tbuckley/cabot-search huggingface dataset:
Abstract 3500: Mitochondrially targeted p53 domains as a stand alone or adjunct to paclitaxel for the treatment of ovarian cancer
Authors: Phong Lu, Carol S. Lim
Journal: Cancer Research (2016)

Abstract Although the main function of p53 is a nuclear transcription factor that has important roles in cell cycle arrest, DNA repair, and apoptosis, p53 can directly trigger the intrinsic apoptotic pathway through the mitochondria. p53 has been known to bind to mitochondrial anti-apoptotic proteins (Mcl-1, Bcl-2 and Bcl-XL) and pro-apoptotic proteins (Bak and Bax), which will cause the oligomerization of Bak and Bax. The result is the formation of permeable pores on the mitochondrial outer membrane, which in turn cause the release of cytochrome c and activation of caspase-3. Targeting p53 to the mitochondria is an attractive approach because it can cause a rapid apoptotic response. We have introduced the mitochondrial targeting signal (MTS) from Bak or Bax to the C-terminus of p53 and have shown the superior efficacy of p53-BakMTS and p53-BaxMTS over wtp53 in many human cancer cell lines. We have identified that the DNA binding domain (DBD) of p53 may be the minimal domain of p53 required for apoptosis. Our preliminary data in SKOV-3 ovarian cancer cells also suggests that DBD-BakMTS may work just as well as full length p53-BakMTS. In addition to BakMTS and BaxMTS, attaching pro-apoptotic factors such as Noxa or Bid to p53 has created a chimeric gene construct that show superior cell death activity than wide type p53. Our goal is to use a novel version of p53 directed to the mitochondria as a direct apoptogen to treat ovarian cancer, the most lethal gynecological malignancy with 69% of patients succumbing to this disease. Our next step will be to test these constructs in vivo using the syngeneic ID8 mouse model. To determine the activity of these mitochondrially targeted p53 constructs, TMRE, 7-AAD, and caspase 3/7 assays were performed in many human ovarian cancer cell lines including SKOV-3, OVCAR-3, Kuramochi, and mouse ovarian ID8 cells that have been transfected with our constructs. In all of our cell death and apoptotic assays, p53-Bax-MTS, p53-BakMTS, and p53-Noxa are always superior to wide type p53, regardless of the p53 status of the cells. Furthermore, we have also tested the possibility of combining our p53 constructs with paclitaxel, the current standard of care for ovarian cancer. Our p53 constructs showed a synergistic effect with paclitaxel and was able to reduce its IC5, indicating the possibility of dose-lowering of this highly toxic drug. Our ultimate goal is to use mitochondrially targeted p53 constructs that directly induce apoptosis alone or in combination with other chemotherapy drugs for the treatment of ovarian cancer. Acknowledgements: NIH CA151847 Citation Format: Phong Lu, Carol S. Lim. Mitochondrially targeted p53 domains as a stand alone or adjunct to paclitaxel for the treatment of ovarian cancer. [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 3500.
Abstract 824: Effects of metfornin on mammary carcinogenesis and metabolic profiles in methylnitrosourea-treated rats on standard or Western diets
Authors: Mark S. Miller, Matthew D. Thompson, Ronald A. Lubet, Vernon E. Steele, Harold E. Seifried, Clinton J. Grubbs
Journal: Cancer Research (2016)

Abstract The methylnitrosourea-induced model of ER+ mammary cancer in female Sprague-Dawley rats has been routinely used to screen for chemopreventive agents. We recently reported that metformin was ineffective in reducing cancer formation in rats on a standard (4% fat) diet (Thompson, et al., Cancer Prev Res. 8, 231, 2015). In the present studies, rats were placed on a standard (Teklad) diet or on a Western diet (20% fat, low calcium) at 43 days of age (DOA), and administered MNU at 50 DOA. Rats were administered metformin or vehicle daily by gavage beginning at 57 days of age. Serum from the rats of the various groups was obtained both at 21 days following initial administration of metformin (or vehicle) and at the end of the study (when tumors had developed in most rats). We found an increase in the final body weights, number of mammary cancers, and the final weights of tumors in rats on western diet compared with standard diet. Furthermore, metformin failed to decrease tumor multiplicity in either diet, in fact, it increased final cancer weights (P&amp;lt;.05). Serum from rats in the various groups were examined for approximately 500 metabolites (Metabolon; Research Triangle Park, NC). The Metabolites which were differentially expressed when comparing Western vs standard diets at either time point included myoinositol, scyllo-inositol, 2-hydroxydecanoate, carnitine, tocopherol, and nicotinamide. Certain of these were fatty acids and lipid soluble vitamins that one would expect to be altered by diet. We also compared serum from animals on standard or Western diets at the early or late time points to determine metabolites associated with cancer development. Metabolites whose levels changed in tumor bearing rats included 4-OH-butyrate, acetyl-carnitine, uranate, and threonate. Finally, we compared the effects of metformin treatment in rats on Western or standard diet and found that the metabolic changes associated with metformin treatment were dependent on the diet employed. Thus, metformin altered levels of arachidate and serotonin only in rats on standard diet, while carnnitine and N-delta-acetylornithine were only modulated in rats on Western diet. Again, the most striking result may be that we still failed to observe any efficacy of metformin in animals on standard or Western diet. Citation Format: Mark S. Miller, Matthew D. Thompson, Ronald A. Lubet, Vernon E. Steele, Harold E. Seifried, Clinton J. Grubbs. Effects of metfornin on mammary carcinogenesis and metabolic profiles in methylnitrosourea-treated rats on standard or Western diets. [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 824.
Abstract 2759: USP21 stabilizes the BRCA2/Rad51 complex to ensure cancer genome maintenance
Authors: Jinping Liu, Alex J. Kruswick, Hien Dang, Andy D. Tran, Xin W. Wang, Philipp Philipp
Journal: Cancer Research (2016)

Abstract Cancer is a disease of defective genome maintenance. Paradoxically, however, tumor growth relies on efficient DNA repair to mitigate the detrimental impact of replication-associated DNA double-strand breaks (DSBs). Deleterious mutations in BRCA2, a tumor suppressor that promotes homologous recombination (HR), consequently result in increased susceptibility to genotoxic stress in rapidly dividing tumor cells. While these findings underscore the importance of tightly controlled BRCA2 function for tumor growth, little is known about the factors that regulate this process. Here, we establish the ubiquitin-specific protease USP21 as a positive regulator of BRCA2 stability. USP21 interacts with, deubiquitinates and stabilizes the BRCA2/Rad51 complex and promotes efficient Rad51 loading to DSBs. As a result, depletion of USP21 decreases HR efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated HR defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma (HCC), where it promotes BRCA2 stability and inversely correlates with patient survival. These findings demonstrate a novel deubiquitination mechanism to control BRCA2 levels and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors. Citation Format: Jinping Liu, Alex J. Kruswick, Hien Dang, Andy D. Tran, Xin W. Wang, Philipp Philipp. USP21 stabilizes the BRCA2/Rad51 complex to ensure cancer genome maintenance. [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 2759.
First Report of the HOVON 45: A Phase II Study with Rituximab, High Dose Ara-C and Autologous Stem Cell Transplantation in the Primary Treatment of Mantle Cell Lymphoma.
Authors: Mars B. Van’t Veer, Annelise Notenboom, Marius McKenzie, Hanneke Kluin-Nelemans, Rien van Oers, Jose Zijlstra, Daphne de Jong, Pieter Sonneveld, Anton Hagenbeek
Journal: Blood (2006)
Abstract 2171: Beta-hairpin peptide hydrogels as scaffolds for 3D high-throughput cancer drug discovery
Authors: Peter Worthington, Katherine M. Drake, Andrew D. Napper, Darrin J. Pochan, Sigrid A. Langhans
Journal: Cancer Research (2016)

Abstract High-throughput screening (HTS) remains a promising initial step in discovering novel lead compounds for cancer therapy, but its value is limited by the poor predictability of clinical effectiveness of candidate compounds. One compelling reason for this lack of reliability to predict in vivo efficacy is the fact that most HTS is done using traditional two-dimensional (2D) cell cultures. While 2D cultures are convenient and can easily be automated, compelling evidence suggests that cells cultured in these non-physiological conditions differ from cells grown in the more in vivo like three-dimensional (3D) systems that better mimic microenvironments. Thus, a 3D culture model is expected to be a better platform for cancer drug discovery. Here we demonstrate the feasibility of a beta-hairpin hydrogel as a novel platform for 3D HTS. MAX8 forms a bonded fibrillar hydrogel network under physiological conditions and moreover, due to its unique shear-thinning abilities can be incorporated into standard HTS equipment. MAX8 is biocompatible with a variety of cancer cell lines, can be tuned for porosity, permeability and stiffness, and can be functionalized with common and cell-type specific ligands to more closely resemble an in vivo-like tumor environment. Using medulloblastoma cells that are known to display more immature, tumor-like features in 3D and that were automatically dispensed onto 384-well plates we have developed a robust assay to measure cell viability on a HTS platform that will have broad applicability for other cancers for which 3D HTS is desirable. Citation Format: Peter Worthington, Katherine M. Drake, Andrew D. Napper, Darrin J. Pochan, Sigrid A. Langhans. Beta-hairpin peptide hydrogels as scaffolds for 3D high-throughput cancer drug discovery. [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 2171.
Abstract 4704: The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of human small cell lung cancer
Authors: Sang Hyun Lee, Xuesong Mike Liu, Melody Diamond, Valerie Dostalik, Margaret Favata, Chunhong He, Liangxing Wu, Richard Wynn, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri
Journal: Cancer Research (2016)

Abstract Methylated histone marks on H3K4 and H3K9 are generally coupled with transcriptional activation and repression, respectively. Altered levels of these histone methylation marks lead to abnormal gene expression and are associated with oncogenesis. Lysine specific demethylase 1 (LSD1) catalyzes demethylation of mono and di-methylated lysine 4 and 9 of histone H3 via an FAD-dependent redox-process. Deregulated LSD1 activity perturbs normal gene expression and can lead to cellular transformation. In particular, the function of LSD1 has been reported to maintain stem cell-like gene expression patterns in various cancers, most notably small cell lung cancer (SCLC), a cancer type that is characterized by a highly undifferentiated state and with high unmet medical need. INCB059872 is a potent, selective and orally bioavailable inhibitor of LSD1 that achieves inhibitory activity through the formation of covalent FAD-adducts. The effect of INCB059872 in SCLC cell lines was assessed in vitro and in vivo. In these studies, the proliferation of a panel of SCLC cell lines was inhibited by INCB059872, with EC50 values ranging from 47 to 377 nM. Non-tumorigenic cells, such as IL-2 stimulated T cells from normal donors, by contrast, were significantly less sensitive with IC50 values &amp;gt; 10 μM. Oral administration of INCB059872 on once daily (QD) and alternative day (QoD) dosing regimens inhibited tumor growth in the NCI-H526 and NCI-H1417 human SCLC xenograft models. Consistent with previous reports, INCB059872 treatment in these models led to the induction of the FEZ1 and UMODL1 genes relative to vehicle-treated animals, as part of a gene signature in SCLC cell lines that is predictive of LSD1 responsiveness. Moreover, serum levels of the neuroendocrine marker pro-GRP were markedly reduced at all efficacious dosing regimens in the NCI-H1417 human SCLC xenograft model, suggesting that serum pro-GRP levels could be used as a surrogate pharmacodynamic marker of LSD1 inhibition. Currently, the efficacy of INCB059872 in combination with standard of care therapies for SCLC is under evaluation in these preclinical models. These data support the clinical evaluation of INCB059872 in patients with SCLC. Citation Format: Sang Hyun Lee, Xuesong Mike Liu, Melody Diamond, Valerie Dostalik, Margaret Favata, Chunhong He, Liangxing Wu, Richard Wynn, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri. The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of human small cell lung cancer. [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 4704.
Abstract 3880: Quantitative human secretome: a technology to measure the expression levels of thousand of secreted proteins
Authors: Ruo-Pan Huang, Yingqing Mao, RuoChun Huang, Haw-Han Yen
Journal: Cancer Research (2016)

Abstract The secretome constitutes an increasingly important category of proteins which are involved in a multitude of biological, physiological and pathological processes, and are thus a clinically relevant source for biomarkers and therapeutic targets. The development of cancer often leads to alterations in growth-stimulatory autocrine and paracrine signals which change the expression levels of secreted proteins such as growth factors, cytokines, chemokines, and angiogenic factors. There is thus an urgent need to develop high-content and high-throughput approaches to profile the secretome. Using a sandwich-based ELISA format, we have developed an antibody array technology which can quantitatively measure expression levels of 1000 secreted proteins. Most of the target proteins are detectable at pg/ml levels. We have also developed a multi-layered normalization process (including positive controls, standard curves, and reference samples) which significantly enhances the performance of the platform and may be used for accurate measurement of protein concentrations in a variety of samples, including serum, plasma, tissue lysates, and other fluids. This platform is also high throughput, allowing hundreds of samples to be assayed daily. We have analyzed several hundred serum samples (both normal and cancer patients) using this system. Our results demonstrate that our technologies provide a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to cancer and other human diseases. Citation Format: Ruo-Pan Huang, Yingqing Mao, RuoChun Huang, Haw-Han Yen. Quantitative human secretome: a technology to measure the expression levels of thousand of secreted proteins. [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 3880.
Abstract 2316: GPC3-specific chimeric antigen receptor T cell in combination with Sorafenib as a novel therapeutic treatment for hepatocellular carcinoma
Authors: Thu Le Trinh, Qunfeng Wu, Lung-Ji Chang, Mitchell Ho, Chen Liu
Journal: Cancer Research (2016)

Abstract FDA-approved targeted therapy for advanced hepatocellular carcinoma (HCC) is limited with the only option of Sorafenib treatment with severe side effects. Immunotherapy based on adoptive transfer of tumor-specific T cells have demonstrated a promising clinical outcome for solid tumors. In our study, we developed T cells expressing the fourth generation of GPC3-specific chimeric antigen receptor (α-GPC3 CAR) that efficiently eliminated GPC3-positive HCC cells (Huh7 and HepG2) without killing GPC3-negative primary hepatocytes. This CAR was constructed using a lentiviral vector containing CD28, CD27 and 41BB costimulatory domains, a CD3ζ signaling domain fused to a FKBP-iCasp9 apoptosis inducing gene, and a GPC3-specific sequence derived from HN3, a single-domain VH human monoclonal antibody (gift from Mitchell Ho, NCI). After 16h of incubation at the E (α-GPC3 CAR T cells) : T (Huh7 or HepG2 cells) ratio of 1:1, α-GPC3 CAR T cells effectively lysed Huh7 (39%) and HepG2 (77%) but not primary hepatocytes (9%), while the control CAR T cells (α-CD30 CAR) could not initiate a specific lysis on those cells. At the E:T ration of 3:1, the specific killing increased to 78% (Huh7) and 99% (HepG2) while remaining low with primary hepatocytes (11%). Especially at the very low E:T ratio of 1:10, combination with Sorafenib priming (24h, IC10 concentration) prior to CAR T incubation boosted the specific lysis up to 25% (p = 0.0416). These results indicate that combination of GPC3-specificCAR T cells transfer and Sorafenib regimen could be a promising therapeutic option for the treatment of HCC, with the doses of both CAR T and Sorafenib reduced up to 10 times, hence lower side effects while preserving the efficacy of tumor-specific cytotoxicity. Citation Format: Thu Le Trinh, Qunfeng Wu, Lung-Ji Chang, Mitchell Ho, Chen Liu. GPC3-specific chimeric antigen receptor T cell in combination with Sorafenib as a novel therapeutic treatment for hepatocellular carcinoma. [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 2316.
An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain–Containing 7A–Specific Antibodies in Membranous Nephropathy
Authors: Elion Hoxha, Laurence H. Beck, Thorsten Wiech, Nicola M. Tomas, Christian Probst, Swantje Mindorf, Catherine Meyer-Schwesinger, Gunther Zahner, Phillip R. Stahl, Ruth Schöpper, Ulf Panzer, Sigrid Harendza, Udo Helmchen, David J. Salant, Rolf A.K. Stahl
Journal: Journal of the American Society of Nephrology (2016)

Thrombospondin type 1 domain–containing 7A (THSD7A) is a target antigen identified in adult membranous nephropathy (MN) along with the major antigen phospholipase A 2 receptor 1 (PLA 2 R1). The prevalence of THSD7A-Ab–positive patients is unknown, and it is unclear whether the clinical presentation differs between patients positive for PLA 2 R1-Ab or THSD7A-Ab. We screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Compared with Western blot analysis, the IFT had a 92% sensitivity and a 100% specificity. The prevalence of THSD7A-associated MN in a prospective cohort of 345 patients with MN was 2.6%, and most were women. In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLA 2 R1-associated MN and malignant disease. In all cohorts, we identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis–infiltrated lymph node. We conclude that the IFT allows sensitive and specific measurement of circulating THSD7A-Ab in patients with MN. Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA 2 R1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.
Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity
Authors: Peter Ballard, James W.T. Yates, Zhenfan Yang, Dong-Wan Kim, James Chih-Hsin Yang, Mireille Cantarini, Kathryn Pickup, Angela Jordan, Mike Hickey, Matthew Grist, Matthew Box, Peter Johnström, Katarina Varnäs, Jonas Malmquist, Kenneth S. Thress, Pasi A. Jänne, Darren Cross
Journal: Clinical Cancer Research (2016)

Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported.Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130-40. ©2016 AACR.
Combination Trial of Duvelisib (IPI-145) with Bendamustine, Rituximab, or Bendamustine/Rituximab in Patients with Lymphoma or Chronic Lymphocytic Leukemia
Authors: Ian W. Flinn, Mohamad Cherry, Michael Maris, Jeffrey V. Matous, Jesus G. Berdeja, Manish R. Patel
Journal: Blood (2015)
Detection of FGFR3 by Immunohistochemistry in Multiple Myeloma Is Highly Predictive of t(4;14) by FISH and Is Associated with CD56 (NCAM1) Expression.
Authors: Nizar J. Bahlis, Birgitte Roland, Toni Maggliocco, Ivona Auer, Douglas A. Stewart, Adnan Mansoor
Journal: Blood (2006)