tbuckley/cabot-search huggingface dataset:
Long Non-coding RNA BGas Regulates the Cystic Fibrosis Transmembrane Conductance Regulator
Authors: Sheena M Saayman, Amanda Ackley, Jon Burdach, Matthew Clemson, Dieter C Gruenert, Kiyoshi Tachikawa, Pad Chivukula, Marc S Weinberg, Kevin V Morris
Journal: Molecular Therapy (2016)

Cystic fibrosis (CF) is a life-shortening genetic disease. The root cause of CF is heritable recessive mutations that affect the cystic fibrosis transmembrance conductance regulator (CFTR) gene and the subsequent expression and activity of encoded ion channels at the cell surface. We show that CFTR is regulated transcriptionally by the actions of a novel long noncoding RNA (lncRNA), designated as BGas, that emanates from intron 11 of the CFTR gene and is expressed in the antisense orientation relative to the protein coding sense strand. We find that BGas functions in concert with several proteins including HMGA1, HMGB1, and WIBG to modulate the local chromatin and DNA architecture of intron 11 of the CFTR gene and thereby affects transcription. Suppression of BGas or its associated proteins results in a gain of both CFTR expression and chloride ion function. The observations described here highlight a previously underappreciated mechanism of transcriptional control and suggest that BGas may serve as a therapeutic target for specifically activating expression of CFTR.
Effect of androgen signaling in stromal cells on growth of prostate cancer.
Authors: Chun-Peng Liao, Leng-Ying Chen, Andrea Luethy, Youngsoo Kim, A. Robert MacLeod, Mitchell E. Gross
Journal: Journal of Clinical Oncology (2016)

297 Background: Interactions between epithelial and stroma cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Methods: Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model (Liao, et al Cancer Res, 2010. 70(18):7294). A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. RT-PCR was used to investigate changes in gene expression. Results: Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorigenicity in epithelial cells were investigated. Markers associated with epithelial-mesenchymal transition (EMT, N-Cad) and “stemness” (OCT4, Sox2, Nanog) were increased in human prostate cancer cells grown with low-AR CAFs. Conclusions: Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorigenicity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer.
A phase II study of chlorambucil plus rituximab followed by maintenance versus observation in elderly patients with previously untreated chronic lymphocytic leukemia: Results of the induction phase.
Authors: F. R. Mauro, S. Ciolli, F. Di Raimondo, G. Del Poeta, F. Forconi, A. Cuneo, A. Cortellezzi, F. Nobile, M. Brugiatelli, M. Massaia, S. Molica, L. Trentin, R. Rizzi, L. Orsucci, M. A. Mura, A. Alietti, E. J. Runggaldier, E. Gamba, A. Guarini, R. Foa
Journal: Journal of Clinical Oncology (2011)

6629 Background: The FCR regimen (fludarabine, cyclophosphamide, rituximab) significantly improves the outcome of patients (pts) with chronic lymphocytic leukemia (CLL). However, myelotoxicity and immunosuppression are a limitation to the use of this regimen in elderly patients and in those with co-morbidities. The combination of rituximab (R) with chlorambucil (CLB; R-CLB) is an attractive therapeutic option for this subset of patients considering the expected good tolerability and potentially increased activity of this schedule. This study was designed to determine whether the R-CLB combination is a feasible and beneficial first-line treatment for elderly patients with CLL and to define the role of maintenance with R. Methods: 97 elderly patients requiring first-line therapy received CLB (8 mg/m²/day p.o., d1-d7, courses 1-8) and R (375 mg/m², course 3 and 500 mg/m², courses 4-8) every 28 days. Responsive patients were subsequently randomized to receive R maintenance (375 mg/m² every 2 months for 2 years) or clinical observation. The primary endpoint was the overall response rate after the R-CLB induction phase. Results: The median age of pts was 70.0 years (range: 61-84;≥70: 52.9%) and 47.1% showed ≥1 comorbidities. Binet’s B-C stage was observed in 74.1% of cases, 58% were IgVH unmutated, 24.1% showed adverse cytogenetic abnormalities (11q23-: 19.3%; 17p13-: 4.8%) and 4.8% a p53 mutation. Response was assessed on an ITT basis (at least 1 course of R-CLB) in 85 pts. The ORR was 81.2%, the CR rate, confirmed by CT scan, 16.5%, the CRi 2.4%, the nPR 2.4%, the PR 60% and the treatment failures 18.8% (PD:3.5%; SD:4.7%; early treatment withdrawn, 10.6%). No evidence of residual disease by 4-color flow cytometry in both PB and BM was detected in 2/14 CR patients. The most common hematologic toxicity was neutropenia (grade III-IV: 13.5% of pts). The median number of administered R-CLB cycles in patients <80 years was 6. Conclusions: The results of this study indicate that R-CLB is an active and well tolerated front-line regimen for elderly patients with CLL.
Abstract 3034: Overcoming gefitinib resistance in non-small-cell lung cancer by inducing epidermal growth factor receptor (EGFR) degradation via methionine 790 oxidation
Authors: Elaine Lai-Han Leung, Xing-Xing Fan, Maria Pik Wong, Zhi-Hong Jiang, Zhong-Qiu Liu, Xiao-Jun Yao, Lin-Lin Lu, Yan-Ling Zhou, Li-Fong Yau, Vicky Pui-Chi Tin, Liang Liu
Journal: Cancer Research (2016)

Abstract Personalized therapy is becoming a dominant cancer therapeutic strategy, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small-cell lung cancer (NSCLC) patients with EGFR mutation but they only inhibit EGFR phosphorylation, acquired-resistance still remains unavoidable without EGFRT790M removal. Here, we report a new treatment strategy to overcome such drug resistance by selectively inducing EGFRT790M degradation via specific stimulation of methionine 790 (M790) oxidation. The basal reactive oxygen species (ROS) levels in EGFRT790M containing gefitinib-resistant NSCLC cell lines were substantially high and 63 clinical lung tumors showed higher NADPH oxidase 2 (NOX2) expression than 61 normal lung tissues which may contribute to high basal ROS in cancer. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, resulted in EGFR over-oxidation and degradation as well as apoptosis. By contrast, such responses were lacking in EGFRWild-type (WT) cells, suggesting a new promising drug development strategy with wide therapeutic window between EGFRT790M and EGFRWT. Selective EGFRT790M degradation was manipulated by REDOX imbalance between NOX3 and methionine reductase (MsrA). When NOX3 was activated, NADPH, the key substrate of MsrA, was depleted to generate excessive ROS, resulting in inhibition of MsrA physiological reduction function on oxidized-methionine, thus localized methionine 790 oxidation of EGFRT790M occurred. Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation and EGFR degradation were confirmed. These findings indicate that specific inducing EGFRT790M degradation via manipulating REDOX imbalance between NOX3 and MsrA would be promising strategy for treating gefitinib-resistant NSCLC. Citation Format: Elaine Lai-Han Leung, Xing-Xing Fan, Maria Pik Wong, Zhi-Hong Jiang, Zhong-Qiu Liu, Xiao-Jun Yao, Lin-Lin Lu, Yan-Ling Zhou, Li-Fong Yau, Vicky Pui-Chi Tin, Liang Liu. Overcoming gefitinib resistance in non-small-cell lung cancer by inducing epidermal growth factor receptor (EGFR) degradation via methionine 790 oxidation. [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 3034.
Proxe: A Public Repository of Xenografts to Facilitate Studies of Biology and Expedite Preclinical Drug Development in Leukemia and Lymphoma
Authors: Mark A. Murakami, Alexandra N. Christodoulou, Amanda L Christie, Tiffany DeSouza, Abner Louissaint, Una Vojinovic, Raphael Koch, Loretta S. Li, Scott P. Kallgren, Prakash Rao, Johannes Köster, Raga Vadhi, Eilene Duberow, Elizabeth A. Morgan, Hongjun Wang, Samia S. Ahmed, Katharine L. Majewski, Marina Konopleva, Jerome Tamburini, Alejandro Gutierrez, Michelle Kelliher, Julia Etchin, Irmela Jeremias, Andrew P. Weng, Andrew L Kung, Andrew A Lane, Francine Garnache-Ottou, Shai Izraeli, Eric Jacobsen, Ilene Galinsky, Richard M. Stone, Marian H. Harris, David M. Dorfman, Jon C Aster, Henry Long, Lewis B. Silverman, David M Weinstock
Journal: Blood (2015)
Abstract 1409: Is it what's on the inside that counts? Melanoma mutation profiling and outcomes with immunotherapy
Authors: Morganna L. Freeman, Howard McLeod.
Journal: Cancer Research (2016)

Abstract Extraordinary advances have been made in the treatment of melanoma over the last few years; immune checkpoint blockade has provided durable responses and meaningful survival outcomes for patients with metastatic disease, yet predicting such responses remains a nascent science. More importantly, the toxicity and financial burden of receiving such therapy warrants a personalized, or precision medicine, approach to appropriate selection of treatment, thus molecular predictors of response may become as important as biomarkers such as PDL1 expression. Recently the high mutational burden of malignant melanoma was shown to be related to the degree of response to the anti-CTLA4 antibody ipilimumab, but mutational burden alone was not sufficient to predict benefit1. Another study has shown NRAS-mutant had a trend to superior outcomes compared with other cohorts in terms of response to therapy with anti-PD1 antibodies and progression-free survival2. Moreover, insight into the molecular evolution of melanoma was recently established3, wherein somatic mutations in oncogenes such as BRAF, NRAS, GNAQ, or GNA11 occur early during progression and additional mutations of TERT, CDKN2A, TP53, and PTEN are seen in late-stage disease. To better evaluate the relationship of these mutations to immunotherapy response, our institution has profiled 95 patients with melanoma with next-generation sequencing (NGS). Of the 95 patients profiled, the most common mutations identified were BRAF (38%), NRAS (21%), TP53 (18%), PTEN (14%), TERT (9%), and CDKN2A (8%). We are presently conducting a retrospective analysis of these selected oncogenes as they relate to clinical responses, and intend to report disease outcomes (duration of response, progression free survival, and overall survival) as they relate to checkpoint inhibition. Citation Format: Morganna L. Freeman, Howard McLeod. Is it what's on the inside that counts? Melanoma mutation profiling and outcomes with immunotherapy. [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 1409.
Phase II clinical trial of six mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumors.
Authors: Shibani Nicum, Claire E Brooks, Rose Wharton, Lucy Boyle, Stanley B. Kaye, Charlie Gourley, Marcia Hall, Ana Montes, Sarah R Pearson, Patrick Julier, Rachel A Midgley, Anna Schuh, Susan J. Dutton
Journal: Journal of Clinical Oncology (2013)

TPS5615 Background: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumor cells with these mutations demonstrate increased sensitivity to cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor, AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin (Issaeva 2010). Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. This multi-center phase II single arm trial was set up to investigate the activity and safety of 6MP with methotrexate in patients with breast or ovarian cancer who are known to have a BRCA mutation. Methods: Two-stage Simon compromise design (Jung 2001, Jung 2004) with α=0.20, power=90% to detect an increase in activity from 10 to 20%. 1st stage: if ≤ 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility; 2nd stage: if ≥9/65 evaluable patients respond at 8 weeks the treatment will be regarded as potentially effective and a phase III trial will be considered if the treatment appears safe and well-tolerated. 65 patients with BRCA defective cancer progressing after at least one prior chemotherapy or relapsed platinum resistant ovarian cancer, ECOG performance status 0-2 will be recruited and treated with daily 6MP (75mg/m 2 ) and weekly methotrexate (20mg/m 2 ) until progression. The starting dose was later reduced by 25% due to excess of expected toxicity. Patients with low TPMT activity or a low/low genotype are excluded due to the risk of increased toxicity. Prior treatment with a PARP inhibitor is permissible. Primary outcome: objective response at 8 weeks: complete, partial response or stable disease defined by RECIST 1.1. Secondary outcomes include safety, PFS, OS and quality of life. Of the 46 patients screened for TMPT activity between 15 Jun2009 and 05Dec 2012 from 12 UK sites, 31 patients were recruited. The pre-specified activity goal for the 1st stage was met and accrual into the 2nd stage continues. Clinical trial information: 2009-016846-16.
Abstract 1902: Downregulation of MYC by miR-3189-3p in glioblastoma
Authors: Duane Jeansonne, Krzysztof Reiss, Francesca Peruzzi
Journal: Cancer Research (2016)

Abstract Glioblastoma is a devastating malignancy with a median survival of approximately 15 months. This aggressive tumor originates from the glial cells and accounts for nearly 50% of adult brain tumors. Glioblastomas are characterized by rapid proliferation and resistance to standard treatment of surgery, temazolamide and radiation therapy. MicroRNAs are short single-stranded non-coding RNAs that regulate gene expression in both normal and pathological conditions. We have previously found downregulation of miR-3189-3p in glioblastomas and astrocytomas. Using in vitro models, we demonstrated that ectopic expression of this miRNA inhibited glioblastoma cell growth and migration through downregulation of the splicing factor SF3B2 and the guanine nucleotide exchange factor p63RhoGEF, respectively. The miR-3189-3p-mediated inhibition of glioblastoma growth in vivo further confirmed the anti-cancer activity of this microRNA. Given the strong biological effect of this miRNA on glioblastoma cells, we sought to investigate the implication of other gene targets in miR-3189-3p-mediated effects. The elevated expression of MYC oncogene is found in a variety of cancer types, including glioblastoma. Here, we demonstrated that overexpression of miR-3189-3p results in downregulation of MYC. Since this gene is not a predicted target for miR-3189-3p, we hypothesized that this modulation of MYC expression is mediated through the translational repressor, TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAL1, also called TIAR). We tested the levels of TIAR in cells treated with miR-3189-3p and found no changes in TIAR expression. However, the downregulation of MYC was dependent on TIAR expression, as determined through siRNA-mediated downregulation of TIAR. Further studies are needed to elucidate molecular mechanisms of TIAR-dependent downregulation of MYC by miR-3189-3p. In addition, a putative binding site for miR-3189-3p is located within the open reading frame of MYC; therefore, studies will be performed to determine whether miR-3189-3p downregulates MYC by directly binding outside the 3’-UTR of this transcript. Citation Format: Duane Jeansonne, Krzysztof Reiss, Francesca Peruzzi. Downregulation of MYC by miR-3189-3p in glioblastoma. [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 1902.
Abstract 4681: Oseltamivir phosphate completely ablates tumor refractoriness to conventional chemotherapeutics abraxane and gemcitabine in xenografts of tumors in mouse model of human pancreatic cancer
Authors: Myron R. Szewczuk
Journal: Cancer Research (2016)

Abstract Pancreatic cancer, the fourth leading cause of cancer-related death worldwide, is highly aggressive and associated with a poor prognosis. Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rates in patients diagnosed with pancreatic cancer. Gemcitabine, a chemotherapeutic agent, is the current standard of care for patients with the disease. Although gemcitabine has higher success rates than any other chemotherapeutic in use, patients receiving gemcitabine still only have progression-free survival in the range of 0.9-4.2 months. Given the poor response rate to gemcitabine, pancreatic cancer cells develop rapid resistance to this drug. Here, we investigated the proof of concept for a reported entirely new anticancer drug, oseltamivir phosphate (OP), to overcome tumor refractoriness to gemcitabine and abraxane in heterotopic xenografts of pancreatic MiaPaCa-2 tumors growing in RAGxCγ double mutant mice. The data clearly indicate that mice treated with 50mg/kg abraxane alone (1x weekly, i.p.) at Day 33 post implantation slightly restrained tumor growth until Day70 at which time the tumor developed resistance to abraxane and rapidly increased in tumor volume and spread to the lungs. In contrast, abraxane in combination with OP 20mg/kg (3x weekly, i.p.) abrogated the tumor resistance to abraxane and impeded tumor growth and metastatic spread to the lung. Very interestingly, with comparable results to abraxane/OP, mice treated with 30mg/kg gemcitabine (1x weekly, i.p.) at Day31 post implantation developed tumor resistance at Day50 to gemcitabine and rapidly increased in tumor volume and spread to the lung. Gemcitabine in combination with 20mg/kg OP (3x weekly, i.p.) completely impeded the tumor growth, chemoresistance and spread to the lungs with long term survival at Day 240 with no relapse and metastasis. The significance of these findings is the first to show that OP in combination with standard, clinical chemotherapeutics can impede (a) human pancreatic tumor growth, (b) tumor neovascularization, (c) liver and lung metastases, and (d) tumor refractoriness to conventional chemotherapeutics, as well (e) significantly extending survival rates with no relapse and metastasis. Citation Format: Myron R. Szewczuk. Oseltamivir phosphate completely ablates tumor refractoriness to conventional chemotherapeutics abraxane and gemcitabine in xenografts of tumors in mouse model of human pancreatic 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 4681.
Abstract 285: Disulfiram, a dual MGMT and aldehyde dehydrogenase inhibitor, sensitizes ER-positive breast cancer cells to temozolomide and cyclophosphamide
Authors: George C. Bobustuc, Deborah Donohoe, Alisher Holmuhamedov, Srivenugopal Kalkunte, Santhi D. Konduri
Journal: Cancer Research (2016)

Abstract Background: O6 methylguanine DNA methyltransferase (MGMT) is overexpressed in a majority of cancers, including breast cancer. MGMT is a DNA repair protein leading to chemo resistance. MGMT expression directly correlates with ER expression and tamoxifen resistance. Aldehyde Dehydrogenase (ALDH) activity, as a progenitor/stem cell marker, while it has been reported to inversely correlate with MGMT expression in other cancers, has also been linked to chemotherapy and radiation resistance. Methods: We have tested the effect of Antabuse (disulfiram, DSF), as a dual MGMT and ALDH inhibitor, at nontoxic doses, in combination with Temozolomide (TMZ) or/and Cyclophosphamide (CP) on ER+ breast cancer cells. Results: DSF at very low doses (achievable in human serum with standard DSF clinical dosing) decreases ER+ breast cancer cell growth (MCF7, T47D and ZR75) in a dose-dependent manner. DSF further sensitizes breast cancer cells to TMZ or/and CP and significantly inhibits breast cancer growth without causing unwanted side effects on the normal breast epithelial cells. Dose effect and isobologram studies confirm synergistic activity of DSF + CP and moderate synergism for DSF + TMZ. DSF, alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP), significantly inhibits expression of MGMT, aldehyde dehydrogenase, ERα, E2F and BIRC5 gene (survivin) - all involved in breast cancer tumorigenesis. DSF, alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP) caused significant apoptosis in breast cancer cells. In a dose dependent manner, DSF inhibited colony formation, effect which was further enhanced by addition of TMZ/CP (DSF ± TMZ/CP). Similarly, DSF alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP) decreased the metastatic potential of breast cancer cells. Conclusions: Our findings suggest that DSF as dual inhibitor of MGMT and ALDH significantly enhances the antitumor effect of alkylators as CP and TMZ in ER+ breast cancer Citation Format: George C. Bobustuc, Deborah Donohoe, Alisher Holmuhamedov, Srivenugopal Kalkunte, Santhi D. Konduri. Disulfiram, a dual MGMT and aldehyde dehydrogenase inhibitor, sensitizes ER-positive breast cancer cells to temozolomide and cyclophosphamide. [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 285.