Mov­ing to­wards per­son­al­ized cancer ther­apy

The “magic bul­let” for the treat­ment of spe­cific dis­eases has been the holy grail of medicine since the dis­cov­ery of ar­sphenamine for the treat­ment of syphilis by Paul Er­lich in the early 20th cen­tury. Over the last five decades, the cu­mu­la­tive ef­forts of

BioSpectrum (Asia) - - BIO CONTENT - Dr Hsieh Wen-Son, Med­i­cal On­col­ogy Spe­cial­ist, Icon SOC Far­rer Park Med­i­cal Clinic, Sin­ga­pore

In the late 1990’s, the first de­signer tar­geted anti-cancer Glivec came into use as a re­sult of un­der­stand­ing of the causative role of the fu­sion pro­tein BCR-ABL in chronic myel­oge­nous leukaemia (CML). Glivec specif­i­cally in­hibits the ty­ro­sine ki­nase do­main of BCR-ABL, pre­vent­ing the ac­ti­va­tion of in­tra­cel­lu­lar sig­nalling which is re­spon­si­ble for the ma­lig­nant trans­for­ma­tion of the CML cell. Glivec turned a dis­ease with low cure rates and rel­a­tively toxic treat­ments, such as in­ter­feron and al­lo­geneic stem cell trans­plants, into a highly cur­able and con­trol­lable dis­ease with low treat­ment re­lated tox­i­c­i­ties.

Fol­low­ing the re­sound­ing suc­cess of Glivec, nu­mer­ous ad­vances have been made in the treat­ment of other can­cers. Nowhere has the ef­fect been as dra­matic as non-small cell lung cancer. In the early part of the 21st cen­tury, the treat­ment of metastatic non-small cell lung cancer had made lit­tle ad­vance over the pre­vi­ous two decades. A large trial in­volv­ing over a thou­sand pa­tients with stage IV non-small cell lung cancer com­par­ing four dif­fer­ent reg­i­mens of chemo­ther­apy showed rel­a­tively unin­spir­ing av­er­age sur­vival times of eight to 10 months. Since then, a num­ber of tar­getable onco­gene driv­ers have been dis­cov­ered in non-small cell lung cancer. Treat­ment of these onco­gene driven tu­mours – with spe­cific small mol­e­cules in­hibit­ing ac­ti­vated en­zymes re­sult­ing from these gene mu­ta­tions – re­sult in higher rates of cancer shrink­age and longer pe­ri­ods of cancer con­trol with much less side ef­fects than with tra­di­tional cy­to­toxic chemo­ther­apy. The first of these mu­ta­tions, those in the epi­der­mal growth fac­tor ty­ro­sine ki­nase do­main (EGFR TK), were found in 2005 and we now have

four such in­hibitors in clin­i­cal use and four to five more in clin­i­cal de­vel­op­ment. Iressa and Tarceva are first gen­er­a­tion EGFR TK in­hibitors. Gilotrif and Ta­grisso are sec­ond and third gen­er­a­tion in­hibitors. Use of these in­hibitors have in­creased the sur­vival of pa­tients with metastatic EGFR TK mu­tated non­s­mall cell lung cancer from an av­er­age of eight to 10 months to three to five years. A num­ber of other driver onco­genes have been iden­ti­fied and small mol­e­cule in­hibitors dis­cov­ered. These driver onco­genes in­clude re­arrange­ments of EML4-ALK, RET, and ROS1 as well as mu­ta­tions in Braf (V600E). Treat­ment of the lung can­cers with these mu­ta­tions with the spe­cific in­hibitors have sim­i­larly im­proved re­sults as those with EGFR TK in­hibitors in EGFR TK mu­tated lung


An­other ad­vance­ment in the treat­ment of metastatic lung cancer is the de­vel­op­ment of im­munother­apy. Dis­cov­ery of the reg­u­la­tors of the im­mune sys­tem and the fac­tors that lead to an anti-tu­mour im­mune re­sponse has also led to the de­vel­op­ment of more ef­fec­tive and less toxic im­munother­a­pies. Cy­tokines such as in­ter­feron and In­ter­leukin-2 have been used for the last three decades to treat tu­mours such as CML and re­nal cell car­ci­noma with limited ef­fec­tive­ness and fre­quent se­ri­ous side ef­fects. An­tiCTLA4 an­ti­bod­ies (Ipilu­mumab) demon­strated the abil­ity to in­duce po­tent anti-tu­mour im­mune re­sponses in pa­tients with metastatic melanoma, re­sult­ing in cures in a sub­set of pa­tients with a pre­vi­ously in­cur­able dis­ease. An­ti­bod­ies against the pro­grammed death-1 (PD1) mol­e­cule came into rou­tine clin­i­cal use four years ago and is now a stan­dard of care treat­ment for a num­ber of dif­fer­ent tu­mour types in­clud­ing lung cancer, melanoma, re­nal cell car­ci­noma, hep­a­to­cel­lu­lar car­ci­noma, tran­si­tional cell car­ci­noma of the blad­der, and squa­mous cell car­ci­noma of the head and neck.

The PD1 path­way is im­por­tant in pre­vent­ing au­toim­mu­nity and pre­vent­ing the re­jec­tion of trans­planted or­gans. How­ever, tu­mours have co-opted the PD1 path­way to evade anti-tu­mour im­mune re­sponses. Block­ade of the PD1 path­way re­sult in po­tent and long last­ing anti-cancer im­mune re­sponses in a sub­set of cancer pa­tients with rel­a­tively few se­ri­ous side ef­fects. In about 20 per cent of pa­tients with pre­vi­ously un­treated metastatic lung cancer iden­ti­fied by high lev­els of ex­pres­sion of the pro­grammed death lig­and on tu­mour tis­sue, treat­ment with anti-PD1 an­ti­bod­ies is su­pe­rior to chemo­ther­apy in terms of rates of tu­mour shrink­age, dis­ease con­trol, and sur­vival. Anti-PD1 an­ti­bod­ies are also bet­ter than other treat­ments in pre­vi­ously treated lung cancer. By adding Ipilu­mumab to anti-PD1 an­ti­bod­ies, one can im­prove the ther­a­peu­tic ben­e­fit of im­munother­apy at the cost of more side ef­fects. How­ever, fur­ther clin­i­cal tri­als are on­go­ing with novel com­bi­na­tions of im­munother­a­pies to im­prove ef­fi­cacy while re­duc­ing side ef­fects. In ad­di­tion to the ad­van­tages of good prob­a­bil­ity of dis­ease con­trol with low rates of se­ri­ous side ef­fects, im­munother­apy also has the ad­van­tage of pro­longed dis­ease con­trol which can last for a num­ber of years af­ter ces­sa­tion of treat­ment due to an on­go­ing ac­tive im­mune re­sponse against the tu­mour.

Lung cancer is an im­por­tant dis­ease in Asia due to the epi­demi­ol­ogy of the dis­ease and the molec­u­lar char­ac­ter­is­tics of the lung cancer found in Asia.

Firstly, the large pop­u­la­tion in Asia, fre­quency of to­bacco use and the en­vi­ron­men­tal pol­lu­tion as­so­ci­ated with rapid in­dus­tri­al­iza­tion will cause an epi­demic of lung cancer in Asia in the com­ing years. Se­condly, for rea­sons that are not com­pletely clear, there is also a much higher rate of lung cancer in non-smok­ers in Asia which are of­ten onco­gene driven and can be treated molec­u­larly tar­geted ther­a­pies as de­scribed above. The large tri­als which demon­strate the ben­e­fit of such ther­a­pies have largely been con­ducted in Asia. Due to these fac­tors, the de­vel­op­ment of lung cancer ther­apy will be­come more fo­cused in Asia.

None of these ad­vances would be pos­si­ble with­out care­fully con­ducted ba­sic and clin­i­cal re­search.

Hav­ing been in­volved in lab­o­ra­tory and clin­i­cal re­search for the last two decades, it has been grat­i­fy­ing to see the re­sults of ba­sic un­der­stand­ing of tu­mour bi­ol­ogy trans­lated into bet­ter test­ing and treat­ments for pa­tients. It is an it­er­a­tive process where hy­poth­e­sis are tested in the lab­o­ra­tory and the re­sults are ap­plied to de­sign treat­ments for pa­tients. The clin­i­cal tri­als are then con­ducted to test for the safety and ef­fi­cacy of the novel treat­ments, cul­mi­nat­ing in large ran­dom­ized tri­als which test the novel treat­ment ei­ther in com­bi­na­tion with stan­dard ther­apy or in com­par­i­son with the cur­rent stan­dard of care. Ob­ser­va­tions and hy­poth­e­sis are then taken back to the lab­o­ra­tory to fur­ther im­prove out­comes. For ex­am­ple, the EGFR TK in­hibitors were syn­the­sized to tar­get the EGFR path­way in gen­eral be­fore EGFR TK mu­ta­tion were even known. How­ever, when only a sub­set of pa­tients seem to re­spond to these med­i­ca­tions, fur­ther test­ing was done and the EFGR TK mu­ta­tions were dis­cov­ered. The EGFR TK mu­ta­tions are now the sin­gle pre­dic­tor of ben­e­fit to EGFR TKIs. Through this process, we can achieve the goal of per­son­al­ized cancer ther­apy.

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