Browsing by Author "Simmons, A."

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)
    (BMC, 2021-05-24) Grivas, P.; Loriot, Y.; Morales-Barrera, R.; Teo, M. Y.; Zakharia, Y.; Feyerabend, S.; Vogelzang, N.J.; Grande, E.; Adra, N.; Necchi, A.; Rodriguez-Vida, A.; Gupta, S.; Josephs, D.H.; Srinivas, S.; Wride, K.; Thomas, D.; Simmons, A.; Loehr, A.; Dusek, R.L.; Nepert, D.; Chowdhury, S.; Medicine, School of Medicine
    Background: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. Results: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. Conclusions: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.
  • Thumbnail Image
    Item
    Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease
    (Nature Publishing Group, 2011-11) Furney, SJ; Simmons, A.; Breen, G.; Pedroso, I.; Lunnon, K.; Proitsi, P.; Hodges, A.; Powell, J.; Wahlund, L-O; Kloszewska, I.; Mecocci, P.; Soininen, H.; Tsolaki, M.; Vellas, B.; Spenger, C.; Lathrop, M.; Shen, L.; Kim, S.; Saykin, AJ; Weiner, MW; Lovestone, S.; Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed Consortium; Radiology and Imaging Sciences, School of Medicine
    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with considerable evidence suggesting an initiation of disease in the entorhinal cortex and hippocampus and spreading thereafter to the rest of the brain. In this study, we combine genetics and imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed study. To identify genetic susceptibility loci for AD, we conducted a genome-wide study of atrophy in regions associated with neurodegeneration in this condition. We identified one single-nucleotide polymorphism (SNP) with a disease-specific effect associated with entorhinal cortical volume in an intron of the ZNF292 gene (rs1925690; P-value=2.6 × 10(-8); corrected P-value for equivalent number of independent quantitative traits=7.7 × 10(-8)) and an intergenic SNP, flanking the ARPP-21 gene, with an overall effect on entorhinal cortical thickness (rs11129640; P-value=5.6 × 10(-8); corrected P-value=1.7 × 10(-7)). Gene-wide scoring also highlighted PICALM as the most significant gene associated with entorhinal cortical thickness (P-value=6.7 × 10(-6)).
  • Thumbnail Image
    Item
    Identification of functional variants from whole-exome sequencing, combined with neuroimaging genetics
    (Springer Nature, 2013) Nho, K.; Corneveaux, J. J.; Kim, S.; Lin, H.; Risacher, S. L.; Shen, L.; Swaminathan, S.; Ramanan, V. K.; Liu, Y.; Foroud, T.; Inlow, M. H.; Siniard, A. L.; Reiman, R. A.; Aisen, P. S.; Petersen, R. C.; Green, R. C.; Jack, C. R.; Weiner, M. W.; Baldwin, C. T.; Lunetta, K.; Farrer, L. A.; Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study; Furney, S. J.; Lovestone, S.; Simmons, A.; Mecocci, P.; Vellas, B.; Tsolaki, M.; Kloszewska, I.; Soininen, H.; AddNeuroMed Consortium; McDonald, B. C.; Farlow, M. R.; Ghetti, B.; Indiana Memory and Aging Study; Huentelman, M. J.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
  • Thumbnail Image
    Item
    Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment
    (Springer Nature, 2013) Nho, K.; Corneveaux, J. J.; Kim, S.; Lin, H.; Risacher, S. L.; Shen, L.; Swaminathan, S.; Ramanan, V. K.; Liu, Y.; Foroud, T.; Inlow, M. H.; Siniard, A. L.; Reiman, R. A.; Aisen, P. S.; Petersen, R. C.; Green, R. C.; Jack, C. R.; Weiner, M. W.; Baldwin, C. T.; Lunetta, K.; Farrer, L. A.; Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study; Furney, S. J.; Lovestone, S.; Simmons, A.; Mecocci, P.; Vellas, B.; Tsolaki, M.; Kloszewska, I.; Soininen, H.; AddNeuroMed Consortium; McDonald, B. C.; Farlow, M. R.; Ghetti, B.; Indiana Memory and Aging Study; Huentelman, M. J.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.