WAR AGAINST CAN­CER

RE­SEARCH ON THE DIS­EASE IS AT THE TIP­PING POINT OF MA­JOR BREAK­THROUGHS. AD­VANCES IN GENE SE­QUENC­ING, IN­NO­VA­TIVE DI­AG­NOS­TICS OPEN UP A WHOLE NEW WORLD OF POS­SI­BIL­I­TIES FOR TREAT­MENT IN IN­DIA

India Today - - INSIDE - BY DA­MAYANTI DATTA

New break­throughs in drugs and ther­a­pies might make it pos­si­ble to con­quer the deadly dis­ease

He was a ruggedly hand­some man in life: shirt un­but­toned, mus­cles rip­pling, cig­a­rette dan­gling rak­ishly from his lips. He was un­recog­nis­able in death: pinched, pale, al­most skele­tal. For those who knew him on­screen, there was shock and de­spair at the fi­nal ter­ror of his ill­ness. Vinod Khanna, one of the last screen ti­tans of a gen­er­a­tion, bat­tled a lethal form of blad­der can­cer, re­sis­tant to chemo­ther­apy, for six long years and fi­nally suc­cumbed on April 27. That very week, how­ever, the world of sci­ence cel­e­brated a “huge break­through”: the dis­cov­ery of a new drug based on malaria pro­teins that can dra­mat­i­cally re­duce hardto-treat blad­der can­cers.

Another break­through, another life. “It’s fi­nally here. A new ray of hope in the field of can­cer. ‘Nivolumab’ for ag­gres­sive Hodgkin’s lym­phoma. Spread t word.” Mamta Mohandas, 32, calls her­self ‘Ac­tor. Singer. Sur­vivor’ on Twit­ter and posts mes­sages of hope to her 495K fol­low­ers. Her ris­ing ca­reer graph in Malay­alam and Tel­ugu cinema, de­spite her seven-year-long fight against an ag­gres­sive lymph can­cer, Dif­fuse Large B-Cell Lym­phoma, is leg­end. Ever

since she joined a clin­i­cal trial for an ex­per­i­men­tal drug in Los An­ge­les, USA, the south­ern beauty has been up­beat. “It’s work­ing for me,” she in­forms her fans. “Brave girl”, “love u”, “jaldi aaja”, they re­spond.

TIME OF BREAK­THROUGHS

It is the best of times, it is the worst of times, on the can­cer front. Sci­en­tists con­tinue to be baf­fled by the com­plex­ity and smart­ness of can­cer cells: that they find ways to dodge even the most pow­er­ful ther­a­pies, that ‘can­cer’ en­com­passes not one but hun­dreds of dis­tinct dis­eases, that each in­di­vid­ual can­cer be­haves dif­fer­ently, that two peo­ple with the same can­cer, at the same stage, re­ceiv­ing the same treat­ment, can ex­pe­ri­ence rad­i­cally dif­fer­ent out­comes. As US-based on­col­o­gist and Pulitzer­win­ning writer Dr Sid­dhartha Mukher­jee says, “All can­cers are alike, but they are alike in a unique way.” With all that, can­cer is catch­ing up with heart dis­ease as the lead­ing cause of deaths glob­ally, re­ports the World Health Or­ga­ni­za­tion. In In­dia, the lat­est study based on the Na­tional Can­cer Registry shows that there are 1.45 mil­lion new cases ev­ery year, a preva­lence of over 3 mil­lion at any point of time, over 680,000 deaths a year. Al­though early de­tec­tion saves lives, just 12.5 per cent In­di­ans call on a doc­tor in the early stages.

But it’s also a time of ex­cep­tional break­throughs and in­no­va­tions. No, there is no sin­gle death-de­fy­ing magic bul­let, but new gen­er­a­tions of life-sav­ing and life-ex­tend­ing ‘smart drugs’ are cur­rently be­ing de­vel­oped and tested. At the root of all this is the idea that the cure for can­cer is in­side the pa­tient. And the mantra in labs around the world is ‘pre­ci­sion medicine’. That is, a line of treat­ment that is per­son­alised to a pa­tient’s ge­netic make-up or molec­u­lar changes within one’s tu­mour. Up un­til now, ther­a­pies have all been geared to treat can­cer based on where it is lo­cated, say, in the breast, blad­der or lung. Now, the shift is in­creas­ingly ev­i­dent in find­ing pre­ci­sion medicine tar­geted at ge­netic glitches. On May 23, in a first, a can­cer drug has won ap­proval from the US Food and Drug Ad­min­is­tra­tion (USFDA) that can be given to any­one who har­bours spe­cific ge­netic ab­nor­mal­i­ties found in as many as 15 dif­fer­ent types of can­cers— all in pa­tients for whom tra­di­tional treat­ment, like chemo­ther­apy, has failed.

There has not been so much ex­cite­ment as there is now since 2001, when one of the first can­cer ther­a­pies to show the po­ten­tial for tar­geted ac­tion, Ima­tinib, was ap­proved. Thou­sands of clin­i­cal tri­als are hum­ming with promis­ing drug pipe­lines, many of

which are be­ing used by doc­tors to ben­e­fit pa­tients. “It’s an ex­cit­ing time,” says Dr Anil Suri, direc­tor of the Na­tional In­sti­tute of Im­munol­ogy in Delhi and the man who dis­cov­ered SPAG9, the can­cer anti­gen to be used in In­dia’s first anti-can­cer vac­cine, now un­der phase II clin­i­cal trial in cer­vi­cal can­cer pa­tients. “Can­cer re­search is at the tip­ping point of ma­jor break­throughs. Ad­vances in molec­u­lar bi­ol­ogy, next-gen­er­a­tion gene se­quenc­ing, big data and in­no­va­tive di­ag­nos­tics are open­ing up a whole new world of pos­si­bil­i­ties.”

THE PAR­A­DIGM SHIFTS

The war on can­cer is now look­ing within, at the pa­tient’s own ar­se­nal of weapons: genes, mol­e­cules and the im­mune sys­tem. The con­ven­tional reg­i­men of surgery-ra­dio­ther­apy-chemo­ther­apy is slowly but surely giv­ing way to tar­geted, per­son­alised treat­ments and more in­tri­cate di­ag­nos­tic tools. Com­bi­na­tion ther­a­pies to keep can­cers in check are be­ing worked upon. The emerg­ing field of can­cer im­munother­apy, or us­ing the body’s own im­mune sys­tem to help fight off the dis­ease, is es­pe­cially promis­ing. Of the 30 new drugs for more than a dozen dif­fer­ent types of can­cers ap­proved by the USFDA in the past one year, al­most all are in im­munother­apy. In­dian sci­en­tists, too, are en­gaged in the bat­tle to un­lock the an­swers on how to pre­vent, de­tect and treat pa­tients, in the best ex­am­ple of ‘Make in In­dia’.

A par­a­digm shift is tak­ing place, with the ap­proach mov­ing to­ward a reg­i­men where can­cer may not have to be cured, but con­trolled, say, like di­a­betes or heart dis­ease, ex­plains Dr Mam­men Chandy, direc­tor of Tata Med­i­cal Cen­tre, Kolkata, and chair of the Hu­man Genome Task Force of the depart­ment of biotech­nol­ogy (DBT), Union ministry for sci­ence and tech­nol­ogy. “With greater knowl­edge of the molec­u­lar ge­net­ics of can­cer, we can study ge­netic mu­ta­tions in a pa­tient and tar­get these with spe­cific drugs,” he says. A whole range of new drugs to­day can shrink and kill can­cer cells with­out col­lat­eral dam­age. “We can pre­cisely quan­tify the ex­tent of the dis­ease at di­ag­no­sis with bet­ter imag­ing tech­niques.” The pre­ci­sion and ac­cu­racy of ra­di­a­tion tech­nol­ogy make it pos­si­ble to hit tu­mours with min­i­mal dam­age to sur­round­ing nor­mal cells. “In sev­eral can­cers, a pa­tient can now pop a pill a day and live a nor­mal life for many years. We are, thus, con­vert­ing can­cer into a chronic dis­ease that one can live with.”

LAN­GUAGE OF GENES

ATCG. ATCG. AGGCCTT. Oops, a ty­po­graph­i­cal er­ror. A tiny mis­take can change the mean­ing of a sen­tence. What if there’s a typo in your genes? Imag-

ine a so­cial net­work hum­ming in each of your 37.2 tril­lion cells, with up to 100,000 genes talk­ing to each other in a chem­i­cal code of four let­ters, A,T, C and G—to post, copy, tweak, re­peat, adapt, mod­ify mes­sages and in­struc­tions con­stantly—for you to func­tion. The proof­read­ing tools in­side cells cor­rect some ty­pos, junk many, but some get over­looked. And they fes­ter. Like fake news on so­cial me­dia, they spread lies, send­ing wrong sig­nals to other cells giv­ing rise to a se­ries of mis­takes, some­times pro­foundly al­ter­ing the bi­ol­ogy of cells. If 10 mil­lion cells re­peat the same er­ror, a tu­mour forms—as big as the head of a pin—and starts shed­ding bits of its genes into the blood­stream, like a trail of bread crumbs.

Fran­cis S. Collins, ge­neti­cist and head of the Na­tional In­sti­tutes of Health, US, wrote in his book Lan­guage of God: A Sci­en­tist Presents Ev­i­dence for Be­lief: “Sci­ence re­veals that the uni­verse, our own planet and life it­self are en­gaged in an evo­lu­tion­ary process. The con­se­quences of that can in­clude the un­pre­dictabil­ity of the weather, the slip­page of a tec­tonic plate, or the mis­spelling of a can­cer gene in the nor­mal process of cell di­vi­sion.” With the Hu­man Genome Project (HGP), a mas­sive in­ter­na­tional ef­fort to un­lock the se­crets of our ge­netic script, tak­ing off in 1991, can­cer re­search got a mas­sive leg up. Genes could be iso­lated from cells in pure form, an­a­lysed in full de­tail, mul­ti­plied man­i­fold in the lab, changed at will. They could also be used to dis­cover de­fects in the blue­print of one’s body and to take proac­tive mea­sures to stem the con­se­quences—most sig­nif­i­cantly, the pro­cesses that give rise to can­cers. The 2015 No­bel Prize in Chemistry was awarded to three sci­en­tists for ex­plain­ing pre­cisely how cells make mis­takes, re­pair those and pre­dis­pose peo­ple to can­cer when re­pair mech­a­nisms fail.

THE NEW STRAT­EGY

Now can­cer re­searchers from Johns Hop­kins Univer­sity and Har­vard Med­i­cal School have pub­lished a new study on the bi­ol­ogy of can­cer cells (Sci­ence, March 2017) that has kicked up a new de­bate. Based on the math­e­mat­i­cal mod­el­ling of 32 types of can­cers from 69 coun­tries, they ar­gue that about 66 per cent of can­cers oc­cur due to ran­dom mis­takes dur­ing cell di­vi­sion, with only 29 per cent due to en­vi­ron­men­tal fac­tors (say, smok­ing or sun ex­po­sure) and 5 per cent to in­her­ited ge­netic traits. These per­cent­ages, how­ever, vary from can­cer to can­cer. In some lung tu­mours, en­vi­ron­men­tal fac-

tors ac­count for 65 per cent, while in prostate, brain and bone can­cers, more than 95 per cent are due to ran­dom er­rors in cells. The study, de­spite the fears that its con­clu­sions would un­der­cut pre­ven­tion ef­forts, has evoked the need for a new strat­egy, one that would em­pha­sise early de­tec­tion and treat­ment, in ad­di­tion to pre­ven­tion.

The prob­lem with early de­tec­tion is that when tu­mours form, they do not shed enough of a “bread crumbs trail” that can be picked up by CT-MRI-PET scans or by nee­dle biop­sies for pos­si­ble ma­lig­nancy. But what if can­cer can be de­tected at such an early stage? The idea of a sim­ple blood test as an al­ter­na­tive has come up re­cently. In In­dia, Ben­galuru-based ge­netic di­ag­nos­tics com­pany, Strand Life Sciences, has started of­fer­ing the first phase of liq­uid biop­sies: a sim­ple, non-in­va­sive di­ag­nos­tic test us­ing cir­cu­lat­ing tu­mour genes in a pa­tient’s blood, the first such test in In­dia. “In the case of can­cer pa­tients, such blood tests can pro­vide early in­for­ma­tion about tu­mour pres­ence, re­lapse af­ter ther­apy and re­sponse to ther­apy,” ex­plains Dr Vi­jay Chan­dru, CEO of Strand, who launched the test in April in as­so­ci­a­tion with the Mazum­dar Shaw Cen­tre for Trans­la­tional Re­search, also in Ben­galuru.

But what about ther­a­pies? Ever since for­mer US pres­i­dent Jimmy Carter an­nounced in 2015 that he was free of a deadly form of skin can­cer af­ter re­ceiv­ing surgery, ra­di­a­tion and “a new kind of treat­ment”, he be­came a poster boy for the ex­cit­ing new field: im­munother­apy. Dr Suri ex­plains that nor­mal cells of the body die when they are not needed, are dam­aged, or are in­fected with virus, bac­te­ria, par­a­sites or fungi. “The im­mune sys­tem, the body’s first line of de­fence, keeps track and as soon as it de­tects any­thing ab­nor­mal or un­known, it at­tacks and kills it,” he says. But can­cer cells trick the im­mune sys­tem into not recog­nis­ing them as a threat. “This al­lows the tu­mours to grow and spread,” he says. In im­munother­apy, the im­mune sys­tem is en­listed to at­tack and force can­cer cells to kill them­selves.

MAKE IN IN­DIA

Where does In­dia stand in all this? In­dian can­cer pa­tients have been the key part­ners in dis­cov­ery of can­cer anti­gen SPAG9, which is be­ing used for per­son­alised in­ter­ven­tion by mod­u­lat­ing the im­mune re­sponse, says Dr Suri. “Most new tech­nolo­gies are avail­able in the coun­try,” says Dr Thangara­jan Ra­jku­mar, head of molec­u­lar on­col­ogy, Can­cer In­sti­tute (WIA), Ad­yar, Chennai. “It is the cost of the newer ther­a­pies that is the ma­jor im­ped­i­ment. But that’s true not only for In­dia. Even some de­vel­oped coun­tries are find­ing it dif­fi­cult to pro­vide can­cer care to peo­ple be­cause of the pro­hib­i­tive costs.” The in­sti­tute is con­duct­ing clin­i­cal tri­als of In­dia’s first ther­a­peu­tic anti-can­cer vac­cine, SPAG9, in col­lab­o­ra­tion with Dr Suri and funded by the depart­ment of biotech­nol­ogy and depart­ment of sci­ence and tech­nol­ogy, Gov­ern­ment of In­dia. “Rather than di­rectly at­tack­ing can­cer cells, this ther­apy in­volves prim­ing a pa­tient’s own im­mune cells to fight the can­cer,” he says. “Our im­mune sys­tem pre­vents most of us from de­vel­op­ing can­cer, but once can­cer de­vel­ops, the im­mune sys­tem be­comes very sub­dued. The newer im­munother­a­pies

are ad­dress­ing pre­cisely this area, with great re­sults.”

With cer­vi­cal can­cer ris­ing dra­mat­i­cally among In­dian women—nearly 23 per cent of all can­cers in women and over 100,000 deaths a year—it might just be a game-changer. One of the pa­tients in­cluded in phase I of the clin­i­cal tri­als at the Can­cer In­sti­tute, whose per­sis­tent cer­vi­cal can­cer had spread to the lungs even af­ter ra­dio­ther­apy, has been dis­ease-free now for over nine years. The vac­cine is be­ing man­u­fac­tured at a world-class in­dus­trial fa­cil­ity, owned by Bio­con. Re­searchers at the in­sti­tute have also de­vel­oped a sim­ple kit for cer­vi­cal can­cer screen­ing, a biomarker panel for early di­ag­no­sis of ovar­ian can­cer and a ther­apy to in­hibit an ag­gres­sive bone can­cer, Ewing’s sar­coma—all await­ing fur­ther ver­i­fi­ca­tion.

“There are ma­jor in­sti­tu­tions across the coun­try work­ing on ba­sic, trans­la­tional and clin­i­cal re­search as ap­plied to can­cer,” says Dr Ra­jku­mar. New and po­ten­tially ther­a­peu­tic mol­e­cules have been iden­ti­fied at the In­dian In­sti­tute of Sci­ence, Ban­ga­lore, he points out. A multi-cen­tre study un­der Pro­fes­sor Partha Majumdar of the Na­tional In­sti­tute of Bio­med­i­cal Ge­nomics at Kalyani, West Ben­gal, and Dr Ra­jiv Sarin of Tata Me­mo­rial Cen­tre’s ACTREC (Ad­vanced Cen­tre for Treat­ment, Re­search and Ed­u­ca­tion in Can­cer) in Mumbai, are do­ing promis­ing work in can­cer ge­nomics. Truly cut­ting edge re­search may be tak­ing place only at a few cen­tres, but at hos­pi­tals and lab­o­ra­to­ries across the coun­try, in­no­va­tive molec­u­lar ge­netic tests, tech­nol­ogy and tech­niques are be­ing used. From next gen­er­a­tion se­quenc­ing (NGS) tech­nol­ogy to de­tect­ing ge­netic change driv­ing a can­cer, molec­u­lar di­ag­no­sis and mon­i­tor­ing, best-in-class ra­dio­ther­apy equip­ment, new small mol­e­cules to specif­i­cally tar­get the tu­mour cells, stem cell trans­plan­ta­tion, hor­mone ther­apy to cel­lu­lar ther­apy, it’s all hap­pen­ing.

RUSH FOR DRUGS

In De­cem­ber 2015, when Jimmy Carter called a press con­fer­ence to an­nounce that he had been cured of his can­cer, the ‘break­through’ im­munother­apy drug, Pem­brolizumab, sold by pharma gi­ant Merck as Keytruda, got a new moniker—“the pres­i­dent’s drug”. Keytruda, along with Bris­tol-My­ers Squibb’s Op­divo (Nivolumab), is one of a grow­ing num­ber of ‘im­muno-onco’ drugs that un­leash the body’s im­mune sys­tem to fight ma­lig­nant cells. Keytruda and Op­divo, ef­fec­tive against some forms of lung, skin, kid­ney and other can­cers, are set to launch in the In­dian mar­ket soon. Pro­hib­i­tively ex­pen­sive, above Rs 1 crore for an en­tire treat­ment, the drugs may not be for the gen­eral pub­lic. But they are shap­ing up to be the big­gest block­busters for the global pharma in­dus­try.

Most patented medicines are un­af­ford­able to the av­er­age pa­tient in In­dia, even if priced lower than their west­ern coun­ter­parts. But In­dian com­pa­nies, with

their track record in generic drugs, are emerg­ing as strong global play­ers in the biosim­i­lar (or ex­act copies of bi­o­log­i­cal medicines that are al­ready ap­proved) seg­ment of molec­u­larly tar­geted can­cer drugs. From Bio­con, Ci­pla, Aurobindo Pharma, Dr Reddy’s Lab­o­ra­to­ries, In­tas Phar­ma­ceu­ti­cals to Hetero Drugs, they are all ex­pand­ing their biosim­i­lar port­fo­lios. Roche has teamed up with Em­cure Phar­ma­ceu­ti­cals to man­u­fac­ture and sell its breast can­cer drug, Her­ceptin, at a re­duced price in In­dia. “Biosim­i­lars have made can­cer treat­ment af­ford­able to the mid­dle class, and most com­pa­nies have com­pas­sion­ate us­age pro­grammes,” says Dr Chandy.

Im­munother­apy is emerg­ing as a ‘sweet spot’ among smaller re­search com­pa­nies as well as in­vestors. Biotech com­pany Auri­gene Dis­cov­ery Tech­nolo­gies of Ben­galuru has got into off-li­cence deals with global pharma com­pa­nies like Curis, Orion and Pierre Fabre for its novel im­munother­apy mol­e­cules. Delhi-based Cu­radev, a drug dis­cov­ery com­pany, has en­tered into col­lab­o­ra­tion with Roche. Ratan Tata, chair­man emer­i­tus of Tata Sons, has in­vested an undis­closed amount in bio­phar­ma­ceu­ti­cal firm In­vic­tus On­col­ogy, Delhi, to de­velop a can­cer tech­nol­ogy plat­form.

THE NEW NEW

Jugnu Jain, molec­u­lar ge­neti­cist, cell bi­ol­o­gist and in­ven­tor with three patents, re­turned to In­dia from the US in 2011 and re­alised, sur­pris­ingly, that In­dia did not have a hu­man biobank. Glob­ally, there are over 350. “Left­over tis­sues from surgery or di­ag­nos­tic pro­ce­dures, say, can­cer tis­sue, blood or urine, are pre­cious,” she says, “highly sought af­ter world­wide by re­searchers, di­ag­nos­tics, biotech and pharma com­pa­nies” to val­i­date their drug can­di­dates in tar­get pa­tient pop­u­la­tion sam­ples, prior to launch­ing clin­i­cal tri­als. They spur re­search into dis­eases: from iden­ti­fy­ing risk fac­tors to di­ag­nos­ing early, screen­ing family mem­bers at risk to cus­tomis­ing a pa­tient’s treat­ment to im­prove out­comes. Re­sults from such stud­ies can boost, some­times even re­place, the need to test new drugs. Ul­ti­mately, the war against can­cer de­pends on can­cer re­search.

Jain co-founded a health sci­ence firm, Saarum In­no­va­tions, and fi­nally set up In­dia’s first com­mer­cial biobank and per­son­alised medicine com­pany, Sapien Bio­sciences—a joint ven­ture with Apollo Hos­pi­tals, in Hy­der­abad in 2013. The work is in full flow. Imag­ine live can­cer cells grow­ing in the lab. Study those to un­der­stand the com­plex­ity of a tu­mour, screen new drug can­di­dates, use cul­tured can­cer cells as mod­els to in­ves­ti­gate the changes that may have caused can­cer, or its spread, or its re­sis­tance to a ther­apy. There are many other ap­pli­ca­tions of fresh sam­ples in a biobank, she says. “Sev­eral com­pa­nies in China have built thou­sands of can­cer mod­els in biobanks, which are be­ing used by pharma com­pa­nies to screen drug mol­e­cules. We can too.”

With ex­cite­ment build­ing around the in­no­va­tive re­search in the can­cer space, it’s hard not to think of a cure. “But to con­quer a com­pli­cated, costly and dev­as­tat­ing dis­ease such as can­cer, many more ma­jor sci­en­tific break­throughs are needed,” says Mukher­jee. Medicine still needs to catch up. The bat­tle still re­lies largely on three brute-force weapons: surgery, ra­di­a­tion and chemo­ther­apy. Can­cer cells are sub­tle and smart. So the treat­ment needs to be more so­phis­ti­cated. And bring­ing in the lat­est and the best are gene ther­a­pies. He points to an im­por­tant de­vel­op­ment that took place in 2013: a unique tech­nol­ogy, the CRISPR-Cas9 sys­tem, cur­rently the most ver­sa­tile method of ge­netic ma­nip­u­la­tion. It’s some­what like con­duct­ing a molec­u­lar surgery on genes: re­move ab­nor­mal se­quences, re­place them with nor­mal ones, pull out genes that give an ad­van­tage to can­cer cells. The idea comes from some types of bac­te­ria that have a built-in gene edit­ing sys­tem against in­vaders, say, a virus. “Your genome has three bil­lion let­ters, ATCGs. If it were to be writ­ten down, it would be 66 full sets of Encyclopaedia Britannica,” he ex­plains. “What if you can take out a let­ter, one that pre­dis­poses you to can­cer, erase or tweak it to your ad­van­tage?”

Can that be the fu­ture of can­cer? Or, per­haps, our fu­ture with­out can­cer?

AC­TOR, SINGER, SUR­VIVOR Im­age from Mamta Mohandas’s In­sta­gram feed. The 32-year-old is part of a clin­i­cal trial of an ex­per­i­men­tal im­munother­apy drug in Los An­ge­les for peo­ple whose dif­fuse large B cell lym­phoma has come back or no longer re­sponds to treat­ment. The new drug helps the body’s im­mune sys­tem at­tack can­cer cells

VIKRAM SHARMA

IN­DIA’S FIRST CAN­CER VAC­CINE Na­tional In­sti­tute of Im­munol­ogy direc­tor Dr Anil Suri, the man who dis­cov­ered can­cer anti­gen SPAG9, which is un­der phase II clin­i­cal trial, with his team

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