Citations

Abstract Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. This concept has recently been exploited in the development of PARP inhibitors as novel chemotherapeutics for breast cancer. While PARP is not essential in normal cells, BRCA mutant cells are dependent on it for their survival. This led to the successful treatment of BRCA mutant tumors of the breast, ovary, and prostate with the oral PARP inhibitor, olaparib. Therapeutic strategies based on such synthetic-lethal (SL) interactions can enable drug targeting of cancer-specific alterations for otherwise undruggable tumor suppressors. Large-scale analyses of genetic interaction networks in model organisms like yeast suggest that disease-specific networks should not only give rise to destructive phenotypes (e.g. uncontrolled cell growth), but will also present unique vulnerabilities that can be exploited for novel therapies. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We have used a combination of computational and experimental approach whereby yeast interactions between human orthologs are filtered by cancer association and prioritized by genomic features, and candidates from the prioritized list are then validated in human cell lines using an RNA interference approach. As a proof of principle, we utilized this approach to discover two previously unknown synthetic lethal/sick interactions, one between SMARCB1 (yeast SNF5) and PSMA4 (yeast PRE9), and another between ASPSCR1 (yeast UBX4) and PSMC2 (yeast RPT1) based on shRNA double knock-down in normal human fibroblast cells. These interactions suggest potentially new therapeutic targets for SMARCB1 and ASPSCR1 mutated cancers, and more broadly, illustrate the potential of this cross-species approach. Citation Format: Michael K. Asiedu, Raamesh Deshpande, Mitchell Klebig, Shari Sutor, Elena Kuzmin, Jeff Piotrowski, Seung Ho Shin, Michael Costanzo, Charles Boone, Dennis A. Wigle, Chad L Myers. A comparative genomic approach for identifying synthetic lethal interactions in human cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-234. doi:10.1158/1538-7445.AM2013-LB-234

This study investigated the effects of visual and inferential complexity on the pictured scene descriptions of right-hemisphere-damaged (RHD) and non-brain-damaged (NBD) adults. The number and accuracy of noun phrases generated by both groups were significantly affected by the inferential complexity of pictured scenes, but not by their visual complexity (as measured by the number of objects and amount of object embedding in the scenes). RHD subjects, particularly those with high levels of neglect, were significantly impaired relative to the NBD subjects in generating accurate inferences from the pictures, but not in their ability to recognize and identify pictured elements.

SummaryReliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow‐up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03–3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.

AbstractBackgroundRegulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development.MethodsThe Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data.ResultsThe literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011.ConclusionsWe summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

ABSTRACTPurposeThis analysis from Avastin® Registries: Investigation of Effectiveness and Safety (ARIES) examined the association between exposure to bevacizumab after disease progression (PD) and postprogression survival (PPS) in bevacizumab‐exposed metastatic colorectal cancer (mCRC) through the application of time‐dependent and time‐fixed analytical methods.MethodsPatients with mCRC who were treated with first‐line bevacizumab and who survived first PD (PD1) were included. A time‐dependent Cox regression model was fitted to assess the effect of cumulative bevacizumab exposure on PPS, while controlling for potential confounders. In addition to support findings from previous studies, a modified intent‐to‐treat (mITT) analysis compared PPS in patients who received bevacizumab beyond disease progression (BBP) with those who did not (No‐BBP).ResultsOf 1550 patients, 1199 survived PD1 and had a median PPS of 13.4 months. Cumulative bevacizumab exposure was associated with improved PPS (p = 0.0040). After adjusting for confounders, the hazard ratios (HRs) for PPS decreased, on average, by 1.2% (range, 1.1–1.3%) with each additional dose of bevacizumab. In the mITT analysis, the median PPS for BBP (n = 438) was 14.4 months vs 10.6 months with for No‐BBP (n = 667). BBP was found to be independently associated with longer PPS in a multivariable Cox regression analysis (HR, 0.84; 95% confidence interval, 0.73–0.97). Protocol‐specified adverse events suspected to be associated with bevacizumab occurred in 13.0% of patients with BBP.ConclusionThis analysis supports the observation that bevacizumab exposure after PD1 is associated with longer PPS in mCRC. Copyright © 2014 John Wiley & Sons, Ltd.

Purpose Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. Patients and Methods Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. Results In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. Conclusion Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

Objective: We evaluate the prevalence, etiology, and outcomes of hypoglycemia requiring emergency medical services (EMS) in patients without diabetes mellitus (non-DM). Methods: We reviewed medical records of all ambulance calls for non-DM with blood glucose <70 mg/dl in Olmsted County, Minnesota, between January 1, 2003, and December 31, 2009. Results: A total of 131 patients (age 51 ± 19 years; 54 % females) made 142 EMS calls, while 10 patients made repeated calls. Causes of hypoglycemia were critical illness (42; 32%), alcohol and polysubstance use (36; 27.5 %), insulinoma/ bariatric surgery (10; 8%), restricted oral intake (7; 5%), and multiple factors (3; 27.5 %). Patients with alcohol and polysubstance abuse were younger ( p = .002). A total of 54 patients had additional hypoglycemia predisposing comorbidities/factors [adrenal insufficiency (2), end-stage renal disease (11) and chronic liver disease (7), beta blockers use (34), and pentamidine use (1)]. Repeated calls and emergency room transportation were similar, but hospitalization varied across the etiologies, with the lowest proportion in the multiple-factor-related hypoglycemia group ( p = .01). Duration of follow-up was 1.28 (interquartile range 0.13–2.70) years. A total of 38 patients died, and age-adjusted mortality varied across different etiologies ( p < .001), with highest among critically ill. Cancer caused the highest number of deaths (7/38; 18%), while 1 death was due to hypoglycemia. Conclusions: There were multiple etiologies for hypoglycemic episodes in community-dwelling non-DM that required EMS. Critical illness, multifactorial causes, and alcohol/polysubstance abuse were common causes. Hospitalization and mortality were higher with critical illnesses.