Search

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.Conclusions: Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. Clin Cancer Res; 21(12); 2715–21. ©2015 AACR.

Supplemental Figure 1. PCR cycle count for NET mRNA expression in peripheral blood mononuclear cells from 7 patients obtained on Day 1 and/or 3 of protocol therapy.

SummaryElevated uric acid (UA) is a key factor for disorders, including gout or kidney stones and result from abrogated expression of Urate Oxidase (Uro) and diet. To understand the genetic pathways influencing UA metabolism we established a Drosophila melanogaster model with elevated UA using Uro knockdown. Reduced Uro expression resulted in the accumulation of UA concretions and diet-dependent shortening of lifespan. Inhibition of insulin-like signaling (ILS) pathway genes reduced UA and concretion load. In humans, SNPs in the ILS genes AKT2 and FOXO3 were associated with UA levels or gout, supporting a conserved role for ILS in modulating UA metabolism. Downstream of the ILS pathway UA pathogenicity was mediated partly by NADPH Oxidase, whose inhibition attenuated the reduced lifespan and concretion accumulation. Thus, genes in the ILS pathway represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones.HighlightsIn Drosophila high uric acid (UA) levels shorten lifespan and cause UA aggregationConserved in flies and humans, the ILS pathway associates with UA pathologiesFoxO dampens concretion formation by reducing UA levels and ROS formationInhibition of NOX alleviates the lifespan attenuation and UA aggregation

Objective: To evaluate if pharmacy students’ participation in personal pharmacogenetic (Pgx) testing enhances their knowledge and attitude towards precision medicine (PM). Methods: First-year pharmacy students were offered personalized pharmacogenetic testing as a supplement to a required curricular pharmacogenomics course. Ninety-eight of 122 (80%) students completed pre- and post-course surveys assessing knowledge and attitudes regarding PM; 73 students also volunteered for personal pharmacogenetic testing of the following drug metabolizing enzymes (CYP2C19, CYP2D6, UGT1A1) and pharmacodynamics-relevant proteins (interleukin (IL)-28B & human lymphocyte antigen HLAB*5701). Results: Among the 122 students, we found that incorporating pharmacogenetic testing improved mean knowledge and attitude by 1.0 and 0.3 Likert points, respectively. We observed statistically significant improvements in 100% of knowledge and 70% of attitude-related statements for students who decided to undergo personal pharmacogenetic testing. Students who were enrolled in the course but did not partake in personalized pharmacogenetic testing had similar gains in knowledge and attitude. Conclusion: This study demonstrates the feasibility and importance of educating future pharmacists by incorporating pharmacogenetic testing into professional school curricula. Students who opt not to participate in genotyping may still benefit by learning vicariously through the shared learning environment created by genotyped students. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received), employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties. Type: Student Project

PurposeVesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features.MethodsWe evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 - 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests.ResultsPatient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity.ConclusionVMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.

Torben S. Mikkelsena,b, Caroline F. Thornc, Jun J. Yangb, Cornelia M. Ulrichh, Deborah Frenchb, Gianluigi Zazab, Henry M. Dunnenbergerb, Sharon Marshi, Howard L. McLeodf, Kathy Giacominie, Mara L. Beckerg, Roger Gaedigkg, James Steven Leederg, Leo Kagerj, Mary V. Rellingb, William Evansb, Teri E. Kleinc, and Russ B. Altmanc,d aDepartment of Pediatric Oncology and Hematology, Aarhus University Hospital, Skejby, Denmark bSt Jude Children’s Research Hospital, Memphis, Tennessee cDepartment of Genetics, Stanford University Medical Center, Stanford dDepartment of Bioengineering, Stanford University Medical Center, Stanford eUniversity of California, San Francisco, California fInstitute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina gDivision of Clinical Pharmacology and Medical Toxicology, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri, USA hGerman Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany iFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada jSt Anna Children’s Hospital, Vienna, Austria