TREAT­MENTS FOR CAN­CER

Health at the cel­lu­lar level

Health & Nutrition - - CONTENTS -

M il­lions of peo­ple die of can­cer ev­ery year. What could lower fu­ture num­bers? Early de­tec­tion could make a big dif­fer­ence. Per­haps sim­ple blood tests will some­day ac­cu­rately iden­tify spe­cific fea­tures in the blood – mark­ers – that in­di­cate can­cer­ous changes be­fore the dis­ease silently reaches more ad­vanced and more dif­fi­cult-to-treat stages. The an­swers to this and many other ques­tions about dis­ease and po­ten­tial treat­ment may lie in the rel­a­tively new field of study called pro­teomics.

BE­YOND THE HU­MAN GENOME

Sci­en­tists in 2001 un­veiled the hu­man ge­netic blue­print, the DNA se­quence of roughly 34,000 genes. This study of hu­man ge­nomics – called the Hu­man Genome Project – was com­plex enough. But the next level – of un­der­stand­ing the pro­teins en­coded by th­ese genes – is many times more com­plex. Pro­teomics has to do with th­ese “ge­neen­coded” pro­teins – not pro­teins as a nu­tri­tional el­e­ment, but rather pro­teins as ac­tors within the body’s mo­ment-to-mo­ment bi­o­log­i­cal pro­cesses. The tis­sues in your body, such as mus­cle, brain, skin and your in­ter­nal or­gans, are made up of thou­sands of pro­teins. All of th­ese pro­teins are in­di­vid­ual work­horses that col­lec­tively carry out the var­i­ous func­tions of your tis­sues. Pro­teins are re­spon­si­ble for cell growth, cell di­vi­sion, en­ergy use (me­tab­o­lism) and cell death (apop­to­sis). In essence, pro­teins ex­press (phe­no­type) the ge­netic in­for­ma­tion (geno­type) in each cell of your body. Ev­ery pro­tein in your body con­tains a spe­cific se­quence of amino acids linked to­gether like a string of beads. Th­ese strings fold into unique shapes and con­fig­u­ra­tions. Each shape cre­ated by th­ese gene-di­rected pro­teins car­ries out a spe­cific func­tion in the cells and tis­sues. For in­stance, skin cells pro­duce the pro­tein ker­atin, the ma­jor com­po­nent of skin cells that are sloughed off. At the same time, blood cells reg­u­larly pro­duce he­mo­glo­bin, the ma­jor pro­tein in red blood cells. Pro­teomics in­volves study­ing the va­ri­ety of pro­teins pro­duced by a par­tic­u­lar cell or tis­sue.

ONE STEP CLOSER TO KNOW­ING

There are many more pro­teins in cells or tis­sues than there are genes. Dif­fer­ent kinds of pro­teins in your body may num­ber any­where from sev­eral hun­dred thou­sand to more than a mil­lion – the fig­ure has yet to be determined. Th­ese pro­teins fold and change shape and func­tion over time. Among ques­tions re­searchers hope to an­swer: How do pro­teins fold into unique shapes or con­for­ma­tions? How do pro­teins in­ter­act with other pro­teins and small mol­e­cules? How are pro­teins mod­i­fied and with what type of mod­i­fi­ca­tions? When, where, why and how are pro­teins re­vealed (ex­pressed) in the body? An­swers to th­ese ques­tions may open the door to cre­at­ing new ap­proaches to both di­ag­nos­ing and treat­ing dis­ease, as well as designing new drugs to treat dis­ease. For ex­am­ple, if the char­ac­ter­is­tics and func­tion of a key pro­tein in a dis­ease were known, it might be pos­si­ble to de­sign a drug mol­e­cule that could bind to that pro­tein and dis­rupt its func­tion in the cell. This could ba­si­cally halt the progress of the dis­ease. It would sig­nal a domino ef­fect that stops, starts or mod­i­fies a spe­cific process.

UL­TI­MATE GOAL

Some es­pe­cially promis­ing ar­eas of study in pro­teomics in­clude meth­ods of bet­ter de­tect­ing early ovar­ian can­cer, prostate can­cer, breast can­cer, colon can­cer, and cer­tain types of ma­lig­nant leukemias and lym­phomas of the blood. For ex­am­ple re­searchers have found that com­par­ing lev­els of cer­tain pro­tein biomark­ers in the blood may prove sig­nif­i­cant to de­tect­ing ovar­ian can­cer, in its ear­li­est stages. One study, pub­lished in the Pro­ceed­ings of the Na­tional Academy of Sciences of the United States of Amer­ica, com­pared the lev­els of four pro­teins in healthy women, with lev­els in women di­ag­nosed with ovar­ian can­cer. Among the women who had ovar­ian can­cer, there was sig­nif­i­cant el­e­va­tion of two pro­teins and re­duced lev­els of two oth­ers. The test cor­rectly dif­fer­en­ti­ated the women who had can­cer from those who didn’t 95 per cent of the time. But un­til a more spe­cific test is de­vel­oped, re­searchers say it’s still too soon to leap from the suc­cess of th­ese early re­sults to screen­ing women in the gen­eral pop­u­la­tion. It’s hoped that fur­ther pro­teomic dis­cov­er­ies can make it pos­si­ble to ac­cu­rately de­tect ovar­ian can­cer at its ear­li­est stages. As knowl­edge is gained about pro­teins and their role in de­ter­min­ing health, re­searchers look for­ward to the day when there can be a more per­son­al­ized ap­proach to treat­ing dis­ease. Re­searchers say they hope to see per­son­al­ized medicine in use within the next gen­er­a­tion.

Pro­teomics is the study of pro­teins en­coded by genes – not pro­teins as a nu­tri­tional el­e­ment, but rather pro­teins as ac­tors within the body’s mo­mentto-mo­ment bi­o­log­i­cal pro­cesses.

PRO­TEOMICS GE­NOMICS VS.

Ad­dress­ing the unique chal­lenges each study poses The big­gest con­cep­tual chal­lenge in­her­ent in pro­teomics lies in the pro­teome’s in­creased de­gree of com­plex­ity com­pared to the genome. For ex­am­ple: ONE GENE CAN EN­CODE MORE THAN ONE PRO­TEIN (even up to 1,000). The hu­man genome con­tains about 21,000 pro­tein-en­cod­ing genes, but the to­tal num­ber of pro­teins in hu­man cells is es­ti­mated to be be­tween 250,000 to one mil­lion. PRO­TEINS ARE DY­NAMIC. Pro­teins are con­tin­u­ally un­der­go­ing changes, e.g., bind­ing to the cell mem­brane, part­ner­ing with other pro­teins to form com­plexes, or un­der­go­ing syn­the­sis and degra­da­tion. The genome, on the other hand, is rel­a­tively static. PRO­TEINS ARE CO- AND POSTTRANSLATIONALLY MOD­I­FIED. As a re­sult, the types of pro­teins mea­sured can vary con­sid­er­ably from one per­son to an­other un­der dif­fer­ent en­vi­ron­men­tal con­di­tions, or even within the same per­son at dif­fer­ent ages or states of health. Ad­di­tion­ally, cer­tain mod­i­fi­ca­tions can reg­u­late the dy­nam­ics of pro­teins. PRO­TEINS EX­IST IN A WIDE RANGE OF CON­CEN­TRA­TIONS IN THE BODY. For ex­am­ple, the con­cen­tra­tion of the pro­tein al­bu­min in blood is more than a bil­lion times greater than that of in­ter­leukin-6, mak­ing it ex­tremely dif­fi­cult to de­tect the low abun­dance pro­teins in a com­plex bi­o­log­i­cal ma­trix such as blood. Sci­en­tists be­lieve that the most im­por­tant pro­teins for can­cer may be those found in the low­est con­cen­tra­tions.

AP­PLY­ING PRO­TEOMICS TO MEDICINE

Pro­teomic tech­nolo­gies will play an im­por­tant role in drug dis­cov­ery, di­ag­nos­tics and molec­u­lar medicine be­cause is the link be­tween genes, pro­teins and dis­ease. As re­searchers study de­fec­tive pro­teins that cause par­tic­u­lar dis­eases, their find­ings will help de­velop new drugs that ei­ther al­ter the shape of a de­fec­tive pro­tein or mimic a miss­ing one.  Al­ready, many of the best­selling drugs to­day ei­ther act by tar­get­ing pro­teins or are pro­teins them­selves. Ad­vances in pro­teomics may help sci­en­tists even­tu­ally cre­ate med­i­ca­tions that are “per­son­al­ized” for dif­fer­ent in­di­vid­u­als to be more ef­fec­tive and have fewer side ef­fects. Cur­rent re­search is look­ing at pro­tein fam­i­lies linked to dis­eases in­clud­ing can­cer, di­a­betes and heart dis­ease.  Iden­ti­fy­ing unique pat­terns of pro­tein ex­pres­sion, or biomark­ers, as­so­ci­ated with spe­cific dis­eases is one of the most promis­ing ar­eas of clin­i­cal pro­teomics. One of the first biomark­ers used in dis­ease di­ag­no­sis was prostate-spe­cific anti­gen (PSA). To­day, serum PSA lev­els are com­monly used in di­ag­nos­ing prostate can­cer in men. Un­for­tu­nately, many sin­gle pro­tein biomark­ers have proven to be un­re­li­able. Re­searchers are now de­vel­op­ing di­ag­nos­tic tests that si­mul­ta­ne­ously an­a­lyze the ex­pres­sion of mul­ti­ple pro­teins in hopes of im­prov­ing the speci­ficity and sen­si­tiv­ity of th­ese types of as­says.  Nan­otech­nol­ogy is the cre­ation of man­u­fac­tur­ing de­vices and com­po­nents that range from 1 to 100 nanome­ters. A nanome­ter is one bil­lionth of a me­ter, or 1/ the width of a 80,000 hu­man hair. Nan­otech­nol­ogy de­vices have the po­ten­tial to greatly ex­pand the ca­pa­bil­i­ties of pro­teomics, ad­dress­ing cur­rent lim­i­ta­tions in se­lec­tively reach­ing a tar­get pro­tein in vivo through phys­i­cal and bi­o­log­i­cal bar­ri­ers, de­tect­ing low abun­dance tar­gets, and pro­vid­ing a “tool­box” to trans­late the dis­cov­ery of pro­tein biomark­ers to novel ther­a­peu­tic and di­ag­nos­tic tests. Typ­i­cal nano-de­vices in­clude nanopar­ti­cles used for the tar­geted de­liv­ery of an­ti­cancer drugs, en­ergy-based ther­a­peu­tics (in­clud­ing heat and ra­di­a­tion) and imag­ing con­trast reagents. Nanowires and nanocan­tilever ar­rays can be used in biosen­sors that mea­sure minute quan­ti­ties of biomark­ers in bi­o­log­i­cal fluid.

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