Com­bat­ting cancer drug re­sis­tance

The race to find more ef­fec­tive and ef­fi­cient cancer treat­ments

The McGill Daily - - Sci+Tech - Na­dia Boachie The Mcgill Daily

There are sev­eral treat­ment op­tions that ex­ist for cancer pa­tients today which were not avail­able a decade ago. Many of th­ese treat­ments are suc­cess­ful and are able to erad­i­cate the cancer, thereby send­ing pa­tients into re­mis­sion. But more of­ten than not, tu­mours re- emerge. Drug re­sis­tance is the re­sult of dis­eases be­com­ing tol­er­ant of phar­ma­ceu­ti­cal treat­ments, and is a ma­jor hur­dle that must be over­come in cancer re­search. Can­cers are liv­ing and evolv­ing be­ings; they ex­hibit a very high “plas­tic­ity,” which is the abil­ity to mu­tate and adapt to new en­vi­ron­men­tal con­di­tions. Re­searchers are try­ing to un­der­stand the rapid mu­ta­tions that oc­cur in cancer genes that en­able them to be­come drug re­sis­tant.

Dr. Janusz Rak is a se­nior sci­en­tist at the Re­search In­sti­tute of the Mcgill Uni­ver­sity Health Cen­tre (RI-MUHC) in the Child Health and Hu­man De­vel­op­ment Pro­gram, and a Pro­fes­sor in the Depart­ment of Pe­di­atrics, Divi­sion of Ex­per­i­men­tal Medicine at Mcgill Uni­ver­sity. Rak de­scribes the two types of drug re­sis­tance as the fol­low­ing:

The first type has “ac­quired re­sis­tance,” which means that a drug that once worked for a given pa­tient no longer works af­ter a pe­riod of time. He ex­plains that this is “a prob­lem that es­sen­tially de­fines the in­cur­abil­ity of cer­tain can­cers.” There are sev­eral chemother­a­peu­tic drugs that are used to treat spe­cific can­cers, but are prone to be­com­ing in­ef­fec­tive over time. Ve­mu­rafenib is an ex­am­ple of a very ef­fec­tive drug used to treat cer­tain types of ma­lig­nant melanoma (skin cancer). It op­er­ates by in­hibit­ing a mu­tant BRAF onco­gene (a type of gene that has the po­ten­tial to cause cancer, usu­ally ex­pressed at high lev­els in cancer pa­tients). Ini­tially, th­ese drugs are ef­fec­tive in shrink­ing tu­mours or even caus­ing their com­plete erad­i­ca­tion, but the ef­fects are short- lived. Tu­mour re­sis­tance to th­ese drugs usu­ally starts with rapid tu­mour shrink­age, which leaves pa­tients feel­ing hope­ful, but it is then fol­lowed by the re­growth of th­ese tu­mours weeks or months later.

The sec­ond type of drug re­sis­tance is called “de novo,” or “in­trin­sic re­sis­tance,” and in­volves drugs that are ex­pected to work but don’t af­fect a given pa­tient at all. This type of drug re­sis­tance ex­ists from the very start of treat­ment. The in­creas­ing preva­lence of th­ese drug re­sis­tant can­cers ne­ces­si­tates fur­ther re­search and treat­ment de­vel­op­ment.

How can­cers evade chemo­ther­apy drugs

The prob­lem with drug re­sis­tance is more re­lated to cancer cells and their bi­o­log­i­cal sur­round­ings than to the drugs them­selves. Some of th­ese eva­sion tac­tics in­clude DNA mu­ta­tions and meta­bolic changes which pro­mote drug in­hi­bi­tion and degra­da­tion. There are a few ma­jor cat­e­gories of mech­a­nisms that can en­able or pro­mote di­rect or in­di­rect drug re­sis­tance in hu­man cancer cells. They in­clude drug ac­ti­va­tion, drug tar­get al­ter­ation, drug ef­flux, DNA dam­age re­pair, cell death in­hi­bi­tion, and the ep­ithe­lial-mes­enchy­mal tran­si­tion (EMT), ac­cord­ing to a re­view pub­lished in the journal Can­cers in 2014. They can act in­de­pen­dently or as a com­bi­na­tion of var­i­ous sig­nal trans­duc­tion path­ways.

The mech­a­nisms in which can­cers evade treat­ments are nu­mer­ous and highly com­plex. For ex­am­ple, DNA dam­age re­pair is a way cancer cells evolve an abil­ity to “re­pair” the dam­age that chemother­a­peu­tics have on cel­lu­lar DNA. Rak ex­plains that “for a frac­tion of glioma ( brain tu­mours), pa­tients’ cancer cells ex­press an en­zyme which re­moves cer­tain dam­aged el­e­ments in DNA, and there­fore pre­vents cancer cell from be­ing killed by the drug called temo­zolo­mide.”

How doc­tors are com­bat­ting drug re­sis­tance of can­cers

Doc­tors are try­ing to over­come drug re­sis­tance by us­ing com­bi­na­tion ther­apy. This in­volves treat­ing cancer with many drugs at once, or in spe­cific se­quences. It is a treat­ment modal­ity that com­bines two or more ther­a­peu­tic agents, and it is a cor­ner­stone of cancer ther­apy. Rak ex­plains that, “com­bin­ing drugs could also ex­ploit dif­fer­ent weak­nesses of cancer cells and be­come syn­er­gis­tic, that is, more ef­fec­tive than a sum of ef­fects associated with in­di­vid­ual drugs.” Com­bi­na­tion ther­apy re­duces drug re­sis­tance, while si­mul­ta­ne­ously pro­vid­ing ther­a­peu­tic anti- cancer ben­e­fits, such as re­duc­ing tu­mour growth and metastatic po­ten­tial, ar­rest­ing mi­tot­i­cally (di­vid­ing) ac­tive cells, re­duc­ing cancer stem cell pop­u­la­tions, and in­duc­ing apop­to­sis (self­pro­grammed cell death).

Com­bi­na­tion ther­apy in­cludes treat­ments of pa­tients with im­munother­a­peu­tic agents. Doc­tors com­bat drug re­sis­tance by chang­ing drugs, com­bin­ing them, and us­ing new ther­a­peu­tic modal­i­ties, such as im­munother­apy, to try to erad­i­cate cancer cells.

Im­munother­apy, also called bi­o­logic ther­apy, is a type of cancer treat­ment that boosts the body’s nat­u­ral de­fenses against can­cers. It is a way of mo­bi­liz­ing the im­mune sys­tem to kill cancer cells. It uses sub­stances made ei­ther by the body or in a lab­o­ra­tory to im­prove or re­store im­mune sys­tem func­tions. This could be achieved ei­ther by vac­cines, or by re­moval of im­muno­sup­pres­sive ef­fects of cancer on the im­mune sys­tem, or by en­gi­neer­ing T cells, a sub­type of white blood cells that play a cen­tral role in cell-me­di­ated im­mu­nity, to kill spe­cific can­cers.

“The big ques­tion is whether it’s the tu­mour cells that are be­com­ing re­sis­tant, or whether the im­mune sys­tem is be­com­ing dys­func­tional, or a com­bi­na­tion of both,” says Dr. Jesse Zaret­sky Uni­ver­sity of Cal­i­for­nia, Los An­ge­les.

Dr. Rak be­lieves “it is prob­a­bly a bit of both.” Tu­mours are ex­er­cis­ing their abil­ity to be­come re­sis­tant but pa­tients may si­mul­ta­ne­ously be ex­pe­ri­enc­ing a dys­func­tional im­mune sys­tem.

Im­munother­apy treat­ments work in dif­fer­ent ways. Some boost the body’s im­mune sys­tem, while oth­ers help train the im­mune sys­tem to at­tack cancer cells specif­i­cally. Im­munother­apy works for some can­cers bet­ter than oth­ers and can be used by it­self or in com­bi­na­tion with other treat­ments.

Some of the lat­est ad­vances in re­search on im­munother­a­pies in­volve check­point in­hibitors to treat cancer. The im­mune sys­tem has check­point pro­teins (such as PD-1 and CTLA-4) which pre­vent it from at­tack­ing the healthy cells. One way can­cers de­velop re­sis­tance is by tak­ing ad­van­tage of th­ese check­points to avoid be­ing at­tacked by the im­mune sys­tem. Check­point in­hibitors have shown im­pres­sive suc­cess in re­cent years; pa­tients with metastatic melanoma as well as those with non-small cell lung cancer are show­ing prom­ise in clin­i­cal tri­als.

Com­bi­na­tion treat­ments and re­search on im­munother­a­pies have shown a lot of po­ten­tial. There is a wealth of hu­man cre­ativ­ity in­volved, and the progress made has been tremen­dous. But de­spite ad­vances in im­munother­a­pies and molec­u­lar-tar­geted ther­a­pies, chemo­ther­apy is still a front­line treat­ment for many can­cers. Re­searchers have been ham­pered by the lack of biomark­ers to pre­dict whether a pa­tient is re­sis­tant to th­ese treat­ments, in which case the ex­po­sure to chemo­ther­apy and its tox­i­c­ity would be un­war­ranted.

The is­sue of cancer drug re­sis­tance is a daunt­ing one, and it is per­ti­nent that more re­search is con­ducted about ways can­cers evade chemother­a­peu­tic treat­ments. Rak ex­presses the need to come up with ef­fec­tive and ef­fi­cient drugs: “As many oth­ers, I per­son­ally be­lieve that for­ma­tion of cancer cells with their enor­mous growth ad­van­tage and abil­ity to spread comes at a cost of cer­tain vul­ner­a­bil­i­ties. Find­ing th­ese cancer vul­ner­a­bil­i­ties is a great way to com­bat or cir­cum­vent drug re­sis­tance.”

Im­munother­apy, specif­i­cally im­mune check­point ther­apy, is one ex­am­ple of an area of cancer re­search that shows prom­ise in com­bat­ing cancer drug re­sis­tance. There needs to be fur­ther re­search to over­come the daunt­ing preva­lence rate of cancer drug re­sis­tance.

There are sev­eral labs at Mcgill which con­duct stud­ies on cancer drug re­sis­tance and im­munother­a­pies. For more in­for­ma­tion on Mcgill labs that con­duct this re­search, check out the funded projects at Good­man Cancer Re­search Cen­tre, Lady Davis In­sti­tute, RI-MUHC, and other sites.

Nelly Wat | The Mcgill Daily

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