Citations

Objective: To review the literature evaluating gabapentin for alcohol withdrawal and dependence. Data Sources: A literature search of MEDLINE (1966 to end of March 2015) and PubMed was performed using the terms alcohol, gabapentin, withdrawal, and dependence. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: English-language prospective studies evaluating gabapentin for alcohol withdrawal and dependence were evaluated. Data Synthesis: A total of 10 publications utilizing gabapentin in alcohol withdrawal (n = 5) and alcohol dependence (n = 5) were included in this review. Limited data suggest that gabapentin can provide benefit in managing mild alcohol withdrawal syndrome. There were 5 reported or suspected seizures in the withdrawal studies, suggesting that additional safety data are necessary before gabapentin monotherapy can be routinely considered. Sleep and mood/anxiety-related outcomes were positively influenced by gabapentin, which may result in long-term benefits if continued beyond the withdrawal period for the treatment of alcohol dependence. Studies evaluating gabapentin for alcohol dependence demonstrated dose-dependent benefits for complete abstinence, rates of no heavy drinking, and cravings. Gabapentin used to treat alcohol dependence was well tolerated with no severe adverse reactions reported in the extant literature. Conclusion: Gabapentin may have a role in the treatment of mild alcohol withdrawal, but future studies should focus on adequate dosing strategies. Gabapentin should be considered for the treatment of alcohol dependence when barriers prevent the use of traditional agents. Additional studies should be conducted to further validate findings from the research conducted to date, but the current literature is promising for gabapentin in the treatment of alcohol dependence.

AbstractTwo recently developed fine-mapping methods, CAVIAR and PAINTOR, demonstrate better performance over other fine-mapping methods. They also have the advantage of using only the marginal test statistics and the correlation among SNPs. Both methods leverage the fact that the marginal test statistics asymptotically follow a multivariate normal distribution and are likelihood based. However, their relationship with Bayesian fine mapping, such as BIMBAM, is not clear. In this study, we first show that CAVIAR and BIMBAM are actually approximately equivalent to each other. This leads to a fine-mapping method using marginal test statistics in the Bayesian framework, which we call CAVIAR Bayes factor (CAVIARBF). Another advantage of the Bayesian framework is that it can answer both association and fine-mapping questions. We also used simulations to compare CAVIARBF with other methods under different numbers of causal variants. The results showed that both CAVIARBF and BIMBAM have better performance than PAINTOR and other methods. Compared to BIMBAM, CAVIARBF has the advantage of using only marginal test statistics and takes about one-quarter to one-fifth of the running time. We applied different methods on two independent cohorts of the same phenotype. Results showed that CAVIARBF, BIMBAM, and PAINTOR selected the same top 3 SNPs; however, CAVIARBF and BIMBAM had better consistency in selecting the top 10 ranked SNPs between the two cohorts. Software is available at https://bitbucket.org/Wenan/caviarbf.

Abstract The BBB can critically limit the delivery of several molecularly-targeted agents into the brain. The discovery of focal BRAF mutations in melanoma has stimulated the development of specific BRAF inhibitors. MEK is downstream of BRAF in the MAPK pathway, and has been targeted for combination therapy with BRAF inhibition. Trametinib is a MEK1/2 inhibitor that has improved survival in combination with dabrafenib in clinical trials for metastatic melanoma. We have recently shown that BRAF inhibitors (vemurafenib and dabrafenib) have limited brain distribution due to active efflux at the blood-brain barrier (BBB). Melanoma metastasizes to the brain and effective treatments require adequate CNS exposure of all drugs used in combination therapy. The study purpose was to investigate mechanisms that influence the CNS distribution of trametinib, particularly focusing on the active efflux transport proteins P-gp and Bcrp in the BBB. Intracellular accumulation and bidirectional flux studies were conducted in polarized MDCKII cells that overexpress human P-gp (MDR1) or murine Bcrp (Bcrp1). The brain and plasma AUCs of trametinib were determined after an intravenous dose of 5 mg/kg in WT, Mdr1a/b (-/-), Bcrp1 (-/-) and Mdr1a/b (-/-) Bcrp1 (-/-) (TKO) mice. The steady-state brain distribution of trametinib was determined using osmotic pumps in WT and Mdr1a/b (-/-) (P-gp KO), Bcrp1 (-/-) (Bcrp KO), and Mdr1a/b (-/-) Bcrp1 (-/-) (TKO) mice. The steady-state brain distribution of a combination of trametinib and dabrafenib were determined in WT and TKO mice. IC50s were determined in patient-derived melanoma cell lines (WT and V600E mutant) using the MTT assay. Intracellular accumulation of trametinib was 45% lower in the MDCKII-MDR1 cells and 81% lower in the MDCKII-Bcrp1 cells as compared to WT. Trametinib permeability was ∼ 2.5 and 3.7-fold greater in the basolateral-to-apical direction as compared to apical-to-basolateral direction in the MDR1 and Bcrp1 cells, respectively. Following a single intravenous dose, the brain-to-plasma AUC ratios were approximately 5-fold greater in P-gp KO and TKO mice as compared to the WT. Interestingly, the brain distribution of trametinib in Bcrp KO mice was no different from WT mice. The steady-state brain to plasma (B/P) ratio of trametinib was 5-fold greater in the TKO mice when compared to the wild-type mice. The B/P ratio of both dabrafenib and trametinib were significantly greater in the TKO mice as compared to WT when dosed simultaneously. The IC50 for trametinib alone was > 10 μM in both the WT (M15) and V600E (M12) mutant cells, while a combination of dabrafenib and trametinib had an IC50 of 2.04 μM in the M12 cells. This study shows that P-gp and BCRP restrict the brain distribution of trametinib with P-gp playing a dominant role in the efflux of trametinib at the blood-brain barrier. These findings are clinically relevant to the efficacy of trametinib in mono or combination therapy for the treatment of melanoma brain metastases. Citation Format: Shruthi Vaidhyanathan, Rajendar K. Mittapalli, Daniel J. Ma, Mark A. Schroeder, Jann N. Sarkaria, William F. Elmquist. Trametinib (Mekinist TM) has limited brain distribution in the mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3714. doi:10.1158/1538-7445.AM2014-3714

Abstract Emerging research on the long-term impact of concussions on athletes has allowed public recognition of the potentially devastating effects of these and other mild head injuries. Mild traumatic brain injury (mTBI) is a multifaceted disease for which management remains a clinical challenge. Recent pre-clinical and clinical data strongly suggest a destructive synergism between brain temperature elevation and mTBI; conversely, brain hypothermia, with its broader, pleiotropic effects, represents the most potent neuro-protectant in laboratory studies to date. Although well-established in selected clinical conditions, a systemic approach to accomplish regional hypothermia has failed to yield an effective treatment strategy in traumatic brain injury (TBI). Furthermore, although systemic hypothermia remains a potentially valid treatment strategy for moderate to severe TBIs, it is neither practical nor safe for mTBIs. Therefore, selective head-neck cooling may represent an ideal strategy to provide therapeutic benefits to the brain. Optimizing brain temperature management using a National Aeronautics and Space Administration (NASA) spacesuit spinoff head-neck cooling technology before and/or after mTBI in contact sports may represent a sensible, practical, and effective method to potentially enhance recover and minimize post-injury deficits. In this paper, we discuss and summarize the anatomical, physiological, preclinical, and clinical data concerning NASA spinoff head-neck cooling technology as a potential treatment for mTBIs, particularly in the context of contact sports.

Abstract Background: The AAA-ATPase p97/VCP facilitates the extraction and degradation of ubiquitinated proteins by converting chemical energy into mechanical force. p97 is closely involved in several facets of protein homeostasis, including ubiquitin-dependent protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. p97 has been increasingly linked to cancer: it showed elevated protein expression in tumors, it can mediate the degradation of proteins in cancer-relevant pathways and is required for orchestrating the ubiquitin-governed DNA-damage response. In this context, p97 inhibitors may have an advantage versus other protein homeostasis inhibitors and may be active in solid tumors where 26S proteasome inhibitors, bortezomib and carfilzomib, have shown poor efficacy. We report here p97 inhibition as a novel approach to exploit cancer cell addiction to protein homeostatic mechanisms. Results: We have discovered novel small molecule inhibitors of p97 ATPase activity with nanomolar enzymatic and cellular potency. In cellular models, treatment of cancer cells with our lead compound CB-5083 causes disruptions in specific p97 functions, including ubiquitin-dependent protein degradation, ERAD, endocytosis and autophagy. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in polyubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Sub-chronic oral administration of CB-5083 is generally well-tolerated with <10% body weight loss and results in potent tumor growth inhibition in several solid tumor xenograft models. This result is in marked contrast to proteasome inhibitors that are inactive in the same solid tumor models. In the Vk*MYC transgenic mouse model of multiple myeloma, CB-5083 treatment resulted in >50% reduction in M-spike. Additional efforts are focused on the development of translational assays to monitor p97 target engagement and antitumor efficacy in upcoming clinical trials of CB-5083. Conclusion: These data demonstrate that CB-5083 is a potent inhibitor of p97 that translates to tumor growth inhibition in multiple rodent models of human cancer. Furthermore, CB-5083 appears to exhibit greater potency over current proteasome inhibitors that further validate targeting p97 and protein homeostasis in the treatment of cancer. Citation Format: Ronan Le Moigne, Steve Wong, Ferdie Soriano, Eduardo Valle, Daniel J. Anderson, Stevan Djakovic, Mary-Kamala Menon, Bing Yao, Julie Rice, Jinhai Wang, Szerenke Kiss Von Soly, Brajesh Kumar, Marta Chesi, P. Leif Bergsagel, Han-Jie Zhou, David Wustrow, Mark Rolfe, F. Michael Yakes. CB-5083 is a novel first in class p97 inhibitor that disrupts cellular protein homeostasis and demonstrates anti-tumor activity in solid and hematological models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 951. doi:10.1158/1538-7445.AM2014-951

Abstract Background: Genome wide association studies (GWAS) have recently identified 8 loci identified with multiple myeloma (MM) susceptibility. We hypothesized that germ line genetic variants may also affect MM progression. We performed the first GWAS of MM survival, by conducting a meta-analysis of two existing studies at University of California San Francisco (UCSF) and the Mayo Clinic, and replicating findings in the International Multiple Myeloma rESEarch (IMMEnSE) consortium. Methods: The UCSF study included 353 MM patients genotyped on an Illumina Omni5 and Illumina 660 array. The Mayo clinic study included 239 MM patients genotyped on an Affymetrix 6.0 array. We imputed missing genotypes using the 1000 Genomes dataset and performed a GWAS for survival using proportional hazards models adjusting for age and gender and genetic ancestry using principal components analysis. We conducted a meta-analysis of the results from the two GWAS. We replicated the top SNPs in the IMMEnSE cohort which included 772 patients with survival data from 7 European countries and one North American site. We used the dataset from Grundberg et al (Nat Genetics 2012) to test for an association between SNPs associated with survival and gene expression in immortalized lymphocytes. We used gene expression data from Zhan et al (Blood 2006) to analyze the association between expression and survival. Results: In meta-analysis, we found a genome wide significant association between SNPs on a region at 16p13 and survival (rs72773978; p=2.9x10e-10). Patients with the minor allele were at increased risk for mortality (HR 2.73; 95% CI: 1.99 - 3.73). The top associated SNPs were all in strong linkage disequilibrium and were centered over the gene FOPNL. We replicated the association in the IMMEnSE cohort and found a significant association between the top SNP from the discovery dataset (rs72773978 p=0.037). We used previously published data to determine the association between gene expression and the top associated SNPs from the GWAS. The top SNP (rs72773978) was not in previously published eQTL databases, so we used rs7201759 which was also associated with survival in our data (p=3.8x10e-10) as a proxy. The minor allele for this SNP was associated with increased levels of expression of FOPNL (p=9x10e-5), but not with expression of any other genes within a 1 megabase region. Finally, we also observed an association between increased expression of FOPNL and shorter survival (HR: 2.62 per standard deviation.; 95% CI: 1.08 - 6.32). Conclusion: Germ line variants at 16p13 near the FOPNL gene are associated with survival among MM patients. FOPNL is thought to be involved in centrosomal function, and centrosomal activity has previously been associated with survival in MM patients. Our results support this previous observation. Furthermore, they suggest that germ line variants could also be useful in assessing prognosis for patients with MM. Citation Format: Elad Ziv, Eric Dean, Donglei Hu, Alessandro Martino, Daniel Serie, Daniele Campa, Blake Aftab, Paige Bracci, Gabriele Buda, Jennifer Caswell, Charles Dumontet, Marek Dudziński, Laura Fejerman, Alexandra Greenberg, Scott Hunstman, Artur Jurczyszyn, Krzysztof Jamroziak, Shaji Kumar, Herlander Marques, Thomas Martin, Joaquin Martinez-Lopez, Vincent Rajkumar, Juan Sainz, Annette Juul Vangsted, Marzena Watek, Jeffrey Wolf, Susan Slager, Federico Canzian, Celine Vachon. Genome wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5078. doi:10.1158/1538-7445.AM2014-5078

Abstract INTRODUCTION Next generation sequencing (NGS) of patients has significantly changed our ways to study cancer genomics as it provides precise estimates of gene expression, fusion transcripts, expressed single nucleotide variants (eSNVs), splice variants and copy number variants. The Breast Cancer Genome Guided Therapy (BEAUTY) is an ongoing clinical study in which RNA sequencing (RNAseq) and whole exome sequencing (WES) are performed prior to, during and after neoadjuvant chemotherapy. Here we report the use of these sequencing technologies to investigate gene expression levels and mutational profiles in a triple negative breast cancer (TNBC) patient enrolled in BEAUTY whose disease did not respond to neoadjuvant paclitaxel and anthracycline/cycphosphamide. METHODS Computational approaches were used to integrate WES and RNAseq data obtained before therapy (V1T), after 12 weekly paclitaxel treatments (V2T) and after anthracycline-based regimen at surgical resection (V3T) to study a single patient with persistent TNBC disease after neoadjuvant chemotherapy. RESULTS Using RNA-Seq data, we identified an inter-chromosomal fusion transcript between chromosome 20 and 22 (GNAS-TTC38) that was highly expressed at V1T, V2T and V3T. We also identified intra-chromosomal fusion transcripts that were expressed at two time points, such as fusion transcript (KANSL1-ARL17A) on chromosome 17 for V1T and V2T and fusion transcript (RBM12B-LINC00535) on chromosome 8 for V2T and V3T time points. Several gene expression changes were also observed. Gene expression analysis of V1T, V2T and V3T tumors was performed. Differential temporal gene expression profiles of 9884 genes that were significant and varying at different time points were obtained for pathway analysis. Pathway analysis of 9884 genes identified up regulation and down regulation of several transcription factors with a fold change of 2x or more. When compared to blood, DNA tumor and RNA-Seq data, we identified 81 common somatic eSNVs that were expressed in both V1T and V2T time points and we are in the process of investigating V3T data. We found alterations of key transporter domains (CD225, Coatamer_beta_C, DUF2435, Dynamitin, EI24, GLTP, LMF1, Porin_3, V-ATPase_C) in our V1T and V2T SNV data. Similar to gene expression analysis, we are in the process of obtaining the list of mutations at various time points to identify driver and passenger mutation candidate genes for this specific TNBC patient. CONCLUSIONS Our initial time-series analysis of eSNV, fusion transcripts and gene expression data demonstrate that intensive analysis for individual patients is feasible. Further investigation of drug transporters and transcription regulators may help develop personalized treatment strategies for patients with disease resistant to current regimens. Citation Format: Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Douglas W. Mahoney, Poulami Barman, Jason P. Sinnwell, Hugues Sicotte, Peter Vedell, Steven N. Hart, Travis J. Dockter, Katie N. Jones, Amy L. Conners, Ann M. Moyer, Daniel W. Visscher, Jia Yu, Bowen Gao, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Jean-Pierre A. Kocher, Eric D. Wieben, Gianrico Farrugia, Cloann G. Schultz, James N. Ingle, Richard Weinshilboum, Matthew P. Goetz, Liewei Wang, Judy C. Boughey. Analysis of sequencing data to identify potential drug targets for an individual newly diagnosed with basal breast cancer who failed to respond to current standard neoadjuvant chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4185. doi:10.1158/1538-7445.AM2014-4185