tbuckley/cabot-search huggingface dataset:
Abstract 1250: Antitumor activities of CD161, a structurally novel and orally bioavailable BET inhibitor, in leukemia and triple negative breast cancer cells <i>in vitro</i> and <i>in vivo</i>
Authors: Longchuan Bai, Yujun Zhao, Liu Liu, Chao-Yie Yang, Donna McEachern, Jeanne Stuckey, Jennifer Meagher, Bo Wen, Duxin Sun, Shaomeng Wang
Journal: Cancer Research (2016)

Abstract Bromodomain and extraterminal (BET) proteins, such as bromodomain-containing protein 2 (BRD2), BRD3 and BRD4, bind lysine acetylated proteins and regulate gene transcription. Several BET inhibitors are currently under clinical development for hematological malignancies and solid tumors. We have recently developed a novel class of BET inhibitor, CD161, which binds the bromodomain 1 (BD1) and BD2 domains of BRD2, BRD3, BRD4 and BRDT with Ki less than 10 nM. Co-crystal structure of CD161 and BRD4 BD2 at 2.5 Å resolution confirmed that the docked CD161 occupies the acetyl-lysine binding pocket of BD2. CD161 has &amp;gt;1000-fold selectivity over other bromodomain containing proteins including CREBBP, ATAD2B, TRIM24 and ASH1L. In human leukemia cell lines MV4-11 and MOLM-13, CD161 strongly inhibits cell growth and induces apoptosis, with IC50s &amp;lt;100 nM. Furthermore, CD161 exerts potent growth-inhibitory activities in a panel of breast cancer cell lines representative of triple-negative breast cancer (TNBC), with IC50s in the sub micromolar range. At 20-50 mg/kg daily oral dosing for 2 weeks, CD161 significantly inhibited the growth of MV4-11 and MDA-MB-231 tumors (TGI: 55-80%) in mouse xenograft models and had no significant effect on body weights. Pharmacokinetics studies show that CD161 has a T1/2 of 2-3 hours and oral bioavailability (F%) of 93% in male Sprague−Dawley rats. Transcriptional profiling revealed that CD161 causes broad transcriptional changes in TNBC cell lines. Our preliminary results suggest the therapeutic potential of CD161 in human leukemia and TNBC. Citation Format: Longchuan Bai, Yujun Zhao, Liu Liu, Chao-Yie Yang, Donna McEachern, Jeanne Stuckey, Jennifer Meagher, Bo Wen, Duxin Sun, Shaomeng Wang. Antitumor activities of CD161, a structurally novel and orally bioavailable BET inhibitor, in leukemia and triple negative breast cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1250.
Abstract 4878: Quantitative cell-based bioassays for therapeutic development targeting immune checkpoint and co-stimulatory receptors
Authors: Jamison Grailer, Pete Stecha, Jun Wang, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng
Journal: Cancer Research (2016)

Abstract Immunotherapy harnesses the immune system to fight cancer and has proven to be a very promising therapeutic strategy. Drug targets in cancer immunotherapy include both inhibitory and co-stimulatory immune receptors on T cells or NK cells, in particular. Current approaches to assay immunotherapy biologics rely on primary cells, are highly variable, and are not suitable for a quality control environment during drug development. We have developed a panel of cell-based assays using a bioluminescent reporter platform that can quantitatively determine the potencies of antibodies and ligand proteins targeting immune checkpoint receptors and co-stimulatory receptors including PD-1, CTLA-4, LAG-3, GITR, 4-1BB, OX40 and CD40. For each target, a stable cell line was generated in an immune cell background to stably express an immune checkpoint or co-stimulatory receptor and a luciferase reporter driven by a response element specifically responding to signaling induced by TCR or directly from the immune receptor. These bioassays reflect biological mode-of-action for each class of drug candidate and are able to determine the potencies for on-market biologic drugs including PD-1 antibodies pembrolizumab and nivolumab, and CTLA-4 antibody ipilimumab. The assay signals are robust, specific, and have good repeatability and linearity. Therefore they can serve as valuable tools for drug screening, QC lot release and stability studies in immunotherapy drug development. Citation Format: Jamison Grailer, Pete Stecha, Jun Wang, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays for therapeutic development targeting immune checkpoint and co-stimulatory receptors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4878.
Abstract 3846: Sensitivity of NOTCH1 mutant T-ALL to ABT-263
Authors: Anahita Dastur, Carlotta Costa, Anthony Faber, Cyril Benes
Journal: Cancer Research (2016)

Abstract Effective targeted therapies are lacking for refractory and relapsed T-cell Acute Lymphoblastic Leukemia (T-ALL). Analysis of a large cell line screen revealed that NOTCH1 mutant T-ALL cells are sensitive to the Bcl-2/xL inhibitor ABT-263. We show that NOTCH1 inhibits the mTOR complex 1, resulting in low MCL-1 levels and sensitization to ABT-263. Further suppression of mTORC1 using small molecule inhibitors in combination with ABT-263 results in very high levels of apoptosis and tumor regressions in vivo. This suggests new therapeutic opportunities for NOTCH1 mutant T-ALL, including in the setting of gamma-secretase inhibitor (GSI) resistance. Citation Format: Anahita Dastur, Carlotta Costa, Anthony Faber, Cyril Benes. Sensitivity of NOTCH1 mutant T-ALL to ABT-263. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3846.
Abstract 4317: Black raspberries show potent activity in prevention of experimental squamous cell esophageal cancer compared to a combination of selective COX-2 and iNOS inhibitors
Authors: Ni Shi, Kenneth M. Riedl, Steven J. Schwartz, Xiaoli Zhang, Steven K. Steven, Tong Chen
Journal: Cancer Research (2016)

Abstract Esophageal squamous cell carcinoma (SCC) remains a major health threat worldwide and preventive strategies are needed. We previously reported that overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are correlated with nitrosamine-induced squamous carcinogenesis of the esophagus and the selective iNOS and COX-2 inhibitors significantly inhibit incidence and progression. We also demonstrated anti-cancer activity of black raspberries (BRB) in a rodent model of esophageal SCC. The objective of the current study was to compare the impact of BRB versus the combination of celecoxib, a selective COX-2 inhibitor, and S,S’-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), a selective iNOS inhibitor, in inhibition of SCC of the esophagus, and to elucidate molecular mechanism of an effective cancer prevention. We found that BRB is superior to the combination of two drugs in suppression of premalignant tissue growth in the rat esophagi. Moreover, rats fed BRB have lower tumor multiplicity than those fed celcecoxib + PBIT. Our data indicated that BRB also shows a potent inhibitory effect on esophageal iNOS and COX-2, in addition to modulating several associated oncogenic cell signaling pathways. We further conducted parallel mechanistic studies in vitro using BRB anthocyanins and the above two drugs. Our findings demonstrated that dietary BRB is superior to the combination of two chemopreventive pharmaceutical agents in prevention of experimental squamous cell esophageal cancer, suggesting the potential value of additional translational studies in developing food-based products using BRB for the prevention of esophageal SCC carcinogenesis in humans (Supported by NIH/NCI R01 CA131073). Citation Format: Ni Shi, Kenneth M. Riedl, Steven J. Schwartz, Xiaoli Zhang, Steven K. Steven, Tong Chen. Black raspberries show potent activity in prevention of experimental squamous cell esophageal cancer compared to a combination of selective COX-2 and iNOS inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4317.
Defining the biological subgroup of multiple myeloma patients which benefits maximally from the overall survival (OS) benefit associated with treatment with zoledronic acid (ZOL).
Authors: G. J. Morgan, F. Davies, W. Gregory, S. E. Bell, A. Szubert, N. Navarro Coy, M. Drayson, R. G. Owen, S. Feyler, J. Ashcroft, F. Ross, J. Byrne, H. Roddie, C. Rudin, G. Cook, G. H. Jackson, K. Boyd, J. A. Child, P. Wu
Journal: Journal of Clinical Oncology (2011)

8083 Background: Myeloma IX examined thalidomide-based induction and maintenance in patients (pts) with multiple myeloma (MM) treated in intensive or non-intensive pathways and SRE reduction with bisphosphonates (BPs; IV ZOL vs oral clodronate [CLO]). In 1960 evaluable pts, ZOL improved OS by 5.5 mo (P = .04) and significantly reduced SRE risk vs CLO (Morgan et al. Lancet. 2010). A biologic basis for this benefit has not been reported. Methods: Here we discuss subgroup analyses (demographics and biologic disease characteristics) that can inform our understanding of how ZOL OS benefit is derived. Baseline bone disease (BD+ or BD−) was screened using axial skeletal surveys. FISH analysis of CD138-selected plasma cells was performed using standard methodology on a subset (n = ~1000); gene expression was assessed using the Affymatrix system. Results: In subgroup analyses, ZOL OS benefit vs CLO was not affected by gender, ISS stage, or specific myeloma genotypes. BD rates at presentation varied between genotypes (higher with hyperdiploidy and t[11:14], lower with t[4;14]). Integration of FISH and ISS data to better delineate high- and low-risk myeloma biology was performed, and evaluation of effects on ZOL’s OS benefits is underway. Previously, among BD− pts (~30% of total), ZOL significantly decreased SRE risk (~30%) vs CLO. For the first time, we report that OS was significantly shorter in BD+ (median 45.5 mo, n = 1401) vs BD− pts (median 51.6 mo, n = 540; P =.009). OS benefit with ZOL vs CLO was apparently most profound in BD+ pts, with no significant OS difference between BPs in BD− pts. Differences in gene expression profiles and myeloma-bone interactions in BD+ and BD– pts may explain the varying OS benefit despite similar SRE prevention with ZOL. Conclusions: ZOL OS benefits vs CLO are independent of demographic and baseline disease characteristics evaluated except for BD. ZOL more effectively reduced SREs than CLO in both BD+ and BD− pts, but OS benefits were restricted to BD+ pts. Further investigations of gene expression profiles are ongoing and may provide further insight into differential interactions between these BPs and myeloma in bone marrow.
The Majority of Patients Receiving Donor Lymphocyte Infusions for Relapsed Chronic Myeloid Leukemia Remain PCR Positive Despite Maintaining Long-Term Remission,
Authors: Andrew J Innes, James Lurkins, Richard M Szydlo, Andrea Guerra, Dragana Milojkovic, Jiri Pavlu, Edward J Kanfer, David Marin, Donald MacDonald, Amin Rahemtulla, Sandra Loaiza, Stephanie Kirschke, Katayoun Rezvani, John Goldman, Jane F Apperley, Francesco Dazzi
Journal: Blood (2011)
Abstract 3750: CD133-targeted oncolytic adenovirus shows therapeutic effect by attacking colon cancer stem cells
Authors: Mizuho Sato, Yoshiaki Miura, Masato Yamamoto
Journal: Cancer Research (2016)

Abstract Colorectal cancer is the third most common cancer in the world and about 50% of patients relapse after treatment. Cancer stem cells (CSCs) have contribution to recurrence, metastasis and and chemotherapy resistant of colorectal cancers. CD133 (Prominin-1), a member of the transmembrane glycoprotein family, is a marker of CSCs in several cancers and is also generally accepted as a colorectal cancer stem cell marker. CD133 expression was correlated with recurrence, metastases and chemotherapy resistance, as well as poor prognosis in colorectal cancer. It is therefore reasonable to develop CSCs-directed therapeutic strategies by employing CD133 as a target molecule. Recently, we have established a method for isolating transductionally-targeted adenovirus by high-throughput screening. In this study, using this adenovirus library screening system, we isolated the CD133-specific Oncolytic Adenovirus (OAd) and tested the oncolytic activity of CD133-targeted Ad in both in vitro and in vivo. CD133-targeted OAd (AdML-TYML) showed strong binding to CD133-positive cells (293-CD133 and LoVo (CD133 (+) human colon carcinoma)), not to CD133-negative cells (parental 293 and LS174T (CD133 (-) human colon carcinoma)) and this virus also showed strong oncolysis selectively in LoVo cells, whereas there was no effect on LS174T cells. In order to assess the effect of AdML-TYML on stemness, tumor establishment assay was performed. AdML-TYML treatment leads to inhibition of tumor establishment of CD133-positive colorectal cancer cell lines in nude mice. 100% of the mice inoculated with non-infected LoVo cells had developed tumors, while 0% of the mice inoculated with AdML-TYML infected LoVo cells had done so. In addition, when the anti-tumor effect of the CD133-targeted OAd was analyzed in established tumors of CD133(+) colorectal cancer subcutaneous xenografts, intra-tumor (i.t.) administration of AdML-TYML exhibited significantly stronger antitumor effect compared to its equivalent Ad5-WT (wild type Ad5 fiber). We focused on the CD133 as a target molecule of CSCs in colon cancer and successfully identified potent CD133-targeting OAd using high-throughput screening system. The CD133-targeted OAd exhibited selective infectivity and oncolysis to CD133-positive cells and anti-tumor effect against established colon cancer cells. Our results suggest that CD133-targeted oncolytic adenovirus selectively eliminate CD133 (+) colorectal cancer stem cells from the tumor and also this virus could be a key tool for the prevention of metastases and relapses in a variety of cancers. Citation Format: Mizuho Sato, Yoshiaki Miura, Masato Yamamoto. CD133-targeted oncolytic adenovirus shows therapeutic effect by attacking colon cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3750.
P1257 : Early identification of patients at risk for chronic hepatitis B and C in arnhem region, the Netherlands
Authors: G. Ter Beest, J. Gisolf, M. Belgers, T. Waegemaeckers, C. Swanink, M. Spanier, J.M. Vrolijk, P. Van Bentum, L. Roovers, C. Richter
Journal: Journal of Hepatology (2015)
Abstract 5254: Andrographolide prevents prostate cancer by targeting CXCR3/CXCR7 and regulators of cell cycle
Authors: Hina Mir, Neeraj Kapur, Rajesh Singh, Guru Sonpavde, James W. Lillard, Shailesh Singh
Journal: Cancer Research (2016)

Abstract Despite state of the art cancer diagnostics and therapies offered in clinics, prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on phases of cell cycle in LNCaP, C4-2b and PC3 cell lines compared to retinoblastoma protein (RB-/-) lacking DU-145 cells. This agent blocked the G2/M transition in LNCaP, C4-2b and PC3 whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to switching of the activation states of cell cycle regulators in these cell lines. AG induced its effect mainly via cyclin A2 and B1 in LNCaP, C4-2b and PC3 cell lines; whereas, cyclin E related regulation was affected in DU-145 cells. Phosphorylation status of Wee1, a nuclear kinase belonging to the Ser/Thr family and CDC2 was also affected by AG. Intriguingly, AG affected cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggest this agent has potential to be used as a therapeutic and/or preventive modality. Citation Format: Hina Mir, Neeraj Kapur, Rajesh Singh, Guru Sonpavde, James W. Lillard, Shailesh Singh. Andrographolide prevents prostate cancer by targeting CXCR3/CXCR7 and regulators of cell cycle. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5254.
Hydatidiform Moles: Genetic Basis and Precision Diagnosis
Authors: Pei Hui, Natalia Buza, Kathleen M. Murphy, Brigitte M. Ronnett
Journal: Annual Review of Pathology Mechanisms of Disease (2017)

Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. Overrepresentation of the paternal genome in sporadic hydatidiform moles (purely androgenetic in complete hydatidiform moles and diandric triploid in partial hydatidiform moles) is a fundamental genetic event leading to global alteration of imprinting gene expression in the molar trophoblast. Rare familial biparental hydatidiform moles (due to NLRP7 or KHDC3L mutations) share such global imprinting alterations, implying a common end point of pathogenesis. Despite being the cornerstone of diagnosis, routine morphologic assessment of hydatidiform moles continues to suffer from interobserver diagnostic variability, emphasizing the need for new diagnostic modalities. Analyses of p57 expression by immunohistochemistry and polymerase chain reaction–based DNA genotyping have emerged as powerful diagnostic methods for accurate classification of hydatidiform moles. Algorithmic approaches combining histology and these ancillary techniques provide the best diagnostic practice currently available.
Abstract LB-183: The impact of protein concentration on the distribution of 111In-antibody conjugate for imaging of programmed death-ligand 1 (PD-L1)
Authors: Jessie Nedrow, Anders Josefsson, Sunju Park, Sagar Ranka, George Sgouros
Journal: Cancer Research (2016)

Abstract Background: Programmed cell Death Ligand 1 (PD-L1) is part of an immune checkpoint system that is essential for preventing autoimmunity. Tumor cells have developed the ability to co-opt these immune checkpoints to suppress anti-tumor immunity. Recent approaches in immunotherapy targeting immune checkpoints have shown great promise in a variety of cancers. PD-L1 overexpression is associated with a poorer prognosis in a variety of cancers, but typically have a stronger response to anti-PD-L1 therapy. PD-L1 is a dynamic biomarker and the ability to image its dynamic nature could provide key information in identifying patients who will best respond to anti-PD-L1 treatment with limited adverse effects. Here we evaluated an 111In-antibody conjugate targeted to PD-L1 for SPECT imaging in an aggressive mouse melanoma model. In addition, we investigated the relationship between the spleen, which we have found to be a sink for anti-PD-L1 antibodies, and specific activity (activity/protein concentration) of the 111In-antibody conjugate. Methods: An anti-PD-L1 antibody was conjugated to DTPA for 111In-labeling. The biodistribution of the resulting conjugate, 111In-DTPA-anti-PD-L1, was performed over a range of specific activities in B16F10 tumor bearing mice. SPECT imaging was also performed with the 111In tracer. Results: 111In-DTPA-anti-PD-L1 (Kd = 0.6±0.1 nM) having a specific activity (SA) of 0.57 Ci/μmol demonstrated uptake in the B16F10 tumor (6.1±2.8%ID/g) at 24 hours, as well as high uptake in the spleen (32.8±5.1%ID/g). Decreasing the SA to 0.01 Ci/μmol blocked PD-L1-postive cells in the spleen (13.4±4.8%ID/g) forcing more of the tracer to remain in circulation, allowing for increase accumulation in the B16F10 tumor (16.8±6.2%ID/g) at 24 hours. The lower SA also demonstrated a reduction in tumor to blood ratios compared to the higher SA (2.2 vs. 4.1), but an increase was shown in the tumor to muscle ratio (27 vs. 4.6). Conclusion: 111In-DTPA-anti-PD-L1 is capable of identifying tumors that overexpresses PD-L1, and has the potential to help select patients that will best respond to anti-PD-L1 therapy. In addition, the further understanding of the spleen/tumor relationship could be utilized to tailor individual doses for anti-PD-L1 therapy and minimize adverse effects. Citation Format: Jessie Nedrow, Anders Josefsson, Sunju Park, Sagar Ranka, George Sgouros. The impact of protein concentration on the distribution of 111In-antibody conjugate for imaging of programmed death-ligand 1 (PD-L1). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-183.
Incidence of osteonecrosis of the jaw (ONJ) in metastatic renal cell cancer patients (mRCC) treated with zoledronic acid (ZA).
Authors: Fruzsina Gyergyay, Krisztian Nagyivanyi, Krisztina Biro, Zsofia Kuronya, Hajnalka Nemeth, Lajos Geczi
Journal: Journal of Clinical Oncology (2015)

e20649 Background: Bisphosphonates inhibit bone resorption and thus bone renewal by suppressing the recruitment and activity of osteoclasts. Bisphosphonates are commonly used in the treatment of mRCC with bone metastases in order to reduce the risk of fracture and bone pain. Since the era of targeted treatment the number of ONJ cases has increased. Methods: Data from 210 consecutive patients treated with intravenous ZA for mRCC, with bone metastases were reviewed. The incidence of ONJ has been retrospectively assessed over time since 2005. Results: 210 patients (M/F: 152/58, median age: 62 yrs., range: 25-84) received 1668 cycles of ZA (median: 4, average 7.9, range 1-72). Altogether 149 pts. received one or several types of targeted treatment (Sunitinib, Nexavar, Everolimus, Temsirolimus, Pazopanib), 61 pts. were treated only with immunochemotherapy. Nine cases of ONJ were identified (M/F: 6/3, median age: 61 yrs., range 38-72). Six pts. received Sunitinib, 2 pts. got Sunitinib and Nexavar and one patient has been treated with Sunitinib, Nexavar and Everolimus. ONJ had been diagnosed after median 21 cycles of ZA, range 10- 46. None of the 61 pts. who did not receive targeted treatment were identified to have ONJ. Conclusions: The risk of ONJ in mRCC pts. treated with targeted treatment and ZA exceeded 6%. Our data suggest the potential synergic antiangiogenic effect of tyrosine kinase inhibitors and ZA.