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.

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

15 LGBTQ lead­ers in bio­phar­ma; Paul Stof­fels’ Gala­pa­gos re­vamp; As­traZeneca catch­es up in AT­TR; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

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Abortion-rights protesters regroup and protest following Supreme Court's decision to overturn Roe v. Wade. (AP Photo/Gemunu Amarasinghe)

Fol­low­ing SCO­TUS de­ci­sion to over­turn abor­tion pro­tec­tions, AG Gar­land says states can't ban the abor­tion pill

Following the Supreme Court’s historic decision on Friday to overturn Americans’ constitutional right to an abortion after almost 50 years, Attorney General Merrick Garland sought to somewhat reassure women that states will not be able to ban the prescription drug sometimes used for abortions.

Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

AstraZeneca's new Evusheld direct to consumer campaign aims to reach more immunocompromised patients.

As­traZeneca de­buts first con­sumer cam­paign for its Covid-19 pro­phy­lac­tic Evusheld — and a first for EUA drugs

AstraZeneca’s first consumer ad for Evusheld is also a first for drugs that have been granted emergency use authorizations during the pandemic.

The first DTC ad for a medicine under emergency approval, the Evusheld campaign launching this week aims to raise awareness among immunocompromised patients — and spur more use.

Evusheld nabbed emergency authorization in December, however, despite millions of immunocompromised people looking for a solution and now more widespread availability of the drug.

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GSK says its drug for chron­ic hep B could ‘lead to a func­tion­al cure’ — but will it be alone or in com­bi­na­tion?

GSK, newly branded and soon-to-be demerged, shared interim results from its Phase II trial on its chronic hepatitis B treatment, one that it says has the “potential to lead to a functional cure.”

At a presentation at the EASL International Liver Congress, GSK shared that in around 450 patients who received its hep B drug bepirovirsen for 24 weeks, just under 30% had hepatitis B surface antigen and viral DNA levels that were too low to detect.

De­spite a slow start to the year for deals, PwC pre­dicts a flur­ry of ac­tiv­i­ty com­ing up

Despite whispers of a busy year for M&A, deal activity in the pharma space is actually down 30% on a semi-annualized basis, according to PwC’s latest report on deal activity. But don’t rule out larger deals in the second half of the year, the consultants said.

PwC pharmaceutical and life sciences consulting solutions leader Glenn Hunzinger expects to see Big Pharma companies picking up earlier stage companies to try and fill pipeline gaps ahead of a slew of big patent cliffs. Though a bear market continues to maul the biotech sector, Hunzinger said recent deals indicate that pharma companies are still paying above current trading prices.

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

The story of Amryt Pharma’s candidate for the genetic skin condition epidermolysis bullosa, or EB, will soon enter another chapter.

After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

Sen. Thom Tillis (R-NC) (J. Scott Applewhite/AP Images)

Phar­ma-friend­ly sen­a­tor calls on FDA for a third time to show patent pro­tec­tions should­n't be blamed for high drug prices

North Carolina Republican Sen. Thom Tillis made a name for himself in the 2020 election cycle as the darling of the pharma industry, accepting hundreds of thousands in campaign contributions, even from the likes of Pfizer CEO Albert Bourla.

Those contributions have led Tillis to attempt to re-write patent laws in pharma’s favor, a move which failed to gain steam in 2019, and request for a third time since January that the FDA should help stop “the false narrative that patent protections are to blame for high drug prices.”

EMA signs off on 3 drugs re­cent­ly re­ject­ed by FDA, in­clud­ing Bio­Mar­in's new he­mo­phil­ia gene ther­a­py

The EMA’s human medicines committee on Friday recommended three new drugs for approval or conditional approval, even as their US counterparts have rejected these three for various reasons.

In a major move, CHMP offered a thumbs-up to a conditional marketing authorization for the first gene therapy to treat severe hemophilia A, although the agency cautioned that it’s so far unknown how long the effects of infusion will last.

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