Dafna Bar-Sagi (Sasha Nialla, NYU Langone Health)

How pan­cre­at­ic RAS tu­mors pro­tect them­selves. Re­searchers point to a new pro­tein — and maybe a new treat­ment

A cou­ple years back, some car­dio­vas­cu­lar spe­cial­ists at Boston’s Brigham and Women’s Hos­pi­tal stum­bled across a sur­pris­ing re­sult.

No­var­tis had tasked them with car­ry­ing out the long-range Phase III tri­al for canakinum­ab, an ex­per­i­men­tal an­ti-in­flam­ma­to­ry drug the com­pa­ny was try­ing to mar­ket for car­dio­vas­cu­lar dis­ease. The main re­sults were mixed — mod­est re­duc­tions in fa­tal car­dio­vas­cu­lar events, clear side ef­fects — but an ad­di­tion­al, ex­plorato­ry analy­sis, turned heads over in on­col­o­gy: Across 10,061 pa­tients, those who had re­ceived canakinum­ab were less like­ly to de­vel­op lung can­cer; 33% less like­ly for the high­est dosage.

“The haz­ard ra­tio was strik­ing,” Kwok-Kin Wong, a lung can­cer spe­cial­ist at NYU’s Gross­man School of Med­i­cine told End­points News, re­fer­ring to the 33% fig­ure and an even high­er num­ber for a dif­fer­ent sub­group.

Kwok-Kin Wong

The ques­tion: Why?

New re­search pub­lished to­day in Can­cer Re­search, from one of the ear­li­est RAS-mu­tant pan­cre­at­ic can­cer re­searchers, may give a peak in­to that ques­tion, while of­fer­ing the po­ten­tial to open up one of the most in­tractable can­cers to the lat­est wave of tar­get­ed ther­a­pies.

A team led by NYU’s Daf­na Bar-Sa­gi dis­cov­ered that RAS-pos­i­tive pan­cre­at­ic can­cer cells emit an im­mune-sig­nal­ing pro­tein called in­ter­leukin-1β – al­so the pro­tein that canakinum­ab, the No­var­tis drug, in­hibits. That pro­tein turns down the im­mune sys­tem near the tu­mor in a va­ri­ety of ways, they found, most no­tably by help­ing build more col­la­gen fibers that es­sen­tial­ly guard the can­cer from T cells that would or­di­nar­i­ly try to in­vade and kill it.

“It’s a wall the tu­mor build around it­self, and does not al­low the im­mune sys­tem in,” Bar-Sa­gi told End­points.

These walls, she said, ac­count­ed not on­ly for the tu­mor’s abil­i­ty to elude the body’s nat­ur­al im­mune sys­tem, but al­so the all-but-com­plete fail­ure of the im­mune-un­leash­ing PD-1 check­point ther­a­pies in pan­cre­at­ic can­cer.

“The PD-1 check­point ther­a­py won’t have an ef­fect if the [im­mune] cell can’t get in­to the tu­mor,” she said. Her pa­per test­ed if an an­ti-in­ter­leukin drug like canakinum­ab could be used in com­bi­na­tion with a PD-1 drug, the for­mer clear­ing the way for the lat­ter, find­ing a 32% re­duc­tion in mice. (No­var­tis did not fund the study but did pro­vide the in­ter­leukin and check­point drugs).

Gre­go­ry L Beat­ty

Gre­go­ry Beat­ty, an as­sis­tant pro­fes­sor of im­munol­o­gy at the Uni­ver­si­ty of Penn­syl­va­nia School of Med­i­cine who was not in­volved with the study, said the study was “ex­cit­ing and ap­plic­a­ble to not on­ly pan­creas can­cer but po­ten­tial­ly oth­er ma­lig­nan­cies.”

“Ap­proach­es to over­come im­mune re­sis­tance in pan­creas can­cer are of ut­most im­por­tance and IL-1b is a nov­el tar­get,” Beat­ty said via email.

Kwok-Kin Wong — who was not in­volved with the study but works at the same in­sti­tu­tion — said the find­ings were im­por­tant for a range of can­cers, in­clud­ing by of­fer­ing a mech­a­nism for the 2017 find­ings in lung can­cer. Lung can­cer spe­cial­ists could look for the same process.

“This pa­per will spur a lot of in­ter­est,” Wong said, not­ing many com­pa­nies al­ready have an in­ter­leukin an­ti­body and a PD-1 on hand. “There’s a lot of ther­a­peu­tic im­pli­ca­tions.”

Bar-Sa­gi was one of the ear­li­est re­searchers in­to RAS mu­ta­tions. She joined James Feramis­co’s Cold Spring Har­bor Lab as a post­doc in 1986, short­ly af­ter the onco­gene was first dis­cov­ered, and quick­ly co-au­thored in Sci­ence one of the first pa­pers sug­gest­ing how the RAS gives rise to tu­mors.

Over the years, though, no one ful­ly iden­ti­fied in­ter­leukin-1β in the tu­mors, even as un­der­stand­ing of RAS pro­gressed to a point at which drug de­vel­op­ers could bring tar­get­ed ther­a­pies in­to the clin­ic.

The rea­son for this was sim­ple, Bar-Sa­gi said, and it has ma­jor im­pli­ca­tions for any fu­ture re­search: The pro­tein doesn’t show up in tu­mor cell cul­tures.

Build­ing off of re­search at her lab, Wash­ing­ton Uni­ver­si­ty of St. Louis and else­where, Bar-Sa­gi de­vised a way of test­ing it in vi­vo. They dis­cov­ered that the tu­mor re­lies on a pre­vi­ous­ly undis­cov­ered lig­and bind­ing to its TLR4 re­cep­tors. By giv­ing an­tibi­otics to clear bac­te­ria in some mice, they found that a warped mi­cro­bio­me may pro­mote the bind­ing, con­tribut­ing to the de­vel­op­ment of can­cer.

On­ly once they in­sert­ed the lig­and in­to cell cul­tures, the cells be­gan pro­duc­ing in­ter­leukin-1β . And when they gave RAS-pos­i­tive mice a com­bi­na­tion of a PD-1 and an in­ter­leukin-1β an­ti­body, they found a 32% re­duc­tion in tu­mors.

Bar-Sa­gi said it’s a break­through that con­tin­ues to point to the im­por­tance of not just the tu­mor but al­so the tu­mor’s ef­fect on the mi­cro-en­vi­ron­ment around it and the im­mune sys­tem there. But to ex­plore that, she said, re­searchers will have to turn away from Petri dish­es and find new meth­ods of study­ing tu­mors — pan­cre­at­ic, lung or oth­er­wise — as they ex­ist with­in the body.

“Many of these ef­fects are not go­ing to be rec­og­nized or will be very hard to study us­ing the con­ven­tion­al study meth­ods,” Bar-Sa­gi said. “And that’s def­i­nite­ly a shift.”

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