Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma

S221. THE EFFICACY OF LUMATEPERONE 42 MG IN THE TREATMENT OF SCHIZOPHRENIA SYMPTOMS ASSOCIATED WITH SOCIAL FUNCTIONING: POST HOC ANALYSIS OF AN ACUTE PLACEBO- AND ACTIVE-CONTROLLED TRIAL

Abstract Background Deficits in social functioning are a core feature of schizophrenia and may be due to the interaction of multiple factors including negative symptoms, depression symptoms, and deficits in social cognition. Social and functional impairment in schizophrenia can be difficult to treat, may not correlate with improvements in psychotic symptoms, and has been associated with poor long-term patient outcomes. Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel agent for the treatment of schizophrenia that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. Lumateperone was shown to be efficacious and well tolerated in 2 acute placebo-controlled studies and its safety and effectiveness was further supported in a long-term open-label study. The effects of lumateperone 42 mg (ITI-007 60 mg) on schizophrenia symptoms associated with social function were investigated in a post hoc analysis of a study that included risperidone 4 mg as an active control (Study 005, NCT01499563). Symptoms associated with social functioning were assessed with the Positive and Negative Syndrome Scale (PANSS)-derived Prosocial factor (PANSS items P3, P6, N2, N4, N7, G16), which has been utilized previously to evaluate the efficacy of various antipsychotics on this functional domain. Methods This is a post hoc analysis of data from a positive placebo- and active-controlled study in patients with an acute exacerbation of schizophrenia. Change from baseline in the PANSS Prosocial factor was assessed in the intent-to-treat (ITT) population and in patients with prominent negative symptoms (PNS, score ≥4 on at least 3 negative symptom items) or moderate-to-severe depression symptoms (Calgary Depression Scale for Schizophrenia [CDSS] ≥6) at baseline. Inferential analysis was conducted using a mixed-effects model for repeated measures (MMRM). Results The ITT population comprised 231 patients (placebo, n=80; lumateperone 42 mg, n=76; risperidone 4 mg, n=75); the PNS and CDSS ≥6 populations comprised 110 and 54 patients, respectively. Lumateperone 42-mg treatment was associated with significantly greater improvement compared with placebo on the PANSS Prosocial factor (least-squares mean difference [LSMD] vs placebo = −2.7; P<.001). Risperidone also was superior to placebo on the PANSS Prosocial factor (LSMD= −1.8; P=.011). Similar treatment effects for lumateperone 42 mg were seen on the PANSS Prosocial factor in patients with PNS at baseline (LSMD −2.6, P=.006). Conversely, in patients with PNS, risperidone treatment showed small and non-significant treatment effects on the PANSS Prosocial factor (LSMD= −0.4; P=.707). In patients with moderate-to-severe depression symptoms at baseline, marked and significant improvements on the PANSS Prosocial factor were seen in lumateperone-treated patients (LSMD= −4.9; P<.001) but not in risperidone-treated patients (LSMD=−1.3; P=.397). Discussion Lumateperone 42 mg significantly improved schizophrenia symptoms related to social functioning. In contrast to risperidone, lumateperone was associated with similar or greater treatment effects on the PANSS Prosocial factor in patients with prominent negative symptoms or moderate-to-severe depression symptoms at baseline. These results suggest that lumateperone may have benefits on schizophrenia symptoms associated with social function

Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats

Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed. The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1). ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1-10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments. ITI-214 inhibited PDE1A (K (i) = 33 pmol) with &gt; 1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR. ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1-10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress

Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders

We report the synthesis and structure–activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT_2A and dopamine D₂ receptors. This work has led to the discovery of 4-((6b<i>R</i>,10a<i>S</i>)-3-methyl-2,3,6b,9,10,10<i>a</i>-hexahydro-1<i>H</i>,7<i>H</i>-pyrido­[3′,4′:4,5]­pyrrolo­[1,2,3-<i>de</i>]­quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT_2A antagonist, postsynaptic D₂ antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders

Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma

International audiencePurpose: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing. Experimental Design: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework. Results: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy. Conclusions: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design