micrornas!as! Biomarkers! Landscape!

Transcription

1 GENReports: Market & Tech Analysis micrornas!as! Biomarkers! Landscape! > Enal Razvi, Ph.D. Managing Director Select Biosciences, Inc.

2 Topic Introduction and Scope! The,focus,of,this,GEN,Market,&,Tech,Analysis,Report,is,to,provide, an, update, on, the, progress, of, micrornas, as, potenbal, biomarkers, for,disease,! This,is,important,given,the,fact,that,microRNA,expression,paEerns, (signatures), represent, the, in# vivo, status, in, physiology, or, disease, and, have, been, shown, to, have, veryhspecific, Bssue, expression, paeerns,! In, this, report, we, document, some, of, the, qualitabve, and, quanbtabve, metrics, as, we, seek, to, map, the, microrna, landscape, vishàhvis,their,ublity,as,biomarkers,! The,quanBtaBve,data,in,this,report,were,updated,in,October,2014, therefore,represent,a,very,uphtohdate,market,picture, microrna,progression,from,research,towards,the,clinic,

3 !35,000!!!30,000!!!25,000!!!20,000!!!15,000!!! Sustained,YearHonHYear,Growth,of,microRNA,Sequence,Content,! Ordinate:,microRNA,Curated,Sequences,in,the,Database,! Abscissa:,Release,Date,and,miRBase,Version,! mirbase,is,hosted,and,maintained,in,the,faculty,of,life,sciences, at,the,university,of,manchester,,uk,! Numbers,illustrate,the,total,number,of,entries,in,the,registry,at, given,bme,intervals,! This,figure,provides,a,perspecBve,on,the,growth,of,the,microRNA, content,available,for,harvest,of,biomarker,candidates,!10,000!!!5,000!!!c!!!! Release Date 12/1/02! 1/1/03! 4/1/03! 5/1/03! 7/1/03! 7/1/03! 9/1/03! 11/1/03! 1/1/04! 4/1/04! 7/1/04! 9/1/04! 12/1/04! 4/1/05! 6/1/05! 10/1/05! mirbase 1.0! 1.1! 1.2! 1.3! 1.4! 2.0! 2.1! 2.2! 3.0! 3.1! 4.0! 5.0! 5.1! 6.0! 7.0! 7.1! 8.0! 8.1! 8.2! 9.0! 9.1! 9.2!10.0!10.1!11.0!12.0!13.0! 14! 15! 16! 17! 18! 19! 20! 21! Version 2/1/06! 5/1/06! 7/1/06! 10/1/06! 2/1/07! 5/1/07! 8/1/07! 12/1/07! 4/1/08! 9/1/08! 3/1/09! 9/1/09! 4/1/10! 8/1/10! 4/1/11! 11/1/11! 8/1/12! 6/1/13! 6/1/14!

4 450 microrna,publicabons,analysis, Cancer,is,the,Key,Driver,of,the,microRNA,Space:, Bars,in,Yellow,Represent,Large,Swaths,of,PublicaBons, which,segregate,within,the,various,cancer,spaces, This,figure,provides,evidence,that,the,researchers, in,the,microrna,space,are,primarily,cancerhfocused,,, Number of Publications ADENOCARCINOMA B-CELL LYMPHOMA BLADDER CANCER BREAST CANCER BURKITT LYMPHOMA CERVICAL CANCER CHRONIC LYMPHOCYTIC COLON CANCER COLORECTAL CANCER EM_TRANSITION HUMAN LYMPHOMA GASTRIC CANCER GLIOBLASTOMA HCC HEPATIC CANCER HEPATOCELLULAR HODGINS LYMPHOMA LEUKEMIA LUNG CANCER METASTASIS MYELODYSPLASTIC MYELOID LEUKEMIA NON-SMALL CELL LUNG OVARIAN CANCER PANCREATIC CANCER PROSTATE CANCER SQUAMOUS CELL THYROID CANCER ALZHEIMERS DISEASE ANGIOGENESIS DIABETES INFLAMMATION OBESITY SCHIZOPHRENIA CARDIOVASCULAR MYOCARDIAL DISEASE MYOCARDIAL NEURODEGENERATIVE NEUROLOGICAL DISEASE NEURONAL PARKINSONS DISEASE BONE MARROW HEMATOPOIESIS HEMATOPOIETIC HEPATITIS C VIRUS STEM CELLS TUMOR SUPPRESSOR

5 mirc1! mirc101! mirc104! mirc106a! mirc10b! mirc112! mirc1206! mirc124! mirc124ca3! mirc125a! mirc127! mirc128b! mirc130! mirc130c! mirc133! mirc134! mirc135b! mirc138! mirc13b! mirc141! mirc144! mirc146a! mirc148! mirc149! mirc151! mirc154! mirc15b! mirc166! mirc16a! mirc17c92!cluster! mirc181a! mirc181d! mirc184! mirc187! mirc19! mirc192! mirc193c! mirc196! mirc196b! mirc1997! mirc19a! mirc2! mirc200a! mirc203! mirc206! mirc20b! mirc212! mirc216! mirc219! mirc221! mirc224! mirc23b! mirc25! mirc26b! mirc277! mirc27a! mirc29! mirc29a! mirc2a! mirc301! mirc302b! mirc303! mirc30b! mirc31! mirc32! mirc323! mirc33! mirc335! mirc339! mirc346! mirc34c! mirc368! mirc372! mirc376! mirc379! mirc39! mirc410! mirc423! mirc430! mirc48! mirc493! mirc503! mirc520c! mirc551b! mirc615! mirc663! mirc691! mirc720! mirc8! mirc9! mirc93! mirc98! mirclet7! Profiling!Expression!of!this!miR! UpCRegulaQng!this!miR! DownCRegulaQng!this!miR!! Data,Based,on,Primary,Survey,of,microRNA,Researchers,! Presents,the, Penetrance,of,Some,but,not,all,microRNAs,in,Research,Currently,! Similar,to,microRNAHfocused,PublicaBons,,Penetrance,of,microRNAHfocused,Researchers,visHàHvis,Specific,microRNAs,is,Yet,Another, Metric,to,Characterize,the,Granularity,of,the,microRNA,Space,Illustrated,here,! The,height,of,each,bar,is,proporBonal,to,the,penetrance,of,that,parBcular,microRNA,into,the,research,community, Study,of,microRNA,Content,by,Researchers,Currently,

6 Selected,Tumor,Classes,Showing,Altered,Expression,[UpregulaBon,,DownregulaBon],of, Various,MicroRNAs, Lung Breast Tissue/Tumor Type Increased Expression Decreased Expression Glioblastoma Chronic Lymphocytic Leukemia (CLL) Lymphoma Colorectal Thyroid Hepatocellular mir cluster mir-17-5p mir-21 mir-29b-2 mir-221 mir-21 mir-155 mir cluster mir-10a mir cluster mir-20a mir-24-1 mir-29b-2 mir-31 mir-221, mir-222 mir-146, mir-181b, mir-197, mir-346 mir-18 mir-224 let-7 family mir-125b, mir145, mir-10b, mir-155, mir-17-5p, mir-27b mir-181a, mir-181b, mir-181c mir-15 mir-16 mir-15a mir-143 mir-145 let-7 mir-199a, mir-195, mir-200a, mir-125a

7 Selected,microRNAs/microRNA,Signatures,in,GI,Tract,Tumors,and, their,potenbal,diagnosbc,significance, microrna, Signature, Tumor,Type, Clinical,Value, Significance, Proposed,Role, mirc15b! DownregulaQon! Gastric!cancer! Prognosis!! Predictor!of!Drug! Resistance! mirc16! DownregulaQon! Gastric!cancer! Prognosis!! Predictor!of!Drug! Resistance! mirc20b! UpregulaQon! Gastric!cancer! Prognosis!! Level!inversely! correlated!with! survival! oncomir! mirc21! UpregulaQon! Gastric!cancer,!Hepatocellular! carcinoma,!esophageal! squamous!cell!carcinoma,! colorectal!cancer,!pancreaqc! cancer! Diagnosis!! Common!Cancer! Biomarker!! Local!Invasion!! Tumor!Grade! oncomir! mirc27a! UpregulaQon! Gastric!cancer,!Esophageal! squamous!cell!carcinoma! Prognosis!! MetastaQc!PotenQal! mirc106a! UpregulaQon! Gastric!cancer! Prognosis!! Tumor!stage! oncomir! mirc122! DownregulaQon! Hepatocellular!carcinoma! Diagnosis!! Tumor!Specific! Tumor!Suppressor! mirc125b! DownregulaQon! Hepatocellular!carcinoma,! Esophageal!squamous!cell! carcinoma! Prognosis!! Good!Survival! Tumor!Suppressor! mirc133b! DownregulaQon! Colorectal!cancer! Diagnosis!! Tumor!vs!Normal! Tumor!Suppressor! mirc150! UpregulaQon! Gastric!cancer! Prognosis!! Level!inversely! oncomir! correlated!with! survival!

8 MicroRNAs,Associated,with,Vascular,Diseases,, InflammaBon,,and,Angiogenesis, DownHRegulated, mirc16,!mirc17c5p,!mirc19b,!mirc22,! mirc23b,!mirc24,!mirc27a,!mirc30ac5p,! mirc30b,!mirc30c,!mirc30ec5p,!mirc107,! mirc126,!mirc130b,!mirc135a,!mirc136,! mirc148a,!mirc150,!mirc182,!mirc186,! mirc192,!mirc199a*,!mirc218,!mirc299c5p,! mirc302b*,!mirc302c*,!mirc325,!mirc339,! mirc342,!mirc452,!mirc452*,!mirc494,! mirc495,!mirc497,!mirc499,!mirc507,! mirc512c5p,!mirc515c5p,!mirc520d*,! mirc520h,!mirc520,!mirc523,!mirc526b,! mirc526b*! UpHRegulated, mirc1,!mirc7a,!mirc7b,!mirc7c,!mirc7d,!mirc7e,! mirc7f,!mirc10b,!mirc17c3p,!mirc21,!mirc23,! mirc24,!mirc26a,!mirc28,!mirc29a,!mirc29b,! mirc29c,!mirc32,!mirc34b,!mirc98,!mirc106b,! mirc125a,!mirc125b,!mirc126*,!mirc129,! mirc129c3p,!mirc130a,!mirc132,!mirc195,! mirc196a,!mirc199a,!mirc199b,!mirc200c,! mirc204,!mirc205,!mirc208,!mirc210,!mirc211,! mirc212,!mirc213,!mirc214,!mirc215,!mirc292c3p,! mirc294,!mirc295,!mirc296,!mirc297,!mirc300,! mirc302a,!mirc320,!mirc322,!mirc330,!mirc331,! mirc333,!mirc340,!mirc341,!mirc343,!mirc365,! mirc367,!mirc372,!mirc373,!mirc377,!mirc381,! mirc382,!mirc423,!mirc424,!mirc429,!mirc432,! mirc500,!mirc520c,!mirc525*! Its,Not,Just,in,Cancer,Where,microRNA,AssociaBons,with,Disease, Have,been,Documented,,

9 Acute myeloid Leukemia (AML) Acute myocardial infarction (AMI) Selected,Plasma,microRNAs,as,Candidate, Biomarkers,in,Various,Disease,Classes Disease Change Biomarker microrna Breast cancer Colorectal cancer Non-small cell lung cancer (NSCLC) Sepsis Type 2 diabetes Pregnancy Down Up Up Up Down Up Down Down Down Up mir-92a mir-1, mir-133, mir-208a, mir-499 let-7a, mir-195 mir-17-3p, mir-135b, mir-222, mir-29a, mir-92a, mir-95 mir-25 mir-23a, mir-25, mir-27a, mir-125b, mir-128b, mir-146a, mir-150, mir-152, mir-223,mir-20b, mir-30e-3p, let-7f mir-146a, mir-223 mir-126 mir-141, mir-149, mir-299-5p, mir-135b Note,the,Disease,Classes,and,the,Fact,that,microRNAs,can,be,Harvested,from,Plasma,opens,up, the,potenbal,for,biofluidhbased,biopsies,for,disease,

10 NIH Funded microrna biomarker Projects 16! 14! 12! 10! 14!! This!Figure!Presents!the!Number,of,Funded,Grants/, Projects!by!the!Various!NIH!Funding!Agencies!! The!focus!of!these!projects!is!on!microRNAs!with! some!aspect!of!the!project!focusing!on! microrna! Biomarkers!! Total!Number!of!Grants/Projects!=!41! 8! 6! 4! 4! 4! 3! 3! 2! 2! 2! 2! 1! 1! 1! 1! 1! 2! 0! NCI! NIA! NCATS! NIAAA! NHLBI! NIDCR! NIGMS! NIDDK! NIAID! NIMH! NIAMS! NEI! NICHD! NIEHS! Data!Source:!US!Dept.!of!Health!and!Human!Services!

11 NIH Funded microrna biomarker Projects $7,000,000! $6,000,000! $5,722,649! $5,000,000!! This!Figure!Presents!the!Dollar,Value,of,Grants/, Funded,Projects!by!the!Various!NIH!Funding!Agencies!! The!focus!of!these!projects!is!on!microRNAs!with! some!aspect!of!the!project!focusing!on! microrna! Biomarkers!! Total!Value!of!these!Grants/Projects!=!$20.46!Million! $4,481,087! $4,000,000! $3,000,000! $2,688,794! $2,136,200! $2,000,000! $1,487,191! $1,000,000! $491,528! $578,131! $671,311! $491,903! $421,414! $363,901!$382,085! $240,000! $307,469! $0! NCI! NIA! NCATS! NIAAA! NHLBI! NIDCR! NIGMS! NIDDK! NIAID! NIMH! NIAMS! NEI! NICHD! NIEHS! Data!Source:!US!Dept.!of!Health!and!Human!Services!

12 In Summary! In! this! report! we! have! sought! to! present! the! landscape! of! microrna! research! as! it! relates! to! the! development! of! micrornacbased! biomarkers!for!various!disease!classes!! Clearly,! the! research! world! of! micrornas! is! driven! by! cancer! primarily! (but!this!is!now!becoming!morecinclusive!of!other!disease!classes!such! as!cardiovascular!disease!and!cns!disease)!! We! further! present! selected! associaqons! of! microrna! signatures! with! various! disease! classes this! snapshot! is! meant! to! illustrate! the! exquisite!specificity!that!such!a!signature!affords!and!the!challenge!is!to! idenqfy!and!validate!such!signatures!across!disease!classes!! Eventually,!these!signatures!can!be!developed!into!diagnosQcs!! Importantly,!the!fact!that!microRNAs!can!be!harvested!from!biological!fluids!enables! the! development! of! biofluid! biopsies! wherein! circulaqng! biomarkers! such! as! micrornas!can!be!captured!and!analyzed!ex!vivo!! The!NIH!is!funding!to!the!tune!of!US$20!Million!research!efforts!some! parts! of! which! impinge! on! microrna! biomarker! validaqon! and! development!