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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Feng Zhang (Susan Walsh/AP Images)

In search of new way to de­liv­er gene ed­i­tors, CRISPR pi­o­neer turns to mol­e­c­u­lar sy­ringes

Bug bacteria are ruthless.

Some soil bacteria have evolved tiny, but deadly injection systems that attach to insect cells, perforate them and release toxins inside — killing a bug in just a few days’ time. Scientists, on the other hand, want to leverage that system to deliver medicines.

In a paper published Wednesday in Nature, MIT CRISPR researcher Feng Zhang and his lab describe how they engineered these syringes made by bacteria to deliver potential therapies like toxins that kill cancer cells and gene editors. With the help of an AI program, they developed syringes that can load proteins of their choice and selectively target human cells.

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Cedric Ververken, Confo Therapeutics CEO

Dai­ichi Sankyo inks $183M dis­cov­ery deal with GPCR biotech for CNS tar­get

Belgian biotech Confo Therapeutics has landed $183 million, plus potential royalties, in a drug-discovery deal with Daiichi Sankyo.

Early Thursday, Confo Therapeutics put out word of the deal that will be focused on small molecule antagonists to go after an undisclosed target that the company says is associated with CNS diseases.

Confo CEO Cedric Ververken told Endpoints News that Daiichi originally reached out to learn about the biotech’s technology. He added that Confo, founded in 2015, will use its platform to drug a GPCR target that Daiichi has struggled with internally.

Dif­fu­sion to hand Nas­daq spot to EIP Phar­ma for PhI­Ib de­men­tia study of ex-Ver­tex drug

One of the more than a dozen bidders for Diffusion Pharmaceuticals’ spot on Nasdaq has prevailed.

Boston biotech EIP Pharma will merge with Diffusion in an all-stock deal, with plans to start a Phase IIb clinical trial in the coming months in a common form of dementia with no approved treatments. The combined company will be renamed CervoMed.

The nine-year-old privately-held EIP is working on a former Vertex drug that it will test in a 160-person Phase IIb in patients with dementia with Lewy bodies, or DLB. The National Institute on Aging is expected to fund that trial with a $21 million grant. With the reverse merger, slated for closing in the middle of this year, EIP will be funded through that readout in the second half of 2024. EIP’s equity and debt holders will own about 77.25% of the combined company.

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Luke Miels, GSK chief commercial officer

GSK picks up Scynex­is' FDA-ap­proved an­ti­fun­gal drug for $90M up­front

GSK is dishing out $90 million cash to add an antifungal drug to its commercial portfolio, in a deal spotlighting the pharma giant’s growing focus on infectious diseases.

The upfront will lock in an exclusive license to Scynexis’ Brexafemme, which was approved in 2021 to treat a yeast infection known as vulvovaginal candidiasis, except in China and certain other countries where Scynexis already out-licensed the drug.

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See­los Ther­a­peu­tics 'tem­porar­i­ly' stops study in rare neu­ro dis­or­der for busi­ness rea­sons

Microcap biotech Seelos Therapeutics is halting enrollment of its study in spinocerebellar ataxia type 3 (also known as Machado-Joseph disease) because of “financial considerations,” and in order to focus on other studies, the company said today, adding that the pause would be temporary.

The study will continue with the patients who have already enrolled, and the data from them will be used to decide whether to continue enrolling others in the future.

Alec­tor cuts 11% of work­force as it dou­bles down on late-stage neu­ro pro­grams part­nered with GSK, Ab­b­Vie

A month after revealing plans to concentrate on its late-stage immuno-neurology pipeline, Alector is trimming its headcount by 11%.

The layoffs will impact around 30 employees across the organization, the company disclosed in an SEC filing, adding that the plan will “better align the company’s resources” with the new strategy. With $712.9 million in cash, cash equivalents and investments as of the end of 2022, Alector believes the reserves will now get it through 2025.

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Mathai Mammen, FogPharma's next CEO

Math­ai Mam­men hands in J&J's R&D keys to lead Greg Ver­dine’s Fog­Phar­ma 

In the early 1990s, Mathai Mammen was a teaching assistant in Greg Verdine’s Science B46 course at Harvard. In June, the former R&D head at Johnson & Johnson will succeed Verdine as CEO, president and chair of FogPharma, the same month the seven-year-old biotech kickstarts its first clinical trial.

After leading R&D at one of the largest drugmakers in the world, taking the company through more than half a dozen drug approvals in the past few years, not to mention a Covid-19 vaccine race, Mammen departed J&J last month and will take the helm of a Cambridge, MA biotech attempting to go after what Verdine calls the “true emperor of all oncogenes” — beta-catenin.

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J&J bows out of RSV vac­cine race, end­ing PhI­II study and ced­ing to Pfiz­er, GSK

Johnson & Johnson announced Wednesday morning it is ending development of its adult RSV vaccine that was in the middle of a 27,200-patient trial, giving up a big slice of what’s expected to be the next multibillion-dollar pharma market.

The decision came down to the shifting RSV “competitive landscape,” a company spokesperson tells Endpoints News, adding the “breadth of options” was much different than when J&J first started its pivotal study. The spokesperson declined to comment on the Phase III data, saying only the shot is undergoing an “ongoing assessment.”

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