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.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

President Donald Trump (via AP Images)

Signs of an 'Oc­to­ber Vac­cine Sur­prise' alarm ca­reer sci­en­tists

President Donald Trump, who seems intent on announcing a COVID-19 vaccine before Election Day, could legally authorize a vaccine over the objections of experts, officials at the FDA and even vaccine manufacturers, who have pledged not to release any vaccine unless it’s proved safe and effective.

In podcasts, public forums, social media and medical journals, a growing number of prominent health leaders say they fear that Trump — who has repeatedly signaled his desire for the swift approval of a vaccine and his displeasure with perceived delays at the FDA — will take matters into his own hands, running roughshod over the usual regulatory process.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.

UP­DAT­ED: Two wild weeks for Grail end in $8B Il­lu­mi­na buy­out

Grail’s whirlwind two weeks have ended in the wealthy arms of its former founder and benefactors.

Illumina has shelled out $8 billion to reacquire the closely-watched liquid biopsy startup they spun out just 5 years ago and sold off much of its shares just 3 years ago. The deal comes nearly two weeks after the well-heeled startup filed for a potentially massive IPO — one that was disrupted just a week later when Bloomberg reported that Illumina was in talks to buy their former spinout for up to $8 billion.

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Roche vaults to the front of the NL­RP3 clin­i­cal race, pay­ing $448M up­front to bag In­fla­zome

Roche is going all in on NLRP3.

The pharma giant is putting down $448 million (€380 million) upfront to snatch Novartis-backed Inflazome, which makes it a clinical player in the space overnight.

Dublin and Cambridge, UK-based Inflazome is the second NLRP3-focused biotech Roche has acquired in less than two years, and although no numbers were disclosed in the Jecure buyout, this is almost certainly a much larger deal.

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Anthony Fauci (AP Images)

A press of­fi­cer at An­tho­ny Fau­ci’s NI­AID was un­masked as a hard-right Covid troll. He just re­tired to­day

William B Crews had been a public affairs specialist at the NIH’s National Institute of Allergy and Infectious Diseases.

That ended today when he informed the agency of his decision to retire, after he was identified as the managing editor at RedState, a prominent Trump loyalist website.

Crews’ RedState duties are performed under the alias streiff. While enjoying the benefits of pseudonymity, he disparaged and worked against NIAID with an incendiary level of rhetoric in the midst of a pandemic.

#ES­MO20: Bris­tol My­ers marks Op­di­vo's sec­ond ad­ju­vant win — eye­ing a stan­dard of care gap

Moving into earlier and earlier treatment lines, Bristol Myers Squibb is reporting that adjuvant treatment with Opdivo has doubled the time that esophageal or gastroesophageal junction cancer patients stay free of disease.

With the CheckMate-577 data at ESMO, CMO Samit Hirawat said, the company believes it can change the treatment paradigm.

While a quarter to 30% of patients typically achieve a complete response following chemoradiation therapy and surgery, the rest do not, said Ronan Kelly of Baylor University Medical Center. The recurrence rate is also high within the first year, Hirawat added.

Donald Trump, AP

Covid-19 roundup: Trump sug­gests Pfiz­er vac­cine could be first ap­proved; VBI Vac­cines inks de­vel­op­ment deal with Cana­da

President Donald Trump commented Monday morning that Pfizer’s Covid-19 vaccine candidate could be the first to win approval by regulators.

During an interview on a Fox News’ morning show, the president said Pfizer was doing “very well” when asked which candidate could be approved, according to a Reuters report. He added that J&J could follow up afterward, saying “they’ll probably be a little later.”

Is­raeli biotech rais­es $57M to go where cur­rent BRAF in­hibitors can't, with back­ing from No­var­tis, SR One

For the blockbuster potential of Novartis’ Tafinlar and Pfizer’s Braftovi, all the BRAF inhibitors on the market so far only target V600 mutations — which accounts for roughly 50% of patients.

Israeli biotech Novellus now has $57 million to develop a drug that they say can help the other 50% who have everything else.

The Series C will fund a Phase II trial for PLX-8394, a “paradox breaker” that could block RAF without activating MAPK signaling. In a Phase I trial, a patient with a BRAF fusion saw their tumor go away after taking the drug, allowing Novellus to hit the ground running.