Jennifer Pietenpol (Joe Howell for Vanderbilt)

Back to the draw­ing board for triple-neg­a­tive breast can­cer tar­gets, re­searchers pro­pose new com­bo ap­proach

The rea­son why triple-neg­a­tive breast can­cer is such a tough dis­ease to treat is large­ly giv­en away in its name. Such tu­mors can’t be de­fined by tra­di­tion­al bio­mark­ers — nei­ther es­tro­gen re­cep­tors, prog­es­terone re­cep­tors, nor ex­cess HER2 pro­tein — forc­ing drug hunters down un­chart­ed new path­ways.

Re­searchers at Van­der­bilt-In­gram Can­cer Cen­ter ex­plored one of them, and turned up with some new sug­ges­tions.

Jo­han­na Schafer

In a new pa­per, the sci­en­tists be­gan with the ob­ser­va­tion that dereg­u­lat­ed MY­CN — a mem­ber of the tran­scrip­tion fac­tor fam­i­ly that ac­ti­vates ex­pres­sion of some onco­genes — has been im­pli­cat­ed in a sub­set of breast can­cers with un­fa­vor­able prog­nos­tic fea­tures and clin­i­cal out­comes. They end­ed by putting forth a new drug reg­i­men that could spark new hope.

“Giv­en that pa­tients with TNBC pri­mar­i­ly re­ceive sys­temic cy­to­tox­ic chemother­a­pies that fre­quent­ly re­sult in un­fa­vor­able out­comes,” they wrote in Sci­ence Trans­la­tion­al Med­i­cine, “we pro­pose the clin­i­cal de­vel­op­ment of com­bi­na­tion BETi and ME­Ki for pa­tients with ad­vanced TNBC, with par­al­lel eval­u­a­tion of MY­CN as a po­ten­tial mark­er for pa­tient se­lec­tion.”

Jo­han­na Schafer, a grad­u­ate stu­dent work­ing in Jen­nifer Pieten­pol’s lab, is the first au­thor, while the pro­fes­sor is the se­nior au­thor.

The MY­CN pro­tein, some­times dubbed N-Myc, has long been stud­ied as a tar­get in neu­ronal or neu­roen­docrine tu­mors, but its role in breast can­cer is less clear. It’s dis­tinct from MYC (c-Myc), though the two are be­lieved to af­fect each oth­er.

Their in­tri­cate re­la­tion­ship would prove cru­cial in ther­a­peu­tic de­vel­op­ment. But the first ques­tion is just how com­mon they are, and ac­cord­ing to the study, the two fam­i­ly mem­bers are “het­ero­ge­neous­ly ex­pressed in sep­a­rate cell nu­clei with­in a giv­en tu­mor in at least 40% of TNBC tu­mors.” In fact, the ex­pres­sion of MY­CN ap­peared to in­crease af­ter neoad­ju­vant chemother­a­py, part of the cur­rent stan­dard of care.

The preva­lence gave them enough rea­son to think about how to tar­get it. When the team se­lect­ed a cell line mod­el, they had an­oth­er find­ing that MY­CN-ex­press­ing cells were es­sen­tial­ly more prone to re­sis­tance to PI3K in­hibitors, which block an al­ter­na­tive path­way for tu­mor growth.

Be­cause the MYC fam­i­ly lack cat­alyt­ic do­mains, the team re­sort­ed to epi­ge­net­ic reg­u­la­tors, screen­ing 158 com­pounds against the cell lines. BET drugs, which block the bro­mod­omain (BRD)-con­tain­ing fam­i­ly of tran­scrip­tion­al reg­u­la­tors, emerged as the win­ner.

It echoes an ear­li­er study, done at Michi­gan State Uni­ver­si­ty, show­ing that the ex­per­i­men­tal class of mol­e­cules can pre­vent the growth of breast and lung can­cers.

But that’s not it — and here’s where the MEK in­hibitors come in.

Most of the MYNC-ex­press­ing TNBCs al­so con­tain MYC-ex­press­ing cells, the re­searchers not­ed, which can still dri­ve can­cer growth. In fact, sin­gle-agent treat­ment with a BETi seemed to have in­creased MYC ex­pres­sion. Adding tram­e­tinib (Mekin­ist) to the cells, how­ev­er, de­creased the amount of both pro­teins. The re­sults were fur­ther test­ed and con­firmed in mouse mod­els.

“As a next step, our re­search team is propos­ing the fur­ther de­vel­op­ment and clin­i­cal tri­als of this com­bi­na­tion ther­a­py,” Pieten­pol, the di­rec­tor of Van­der­bilt-In­gram and EVP for re­search at Van­der­bilt Uni­ver­si­ty Med­ical Cen­ter, said in a state­ment.

In­cyte, which has a pact in place to fund Van­der­bilt re­search such as this study, has a BET in­hibitor in ear­ly de­vel­op­ment.

Forge Bi­o­log­ics’ cGMP Com­pli­ant and Com­mer­cial­ly Vi­able Be­spoke Affin­i­ty Chro­matog­ra­phy Plat­form

Forge Biologics has developed a bespoke affinity chromatography platform approach that factors in unique vector combinations to streamline development timelines and assist our clients in efficiently entering the clinic. By leveraging our experience with natural and novel serotypes and transgene conformations, we are able to accelerate affinity chromatography development by nearly 3-fold. Many downstream purification models are serotype-dependent, demanding unique and time-consuming development strategies for each AAV gene therapy product1. With the increasing demand to propel AAV gene therapies to market, platform purification methods that support commercial-scale manufacturing of high-quality vectors with excellent safety and efficacy profiles are essential.

Cy­to­ki­net­ics’ ALS drug fails PhI­II, leav­ing the biotech with a sin­gle late-stage prospect

Cytokinetics’ candidate for the muscle disease amyotrophic lateral sclerosis, or ALS, failed a Phase III trial, the Bay Area biotech announced Friday morning.

At a second interim analysis of the trial, an independent review committee recommended that Cytokinetics discontinue its COURAGE-ALS trial for reldesemtiv, as it “found no evidence of effect” compared to placebo on the primary or key secondary endpoints.

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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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CHMP gives thumbs-up for We­govy use in ado­les­cents, along with nine new drug rec­om­men­da­tions

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended nine drugs for approval this week while also giving thumbs up for six expanded indications, including Novo Nordisk’s approved obesity medication Wegovy for younger people. Wegovy is already approved as an obesity treatment in the EU for adults, and the new indication would allow prescriptions for adolescents aged 12 and older.

Sar­to­rius to ac­quire French man­u­fac­tur­er for $2.6B+ in cell and gene ther­a­py play

The German life science group Sartorius will be picking up French contract manufacturer Polyplus for the price of €2.4 billion, or $2.6 billion.

On Friday, Sartorius announced the acquisition through its French subgroup, Sartorius Stedim Biotech, which will be acquiring Polyplus from private investors ARCHIMED and WP GG Holdings IV. Polyplus has 270 employees and produces materials and components that go into making viral vectors that are used in cell and gene therapies. This includes DNA/RNA reagents as well as plasmid DNA. Polyplus has locations in France, Belgium, China and the US.

Green­Light re­ceives buy­out of­fer; Apol­lomics com­pletes SPAC merg­er

RNA biotech GreenLight Biosciences has been handed an offer for potential acquisition.

GreenLight said in a release that it has received a non-binding “indication of interest” from Fall Line Endurance Fund to acquire GreenLight’s capital stock for $0.60 per share in cash. The release said any potential agreement between the two parties would depend on certain conditions.

Through a special committee, the biotech will evaluate the offer but added there’s no certainty a deal will go forward. GreenLight will also not make any more announcements until a deal comes through or “otherwise determines” a statement is necessary.

TScan Therapeutics' departing CEO David Southwell and CSO/COO Gavin MacBeath

TCR up­start an­nounces CEO ex­it, with CSO now act­ing re­place­ment

A public T cell biotech’s chief executive has decided to leave the company.

TScan Therapeutics said Friday morning that CEO David Southwell stepped down earlier this week, leaving both his chief executive and board member roles. Filling in is Gavin MacBeath, the company’s CSO and COO. He became the acting CEO on Tuesday, and will continue to remain CSO and COO, TScan’s announcement read.

Sen­ate Fi­nance Com­mit­tee lobs more bi­par­ti­san pres­sure on­to PBMs

Congress is honing in on how it wants to overhaul the rules of the road for pharmacy benefit managers, with a Senate Finance Committee hearing Thursday serving as the latest example of the Hill’s readiness to make changes to how pharma middlemen operate.

While pledging to ensure patients and pharmacies “don’t get a raw deal,” Finance Committee Chair Ron Wyden (D-OR) laid out the beginning of what looks like a major bipartisan effort — moves the PBM industry is likely to challenge vigorously.

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Nicklas Westerholm, Egetis Therapeutics CEO

Ac­qui­si­tion talks on­go­ing for Swedish rare dis­ease biotech Egetis, shares up al­most 40%

Shares of the Sweden-based rare disease biotech Egetis Therapeutics skyrocketed on Thursday afternoon as the company said it’s engaged in “ongoing discussion” with external parties regarding a “potential acquisition.”

Egetis confirmed rumors with a statement on Thursday while noting that there is no certainty that a takeover offer will be made.

Nonetheless, the possibility of an acquisition has shot up Egetis’ share price. By the afternoon on Thursday, its stock price was {$EGTX.ST} up over 38%. An Egetis spokesperson told Endpoints News in an email that it has no further comments.

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