epigenetics advancing personalized nanomedicine in cancer therapy. traduÇÃo

8/11/2019 Epigenetics Advancing Personalized Nanomedicine in Cancer Therapy. TRADUO

1/31


2/31

radicionalmente, os pacientes so tratados por um one5si$e5fits5all abordagem dentro de um

protocolo padro% As 1ecises de tratamento so principalmente decidiu baseando5se no estgio

cl!nico da doena e hist)rico m0dico e familiar do paciente, mas ignorando a biologia do indiv!duo

a conduo de tais doenas ; J =% &mbora &ssas abordagens fe$ alcanar notvel eficcia teraputica

na cura de certos tipos de c-ncer 6por e4emplo, c-ncer testicular, e leucemias peditricas: ; K =, a

ta4a de sobrevida global de pacientes com c-ncer tem melhorado pouco nas (ltimas d0cadas,defendendo a necessidade de novas id0ias e estrat0gias na gesto da doena% A /ova deciso de

tratamento deve integrar biologia doena abrangente, reagentes teraputicas ade+uadas e ve!culo de

entrega de drogas em outros atributos pessoais 6idade, se4o, nutrio, condies psicol)gicas e

intestino microbioma ; 5 M =:% &ssa Integrao trou4e o conceito de medicina personali$ada +ue

aborda o medicamento certo para a pessoa certa no momento certo%

A medicina personali$ada enfati$a a unicidade de uma pessoa, uma doena e um medicamento em

pontos de tempo espec!ficos em +ue prestar cuidados de sa(de individuali$ado para pacientes com o

m4imo de eficcia teraputica no custo dos efeitos adversos m!nimos% A Nedicina personali$ada

tem sido amplamente e com sucesso aplicado O gesto de numerosas doenas humanas,especialmente c-nceres% ' Nelhor e4emplo da terapia do c-ncer personali$ado vem da identificao

e testes cl!nicos do receptor de estrognio 6er: no c-ncer de mama e bcr F abl em cml% Apesar 1os

impressionantes benef!cios cl!nicos da sa(de individuali$ado, as +uimioterapias atuais ainda tm

resultados desanimadores% /esses Pasos, a melhor caracteri$ao da doena utili$ando

biomarcadores apropriados 6por e4emplo, alteraes gen0ticas e epigen0ticas: pode ajudar os

m0dicos a decidir o melhor meio para entregar a droga a fim de proporcionar a eficcia

m4ima% &ntre Nuitos biomarcadores, modificadores epigen0ticos so os jogadores mais

importantes na concepo da medicina personali$ada, por+ue esses marcadores esto fortemente

correlacionados com atributos individuali$ados% Al0m 1isso, as barreiras +ue contribuem para ofracasso +uimioterpico atual poderia ser secundria a entrega da droga abai4o do ideal% Pomo al,

a nanomedicina conseguiu superar essas armadilhas enviando especificamente as drogas para o

lugar certo, com to4icidade sistmica provavelmente redu$ida% /ova /anotecnologia 6reagentes e

dispositivos por e4emplo nano5imagem: tamb0m pode ajudar na descoberta de novos

biomarcadores dos materiais limitados de forma no5invasiva, promovendo assim a sa(de

individuali$ado% @ara ' efeito, o verdadeiro sentido da medicina personali$ada deve ser as

integraes sem costura da medicina, a nanotecnologia e atributos pessoais, com considerao

epigen0tica colocado no local central% Pertamente /anomedicina personali$ado ser teoricamente

ben0fico para todos os tipos de pacientes, mas este artigo enfati$a, principalmente, suas influncias

sobre a gesto do c-ncer, uma ve$ +ue o c-ncer 0 as leses representativamente sistmicas +ue so

as doenas mais letais em todo o mundo%

"o to#

2 a medicina personalizada no tratamento do cancro

2.1. Conceito e medicina personalizada

Pada pessoa 0 verdadeiramente (nico, e por isso so as leses cancerosas% Qingularidade 1e cadapessoa inclui informaes cl!nicas, genRmica e ambiental, bem como a nature$a das doenas,


3/31


4/31

;


5/31

Paracteri$ao de translocaes espec!ficas do paciente revolucionou o tratamento personali$ado do

c-ncer% @or &4emplo, muitos tipos estruturalmente diferentes de anomalias cromossRmicas foram

definidos na leucemia, incluindo t 6


6/31

genoma humano e +ue compem cerca de CED de toda a variao gen0tica humana% /as [ltimas

duas d0cadas, mais de enciamento%/o &ntanto, a maior barreira para a aplicao cl!nica snp em medicina

individuali$ada 0 a discriminao gen0tica a +uesto%

2.".0. Clulas Circulantes de dna rna e tumorais

/o nosso sistema o sangue circula vrios tipos de arn e de adn, na forma de livre ou envoltos em

gl)bulos vermelhos e pla+uetas ou nucleossomas% &stes 'ligos so liberados por apoptose e c0lulas

mortas ou c-ncer e c0lulas regulares como mensageiros, +ue 0 evidente pela funo de

transformao destes oligos de pacientes com c-ncer% 1/A Pirculante foi demonstrado pela

primeira ve$ no sangue humano de doadores saudveis, mulheres grvidas e pacientes cl!nicos em


7/31

Nirs pode ativar ; J = ou reprimir a e4presso do gene alvo e so a maior classe de genes

reguladores% /o Qangue circulante, e4presso diferencial de mirs entre as pessoas normais e

pacientes tem sido evidenciada% @or &4emplo, o n!vel de mir-155, mir-210e mir-21no soro de

pacientes com linfoma de c0lulas b ]0 elevada ; JV =% Nitchell et Alrelataram +ue os n!veis s0ricos

de mir-141pode distinguir pacientes com c-ncer de pr)stata a partir de controles saudveis

; JM =% &stes Nirs circulam esto emergindo como importantes marcadores no5invasivos 6revistoem ; JS =:, o +ue pode beneficiar o diagn)stico e progn)stico, mesmo funcionam como uma

bandeira para a eficcia teraputica% Al0m 1isso, na corrente sangu!nea circula c0lulas tumorais,

+ue so derivados a partir de um tumor primrio, com o potencial para crescer em outra parte do

corpo% ais P0lulas cancerosas circulantes 6ctcs: podem fornecer aos m0dicos uma maneira mais

avanada no5invasivo para descobrir o estgio da metstase do c-ncer, as abordagens

individuali$adas para pacientes, ea maneira de monitorar o progresso da doena% &m "eral, os

marcadores acima mencionados 6adn, arn, e mir ctc:, so distintas entre o cancro e as c0lulas

normais, mesmo as c0lulas cancerosas em diferentes estdios de progresso da doena% ais

Wiomarcadores diversificadas oferecer uma plataforma crucial para compreender a etiologia epatologia dos cancros com um forte apoio para a medicina personali$ada%

2.".. 34micas3 dados o'erecem as in'orma&es mais a5rangentes para a concepo damedicina personalizada

&mbora as identificaes das mutaes da prote!na +uinase levaram O terapia5alvo frut!fera, a ta4a

de sobrevivncia de pacientes com c-ncer aumentou pouco mais de d0cadas% &stes radicional in

vivoe ensaios in vitroso capa$es de medir apenas alguns par-metros na melhor das hip)teses,

proporcionando assim um mero instant-neo dos poss!veis efeitos de uma determinada droga% @ara

Quperar essa alta ta4a de fracasso de drogas, o +ue precisamos 0 o cuidado teraputicopersonali$ado com base em biomarcadores gen0ticos e epigen0ticos abrangentes, +ue s) pode ser

descoberto com sucesso por 5)micas, incluindo genRmica, transcriptRmica, proteRmica,

metabolRmica e epigenomics, atrav0s a utili$ao de tecnologias de alto rendimento 6por e4emplo,

o se+>enciamento de alto rendimento em uma escala do genoma ; JC =:%_micas tecnologias

podem descobrir e caracteri$ar as c0lulas tumorais, tumores e biomarcadores espec!ficos da pessoa

+ue permitam o avano da terapia individuali$ada ; KE =% 2ecentemente, feinberg et ale4ecutar a

anlise do genoma escala imparcial de \ K milhes de sites cpg entre MK indiv!duos com teste

abrangente metilao em relao O base de matri$, e encontrou BBM regies mostrando enorme

variabilidade inter5individual 6regies variavelmente metiladas, vmrs: em todo o genoma % Netade1estes vmrs eram estveis entre os indiv!duos com mais de uma m0dia de


8/31

se+>ncias rearranjadas 6variao K5


9/31

importante, a seleo de portadores de administrao de medicamentos ade+uados 6por e4emplo,

nanopart!culas: conjugado com ligantes individuali$adas corretos ou biomarcadores de pacientes%

/anomedicine, referred by the national institutes of health, is the application of nanotechnology in

medicine% hese applications include the drug delivery, disease detection, diagnosis, and treatment%

he disease areas include cancerous lesions ; E =, cardiovascular system, lungs, blood,

neurological diseases, diabetes, inflammatoryFinfectious diseases, parinson]s or al$heimer]sdisease, orthopaedic problems and so on% he types of nanoparticulates utili$ed are


10/31

tumor, the most difficulties in personali$ed cancer therapy%

".2.2. (pplication !' nanoparticles assists 5iomar$er discover9

/oGadays various nano5therapeutics have reached patients, including anticancer drugs and imaging

agents, but there are only feG clinically approved nanocarriers that incorporate molecules to

selectively bind and target cancer cells ; K =% Individual biomarers are the eys to successfullydevelop and employ personali$ed therapies, because biomarers are crucial to distinguish individual

patient or tumor tissue or even a single tumor cell at a given stage of disease development and

predict the clinical outcomes% It]s highly difficult to identify clinically meaningful biomarers from

a given patient, specifically Gith barely available or detectable materials% In such cases, nano5

particulate systems may be very useful in uncovering prognostic and diagnostic marers, detecting

circulating tumor cells, monitoring therapeutic efficacy in non5invasive Gay% .or e4ample, nano5

materials 6eg biocompatible and stable fluorescent silverFdendrimer nanocomposites: are suitable

for labeling cells in vitro.uantum 1ots as molecular labels have potential to discover the earliest

signs of cancers% Pareful selection and design of nanoparticle surface can specifically condense asubset of biomarers ; , V = and se+uester them for further investigations by high5sensitivity

omics tests% /anobiosensors can improve cancer biomarer discovery by sensitively detecting

multiproteins in various clinical samples ; M=% Nagnetic nanoparticles can capture circulating

tumor cells in bloodstream ; S = thereby promoting tumor detection% 'verall, Ge e4pect that, by

means of novel nanotechnology, the detection of sparse biomarer Gill become true in vivoeven

Ghen the tumor groGth is still undetectable by typical techni+ues%

".2.". 7he Challenge o' nanomedicine

Although nanomedicine has brought considerable advances in fighting cancer regarding to thediagnosis, prognosis and therapeutics, it is still at the early stage of development and meets various

challenges% .or e4ample, there are no efficient Gays to determine the body distribution of

nanoparticulate carriers after system administration, and no suitable imaging modalities to vision

the biodistributions over time ; C =, although radiological imaging can trac and +uantify particle

distribution ; VE =% /anoparticles are to4ic to several organs ; V< VV =, particularly those particles

Gith little solubility or no biodegradation at the accumulation location% 2egarding to the fda5

approved drug5containing nanoparticles, Ghile liposome5encapsulated do4orubicin has brought

striing clinical benefits Gith reduced to4icity 6eg cardioto4icity:, its therapeutic efficacy against

the tested tumors Gas unsatisfactory% @4l remarably increases the efficient of hydrophobic cancerdrug delivery, but there is no obvious enhancement in survival rate% here are multiple hurdles

contributing to such nanomedicine failure, but non5integration of individuali$ed factors 6drug

metabolism rate, epigenetic biomarers, and tumor heterogeneity etc%: may spea really loudly here%

".". (pplication !' nanotechnolog9 in personalized therap9

@ersonali$ation of cancer therapies relies on a better understanding of the disease at the molecular

level, including the mechanisms of cancer initiation and invasion, the identifications of prognostic

and diagnostic biomarers as Gell as the development of novel therapeutic agents% /anotechnology

can create multi5functional platforms, Ghich advance the anti5cancer drug discovery and delivery,the identification of individual omics information ; VM =, and the monitoring of disease course and

treatment outcomes% UoGever, Githout combining nanotechnology Gith personali$ed attributes


11/31

personali$ed nanomedicine, Ge Gould e4pect the chemotherapeutic failure to be continuously

arisen from such independent practice% he uni+ueness of nanoparticulates is their multi5

functionality% Wiotargeting ligands 6eg antibodies, peptides or small molecules:, imaging labels,

therapeutic drugs and others can be integrated into a single nanoplatform, Ghich can ma4imi$e the

therapeutics by specifically delivering drugs 6even drug coctails: to the action sites, identifying

diagnosisFprognosis biomarers and monitoring disease progress after chemotherapy% Quch multi5functional nanoplatform nicely fits the features of personali$ed therapy# early detection,

combination of diagnostics Gith therapeutics%

o date, nanotechnologies have already brought benefits to the personali$ed treatment%

/anotechnology can efficiently and specifically deliver biological therapies, such as cells and genes

that come from a given patient% Qome nanoparticles and nanodevices 6eg nanobiosencors and

nanobiochips: have been conjugated Gith patient5specific ligands targeting special tumor cells to

improve clinical efficacy ; VS =, and such nanoparticle5based drug delivery plus the right dose and

time is re+uired by successful individuali$ed medicine ; VC =% Nolecular imaging is an important

basic technology for personali$ing health care% /ovel molecular imaging tools 6egsuperpapramagnetic contrast agent and perfluorocarbon nanoparticles: Gill enable non5invasive

characteri$ation of patients for delivering personali$ed therapy ; ME =% .or e4ample, vYJ5targeted

paramagnetic nanoparticles have been used to noninvasively detect very small regions of

angiogenesis associated Gith nascent melanoma tumors ; M< = and deliver higher doses of drugs

directly to the tumor site Githout systemic to4icity% he aforementioned achievements offer

opportunities for the progression of personali$ed oncology in Ghich cancer detection, diagnosis and

therapy are tailored to each individual]s molecular signature thereby ma4imi$ing efficacy, but

sparing patients unnecessary to4icity%

"o to#

0. Potential role o' epigenetics in the design o' personalizednanomedicine

0.1. Epigenetic eregulations cause human cancer

0.1.1. Concept !' epigenetics

"enetic alterations 6eg deletions and mutations: could lead to the abnormal signaling pathGays andsometimes drive illnesses% his concept provides a sound rationale for pathGay5based drug

discovery, in Ghich the targeted therapy is built to against both mutant oncoproteins 6it, bcrFabl:

; MB MK = and Gild5type effectors ; M = residing upstream or doGnstream of the dysfunctional

pathGays% In contrast, epigenetics is dealing Gith the modifications of dna and proteins 6eg core

histones:% he term epigenetics Gas first used by british biologist, conrad Gaddington, in


12/31

representing promising targets for therapeutic interventions% As such, epigenetics has become one of

the most attractive fields in the current biomedical research landscape since the inception of

epigenetics in the past century%

0.1.2. Environmental (nd intrinsic signals criticall9 in'luence epigenetics

hat factors determine epigenetic balance It is reported that environmental and lifestyle5relatedinfluences, such as nutrition, to4ins and drugs as Gell as e4posure to stress, can induce epigenetic

changes, indicative of epigenome as a biochemical record of relevant life events ; MV , MS SE =%

Qpecial environment, lie maternal epigenetics and maternal behavior, also impacts epigenetic

variations ; S< , SB =, Ghich is strongly supported by the observed aging5related epigenetic changes

; SJ , SK = and the discoveries shoGing that mono$ygotic tGins have greater differences in global

dna methylation in older than in younger% Quch divergence of epigenome in mono$ygotic tGins is

decreased Ghen they are living in similar environment ; B =% Qpecifically, the en$ymatic activities,

Ghich cataly$e histone modifications, are governed by environmental and intrinsic stimuli ; S =%

Quch stimuli5induced histone modifications can remodel the chromatin and yield short5term orFandlong5term outcomes ; SV =%

/oticeably the change of environmental and intrinsic stimuli for a given person is fre+uent and

dynamic% he dynamic environments create the dynamic epigenetic modifications changing over

time, Ghich are demonstrated by the observation shoGing that an


13/31

among dna methylation and histone modifications%

0.1.".1. (5errant hdac activities drive cancer

Among the numerous posttranscriptional modifications, acetylation and deacetylation are the most

e4tensively studied histone changes, and typically cataly$ed by hat and hdacs, respectively% In

general, histone deacetylation results in chromatin condensation Gith the conse+uence of gene

silencing, in contrast, histone acetylation leads to chromatin rela4ation and gene reactivation% In line

Gith these, abnormal hdac e4pression or activity has been shoGn to be the driving forces in the

development of human malignances ; C =, because aberrant hdac activities could condense the

chromatin and silence tsgs, resulting in unlimited cancer cell proliferation%

'n the basis of se+uence identity and domain organi$ation, hdacs are classified into four classes

; CV =, class i 6hdac


14/31

Qo far strong correlation betGeen epigenetic aberrations and cancers has been established

;


15/31

ser +uantificada por meio de t0cnicas correntes% Netilao 1o dna 0 a conse+>ncia or+uestrada de

muitos atributos individuais e um importante mediador biol)gico dos efeitos ambientais de doenas

humanas ; ncia da fisiologia alterada em c0lulas de c-ncer de conduo% Assim,

a aplicao de biomarcadores epigen0ticos em c-nceres de cura 6por e4emplo, cancro colorectal:

tem +ue ser cauteloso devido aos resultados inconsistentes e inconclusivas de ensaios baseados em

metilao ;


16/31

uma ve$ metilados, ocorre o silenciamento do gene% Pada ipo de tumor tem um perfil (nico de

ilhas cpg hipermetilado ;


17/31

management% Among them, inase5targeted therapies represent several cases of successful

personali$ed medicine, because these approaches emphasi$e patient]s personal attributes at the

molecular or chromosomal level% UoGever, the information used here represents only tiny part of

patient]s molecular signatures, and most clinical and biological characteri$ation still remains

une4plored% his can e4plain Ghy such targeted therapy eventually failed, Ghile successful initially%

o overcome the aforementioned therapeutic pitfalls, comprehensive characteri$ation of the diseasebiology for specific patient 6responder versus non5responder or complete remission versus relapse:

is a must, Ghich shall be assisted through systemic approach using omics technologies% he

omics results are useful for early detection of disease, predicting patient response to therapy and

developing biomarers to enable effective targeting of drug delivery modalities to the disease site%

Among the omics technologies, genomics have achieved the most detailed and comprehensive

studies, but most gene e4pression signatures from cell lines and patient samples, Ghich reflect only

small time GindoG of disease development, are lacing therapeutic meaning thereby not into clinic

yet ;


18/31

"o to#

(gradecimentoshis Gor Gas supported partially by nih grants rE


19/31

.ms5lie tyrosine inase receptor5J"stp

epigenetics advancing personalized nanomedicine in cancer therapy. traduÇÃo

Documents