Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis

Journal of Alzheimer's Disease

Volumn 53, Issue 4, 2016, Pages 1395-1404

  Penninkilampi, Ross ^a   Brothers, Holly M ^b   Eslick, Guy D ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

^b OHIO STATE UNIVERSITY   (United States)

Author keywords

Alzheimer's disease; Amyloid beta peptides; Avagacestat; Gamma secretase; Meta analysis; Semagacestat; Tarenflurbil

Indexed keywords

AVAGACESTAT; GAMMA SECRETASE; SEMAGACESTAT; NEUROLEPTIC AGENT; SECRETASE;

ALZHEIMER DISEASE; CANCER RISK; COGNITIVE DEFECT; DRUG SAFETY; DRUG TARGETING; HUMAN; INFECTION; MAJOR CLINICAL STUDY; META ANALYSIS; MINI MENTAL STATE EXAMINATION; NEOPLASM; OUTCOME ASSESSMENT; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SKIN CANCER; SYSTEMATIC REVIEW; BIBLIOGRAPHIC DATABASE; CHEMICALLY INDUCED; METABOLISM; STATISTICS AND NUMERICAL DATA;

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANTIPSYCHOTIC AGENTS; COGNITION DISORDERS; DATABASES, BIBLIOGRAPHIC; HUMANS; NEOPLASMS; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84981731292     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-160275     Document Type: Review

References (38)

1. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 3, 186-191.
2. Tolia A, De Strooper B (2009) Structure and function of gamma-secretase. Semin Cell Dev Biol 20, 211-218.
3. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer's disease. Lancet 377, 1019-1031.
4. Hardy JA, Higgins GA (1992) Alzheimer's disease: The amyloid cascade hypothesis. Science 256, 184-145.
5. Selkoe DJ (2000) Towards a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci 924, 17-25.
6. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, May PC (2005) Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 28, 126-132.
7. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM (2009) A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 66, 48-54.
8. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, FarlowMR, May PC (2007) Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 30, 317-325.
9. Fleisher A, Raman R, Siemers E, Becerra L, Clark C, Dean R, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ (2008) Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol 65, 1031-1038.
10. Siemers ER, Quinn JF, Kaye J, Farlow M, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC (2006) Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66, 602-604.
11. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS. Alzheimer's Disease Cooperative Study Steering Committee, Siemers E, Sethuraman G, Mohs R; Semagacestat Study Group (2013) A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 369, 341-350.
12. Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC (2014) Safety profile of semagacestat, a gammasecretase inhibitor: IDENTITY trial findings. Curr Med Res Opin 30, 2021-2032.
13. Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, Lentz KA, Wang JS, Denton RR, Pilcher G, Rhyne PW, Raybon JJ, Barten DM, Burton C, Toyn JH, Sankaranarayanan S, Polson C, Guss V, White R, Simutis F, Sanderson T, Gillman KW, Starrett JE Jr, Bronson J, Sverdlov O, Huang SP, Castaneda L, Feldman H, Coric V, Zaczek R, Macor JE, Houston J, Berman RM, Tong G (2013) Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J Pharmacol Exp Ther 344, 686-695.
14. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens R (2013) A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50mgoral dose of the gamma-secretase inhibitor avagacestat. Br J Clin Pharmacol 75, 136-145.
15. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC (2012) Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral gamma-secretase inhibitor BMS-708163 (Avagacestat) : Tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther 34, 654-667.
16. Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM (2012) Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 69, 1430-1440.
17. Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, Curtis C, Soininen H, Thein S, Shiovitz T, Pilcher G, Ferris S, Colby S, Kerselaers W, Dockens R, Soares H, Kaplita S, Luo F, Pachai C, Bracoud L, Mintun M, Grill JD, Marek K, Seibyl J, Cedarbaum JM, Albright C, Feldman HH, Berman RM (2015) Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial. JAMA Neurol 72, 1324-1333.
18. Morihara T, Chu T, Ubeda O, Beech W, Cole GM (2002) Selective inhibition of Abeta42 production by NSAID R-enantiomer. J Neurochem 83, 1009-1012.
19. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, OzolsVV, JessingKW, ZavitzKH, Koo EH, Golde TE (2003) NSAIDs and enantiomers of flurbiprofen target-secretase and lowerA42 in vivo. J Clin Invest 112, 440-449.
20. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44, 181-193.
21. Galasko DR, Graff-Radford N, May S, Hendrix SB, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH (2007) Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 21, 292-299.
22. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA (2008) Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: A randomised phase II trial. Lancet Neurol 7, 483-493.
23. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH. Tarenflurbil Phase 3 Study Group (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 302, 2557-2564.
24. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group (2010) Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surg 8, 336-341.
25. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Clinical trials: Is blinding necessary? Control Clin Trials 17, 1-12.
26. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7, 177-188.
27. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327, 557-560.
28. Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315, 629-634.
29. Orwin RG (1983) A fail-safe N for effect size in metaanalysis. J Educ Behav Stat 8, 157-159.
30. Doody RS, Raman R, Sperling RA, Seimers E, Sethuraman G, Mohs R, Farlow M5, Iwatsubo T6, Vellas B7, Sun X8, Ernstrom K8, Thomas RG9, Aisen PS10; Alzheimer's Disease Cooperative Study (2015) Peripheral and central effects of gamma-secretase inhibition by semagacestat in Alzheimer's disease. Alzheimers Res Ther 7, 36.
31. Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Tong G (2012) A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet 51, 681-693.
32. Bray SJ (2006) Notch signalling: A simple pathway becomes complex. Nat Rev Mol Cell Biol 7, 678-689.
33. Wolfe MS (2008) Inhibition and modulation of gammasecretase for Alzheimer's disease. Neurotherapeutics 5, 391-398.
34. Radtke F, Wilson A, Mancini SJ, MacDonald HR (2004) Notch regulation of lymphocyte development and function. Nat Immunol 5, 247-253.
35. Meehan TP, Fine MJ, Krumholz HM, Scinto JD, Galusha DH, Mockalis JT, Weber GF, Petrillo MK, Houck PM, Fine JM (1997) Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 278, 2080-2084.
36. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, Millar SE, Pear WS, Parmacek MS (2006) Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 66, 7438-7444.
37. Panelos J, Massi D (2009) Emerging role of Notch signaling in epidermal differentiation and skin cancer. Cancer Biol Ther 8, 1986-1993.
38. Madan V, Lear JT, Szeimies R-M (2010) Non-melanoma skin cancer. Lancet 375, 673-685.