PT1913952E - Determinantes moleculares da doença óssea do mieloma e respectivas utilizações - Google Patents

Determinantes moleculares da doença óssea do mieloma e respectivas utilizações Download PDF

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PT1913952E
PT1913952E PT07118621T PT07118621T PT1913952E PT 1913952 E PT1913952 E PT 1913952E PT 07118621 T PT07118621 T PT 07118621T PT 07118621 T PT07118621 T PT 07118621T PT 1913952 E PT1913952 E PT 1913952E
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John D Shaughnessy
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Univ Arkansas
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Description

DESCRIÇÃO
DETERMINANTES MOLECULARES DA DOENÇA ÓSSEA DO MIELOMA E RESPECTIVAS UTILIZAÇÕES
ANTECEDENTES DA INVENÇÃO Âmbito da Invenção A presente invenção refere-se em termos gerais ao estudo do mieloma múltiplo. Mais especificamente, a presente invenção refere-se à identificação dos determinantes moleculares da doença óssea do mieloma através da análise comparativa de perfis de expressão genética global.
Descrição da Técnica Relacionada 0 mieloma múltiplo (MM) é uma situação maligna rara, embora incurável, de células plasmáticas (PC) terminalmente diferenciadas que afecta aproximadamente 15 000 pessoas por ano nos Estados Unidos, representando a segunda situação maligna hematopoiética mais comum. O mieloma múltiplo representa 13% de todos os processos malignos de células linfóides na população de raça branca e 31% dos processos malignos de células linfóides na população negra. As células plasmáticas malignas alojam-se e expandem-se na medula óssea, provocando anemia e imunossupressão devido à perda da hematopoiese normal. O mieloma múltiplo está também associado a osteoporose sistémica e a destruição óssea local, conduzindo a dor óssea debilitante e a susceptibilidade a fracturas, compressão da medula espinal e hipercalcemia. O mieloma é a única situação 1 maligna hematológica consistentemente associada com doença óssea lítica e a destruição óssea local está limitada a áreas adjacentes a células plasmáticas, sugerindo que as células plasmáticas malignas segregam factores que activam a função osteoclástica e/ou a energia osteoblástica. A prevalência de doença óssea varia com a apresentação do mieloma, desde o mieloma assintomático, muitas vezes sem envolvimento ósseo, até ao plasmacitoma solitário, e ao mieloma múltiplo difuso ou focal onde se observam perdas sistémicas de densidade mineral óssea ou lesões ósseas liticas focais em aproximadamente 80% dos doentes.
Nos últimos anos, tornou-se evidente que a doença óssea lítica é não só uma consequência do mieloma, mas está intricadamente envolvida na intensificação da progressão da doença. Uma alteração das taxas de turnover ósseo prediz a progressão clinica da gamapatia monoclonal de significado indeterminado (GMSI) para mieloma manifesto no espaço de 3 anos. Enquanto inicialmente a actividade osteoclástica e osteoblástica estão emparelhadas, este emparelhamento perde-se com a progressão da doença. A actividade osteoclástica mantém-se aumentada e a actividade osteoblástica diminuída, com a consequente doença óssea litica. Estudos no mieloma murino 5T2 e no modelo SClD-hu do mieloma humano primário demonstraram que a inibição da actividade osteoclástica está associada à inibição do crescimento do mieloma e à redução da carga do tumor mieloma. Estes estudos corroboram referências de que a inibição da reabsorção óssea com bisfosfonatos tinha um efeito anti-mieloma.
Enquanto a biologia dos osteoclastos na doença óssea litica associada ao mieloma tem sido investigada intensivamente, sabe-se pouco sobre as alterações associadas à doença na 2

Claims (7)

  1. REIVINDICAÇÕES 1. Método ex vivo de determinar o potencial de desenvolvimento de doença óssea litica num doente com mieloma múltiplo, compreendendo este método a etapa seguinte: examinar o nivel de expressão do homólogo humano de Dickkopf-1 (DKK1) numa amostra corporal ex vivo, caracterizada pelo facto de a expressão aumentada de DKK1 em comparação com a observada num indivíduo normal indicar que o doente tem o potencial de desenvolver doença óssea litica.
  2. 2. Método de acordo com a reivindicação 1, caracterizado pelo facto de o nivel de expressão ser determinado ao nivel do ácido nucleico ou ao nivel da proteina.
  3. 3. Um inibidor da expressão da proteina soluble frizzled related protein 3 (SFRP-3/FRZB) ou do homólogo humano de Dickkopf-1 (DKKl) para uso no tratamento de doença óssea litica num doente com mieloma múltiplo caracterizado pelo facto de o inibidor ser seleccionado entre oligonucleótidos anti-senso de DKKl, os anticorpos anti-DKKl ou os receptores solúveis da proteína ligada aos receptores da lipoproteína(LRP).
  4. 4. Inibidor para utilização de acordo com a reivindicação 3, caracterizado pelo facto da expressão da SFRP-3/FRZB ou de DKKl ser inibida ao nível do ácido nucleico ou ao nível da proteína.
  5. 5. Inibidor para utilização de acordo com as reivindicações 3 ou 4, caracterizado pelo facto de a expressão do gene DKKl com número de acesso NM_012242 ser inibida. 1
  6. 6. Um inibidor farmacológico da proteína DKKl para uso no tratamento de perda óssea relacionada com situação maligna num doente com cancro da mama ou cancro da próstata caracterizado pelo facto de o inibidor ser um anti-corpo anti-DKKl ou um receptor solúvel de LRP.
  7. 7. Inibidor para utilização de acordo com a reivindicação 6, caracterizado pelo facto de a perda óssea relacionada com situação maligna ser transmitida para o osso por metástases do cancro da mama ou do cancro da próstata. 07-04-2011 2 RESUMO DETERMINANTES MOLECULARES DA DOENÇA ÓSSEA DO MIELOMA E RESPECTIVAS UTILIZAÇÕES Para identificar determinantes moleculares de doença óssea litica no mieloma múltiplo, compararam-se os perfis de expressão de ~12 000 genes em células plasmáticas enriquecidas com CD 13 8 provenientes de doentes recém-diagnosticados com mieloma múltiplo que não apresentavam indicios radiológicos de lesões liticas (n=28) com doentes com 3 lesões liticas (n=47). Dois antagonistas da sinalização do WNT segregados, a proteina «soluble frizzled related protein 3» (SFRP-3/FRZB) e o homólogo humano de Dickkopf-1 (DKK1), foram expressos em 40 dos 47 doentes com lesões ósseas liticas, mas apenas em 16 dos 28 que não apresentavam lesões ósseas (P<0,05). O DKK1 e o FRZB não foram expressos em células plasmáticas de 45 dadores com medula óssea normal ou 10 com macroglobulinemia de Waldenstrõm, uma situação maligna das células plasmáticas sem doença óssea. Estes dados indicam que estes factores são importantes mediadores da doença óssea no mieloma múltiplo, podendo ser utilizados inibidores destas proteínas para bloquear a doença óssea. 1
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    BPCMGUSWM =0 =0 21 (n=45) (n=16) W MRI = 0 MRlil MRlil (n=36) (n=33) (n=104) Rq.1B 2 1/43 sm cm mi um. mu mmé «ÍSS SB» SAS1« &®í ΙΐΜβ pmt $MP ítóeat tw NSffif ®wm mn PTTSt iSSlí m m*T mm* mm imt SfiEStt fw Wfil *w» saes m ΆΆΤ mjjx flÊdíí CSLSHf em mt Ηάκδί PHfí mm &mi mm mtVA mu íwim ms mm pjm
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    2/43
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    4/43 1VN1S 5/33 1111 20/21 Presentes Presentes Presentes
    CÉLULAS PLASMÁTICAS NORMAIS fflf
    Rg.3 5/43 SINAL
    SEM DOENÇA OSSEA DOENÇA OSSEA 6/43
    150 MM Recém-diagnosticado 7/43 7000 4000 3000 2000 1000 0 AC “P"em 8/8 ACTem19/22
    111! PC da Amígdala pc da Medula óssea
    8/43
    Sem diagnóstico ósseo Diagnóstico ósseo CPMO normais 9/43
    Sem diagnóstico ósseo Diagnóstico ósseo CPMO normais 10/43
    11/43 3500 3000 2500 2000 1500 1000 500 II -..... JlH illlll------·»·ιΙ _.....lllll PBCTBCTPC BPC WPC WBC CLL raio
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    Flg. 12 13/43
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    Fig. 14 15/43
    Fig.15 35000 30000 25000 20000 15000 10000 5000 25000 FRZB 16/43 iBN FNA
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    Fig. 16 17/43
    Fig. 17 18/43 TJ V *ϋ tj TJ TJ TJ TJ TJ T) TJ Ό TJ TJ TJ TJ TJ T> Ό 1 TI UI 0 H KJ 0 H ui 0 0 UI w 0 0 UI μ μ u> w 0 & μ 10 A cn w 0 •g SI 0 w 0 μ 0 10 N w N μ 0 UI to NJ 10 t 0 σι σι ψ w co * H sl 10 μ 91 σι u UI M 1 N i UI 1 CÕ σι 1 K) KJ KJ KJ K) KJ KJ KJ N Μ
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    (WAA)trTSd Fig. 20 21/43
    Fig.21 22/43
    «h ininnrvioNwoiDiONictfNi/iinttncoNifln cooarNOHuiioinoiN^nrirttfBOQ-íoio^iNOiOhtBeBi/tooninwttfMooin HNHnniNNHflIlN^HflfKIONBNNMIlOOIiinOHOOKNMNO IUIlll&IUlllUl&UililUlÍllUllilÍllD,D.UO.lUaiUall Fig.22 23/43 mim
    Flg.23 24/43
    Fig.24 18000 16000 14000 25/43 IWNT5A IWNT10B
    ΐ u t a η u </i o ui o n w <n tu Φ o> u gj A 01 IV VI 01 O y 3 11 t o o y n 3 n 3 3 o 3 D 3 3 3 3 o 3 3 .3 3 3 3 3 D *0 D 3 3 u w 0 IV W VI ttl N A 01 0 01 H u (0 A 0 01 0 w A 01 A w 0 UI w A (ff VI A iu A μ H u M 0 >u A 10 0 U U μ » u CD 10 N 01 01 10 0 0 vi 0 Ol α μ H 0 01 10 S VI 0 M 01 N A 10 0 μ 01 VI 10 VI M VI N u 10 N N tt 01 01 VI CD (9 H w VI μ I Kl Fíg.25 26/43
    DKK1 anti-humano policlonal da cabra + anti-lgG1 da cabra marcado com rodamina do burro
    lgG1 da cabra + anti-lgG1 da cabra marcado com rodamina do burro Fig. 26 27/43
    a-DKK1
    α- lg kappa Fig. 27 N A Ο Ο Ο Ο Ο Ο
    Ν) 00 \ b w 29/43 16000
    MIELOMA RECÉM-DIAGNOSTICADO 30/43
    Fig. 30 431/43
    PROLIFERAÇÃO DE OB NL PC PROGENITOR DE OB
    Fig. 31 25000 - 20000 15000- 10000 - 5000- ϋϋ *0 U A * Ο ο Ν Μ -f Μ Ν 32/43 PS-341 II 2 2 α mk ο 9 Ν 2 2 η ·α υ ω ω οι 10 <0 0) » ψ ΐ Μ Μ LiLiLiLiLiLj LiLjLjLjLj Fig. 32 33/43
    U ϋϋ ϋϋ ϋϋ ϋϋϋϋϋϋϋϋϋϋϋ Fig.33 34/43
    Fig.34 35/43
    Fig.35 36/43
    37/43
    14Α 148 12Α 128 11Α UB 9A 9B 16.1A 16,1B 5A 5B 2A 2B Fig.37 38/43
    Apoptose das CPMM directa ou indirecta? Apoptose osteoblástica? 39/43
    Fig. 39 40/43
    41/43 Proteína DKK1 (ngh/ml)
    (n = 18) (n=9) (n=41) Fig, 40B Actividade fosfatase alcalina (proteína pmole/min/mg)
    42/43 43/43
    Fig. 41B J ivropllnh»; ratentarnt. (tti hrevets Eurapeán PatentOfíicâ 50238 MUNiCH GERMANV Tel. +49(0)89 2399 -0 Fax +49(0)892399-4465
    Heaton, Joanna Mana Stevens, Hewtett & Perkins 1 St. Augustirtos Plaoe Bríetol BS1 4UD GRANDE BRETAGNE Fteferánce Apíoltoè\kbnMÔj'F4tefjtPJa jmh/8057èp01 07118621.7 - 2402/1913952 Appiioant/Preprietor THE BOARD 0,F TRUSTEES OF THE UNIVERSITY OF ARKANSAS Daclslon to grant a European patent purauant to Article97(1) EPC Follpwjng examinaiicm of Ei.raosai patent applioation No. 07116621.7 a European patent with ttie titte afid the supportlhg doouments índioated ín the cóhimuníeatiõn pursuáiií to Ruie 71(3) EPC dated 22,07.10 is hereby granted in rsspect of the designatéd Gontraçfing States, The reqUést for âméndment3 teoeived at the EPO on 29.11.10 and any subsequent modilícationsagreed With the appiicant have been tateri ínto accóunt. Paterit Nò. 1913952 Dateftf fillrig : 04.12,03 Prioriíy olaimed : Os.i2.02/ySP 431040 Designatéd Gcrrtraoting States and Proprietor(s) : AT BE BG CH CY CZ DE DK EE ES Fl FR GB GR HU IÊ Ff Ll LU MC NL PT RO SE SI SK TR THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ARKANSAS Univeisity of Arkansas System, 24:04 No rth University Avénue Littts Rock, AR 72207-360S/US This deoísion wíll tate eftect on flie date on which the Eurapeán Patent Bulletín menlions the grant (Art. 97(3) EPC). The menSohoftoe grartwilIbe pUblished iii European Paterit Buiietin 11/TO of 09.03.11, Examíning Divisíon Pellegrini P Holiwv M Vogt T
    Regisíered ieiter to EPO postai serviee: 04,02.1:1 EM Forro aOOSA 1297 (M.D2/11)
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US7811750B2 (en) * 2002-12-05 2010-10-12 Board Of Trustees Of The University Of Arkansas Molecular determinants of myeloma bone disease and use thereof
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