PACS-1 in tumorigenesis and a biomarker for poor prognosis. Citation Format: Chinnadurai Mani, Kaushlendra Tripathi, David W. Clark, Gary Thomas, Komaraiah Palle. A novel role for PACS-1 in suppression of oncogenic replication stress in 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 2380.
Abstract 5547: Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy
Authors: Laura R. Moffitt, Amy L. Wilson, Bashirah Basri, Kirsty L. Wilson, Magdalena Plebanski, Andrew N. Stephens
Journal: Cancer Research (2020)

Abstract Ovarian cancer is the most lethal gynecological malignancy and treatment options have not improved in decades. Whilst ovarian tumors have an immune-mediated component, emerging immunotherapies (e.g. anti-PD-1, anti-PD-L1) have failed to achieve robust clinical response for ovarian cancer patients. There is an urgent need to develop new therapeutic strategies to improve survival rates in women, particularly those with recurrent, chemoresistant disease. In an ongoing study we are investigating the repurposing of sitagliptin, an anti-diabetes drug, as a novel immunomodulatory therapy in ovarian cancer. Ovarian tumors were generated in C57BL/6 wild-type mice by intrabursal implantation of ID8 murine ovarian cancer cells. Following the formation of primary tumors (~2 weeks), mice received a daily oral dose of sitagliptin (50mg/kg) until ethical endpoint. Anti-tumor immune responses were examined by flow cytometry and immunohistochemical staining according to tumor stage. Mice were assessed for overall survival compared to paclitaxel chemotherapy as standard-of-care. Daily sitagliptin treatment increased circulating Teff:Treg cell ratios in the blood, peritoneal fluid and tumor tissue at an early stage, and this was sustained throughout disease. Sitagliptin also enhanced T effector cell activation and proliferation, indicating that increased Teff:Treg ratios were a positive indicator of the anti-tumor immune response. Treatment with sitagliptin alone increased median survival time by 27% compared to both untreated controls and paclitaxel as standard-of-care, suggesting a beneficial effect mediated by anti-tumor immune responses. Of particular interest, sitagliptin treatment specifically increased the percentage of CXCR3+ T effector cells in the peritoneal cavity. Recent data has suggested that CXCR3+ T cells are functionally required for immune checkpoint inhibitors to exert efficacy. Thus, we hypothesize that sitagliptin may enhance the efficacy of immune checkpoint inhibitor therapies in ovarian cancers. Our ongoing studies are investigating the combination of sitagliptin with anti-PD-1 and anti-PD-L1 antibodies, as a rational approach to improving their efficacy in ovarian cancers. These studies will identify a clinically relevant and directly translatable approach to improve prognosis for ovarian cancer patients. Citation Format: Laura R. Moffitt, Amy L. Wilson, Bashirah Basri, Kirsty L. Wilson, Magdalena Plebanski, Andrew N. Stephens. Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy [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 5547.