NEWS IN BRIEF

1298 | CANCER DISCOVERY�DECEMBER 2016 www.aacrjournals.org

• Gilead Sciences’ entospletinib, an

inhibitor of the tyrosine kinase Syk,

which blocks B-cell receptor signaling

Three to six more drugs may be

added over the course of the trial, which

will run for 3 to 5 years.

“This is about working toward a

common goal,” said Levine. “We really

want to make a difference for our

patients.” –Karen Weintraub ■

Nobel Prize Honors Autophagy Discovery

Japanese cell biologist Yoshinori

Ohsumi, PhD, has been awarded this

year’s Nobel Prize in Physiology or

Medicine for his discovery of autophagy.

His groundbreaking studies in yeast

illuminated how cells collect and

break down intracellular proteins and

organelles, a process that is critical to

the survival of both normal cells and

some cancerous ones.

“His discoveries opened the path

to understanding the fundamental

importance of autophagy in many

physiological processes, such as in the

adaptation to starvation or response to

infection,” noted the Nobel Committee

in announcing the award in October.

The concept of autophagy was fi rst

observed in the 1960s, but little was

known about its underlying mecha-

nisms until Ohsumi conducted a series

of experiments with baker’s yeast in the

early 1990s. Those studies eventually

led him to identify the genes—and the

proteins they encode—that control

autophagy, and to show that a corre-

sponding mechanism exists in humans.

Autophagy is a self-defense mecha-

nism that prevents the accumulation

of garbage or potentially toxic material

in cells, such as damaged proteins and

organelles. In normal cells, it serves

as a buffer during metabolic stress by

recycling intracellular components. It

also helps to eliminate invading bac-

teria and viruses following infection,

promote embryo development and

cell differentiation, and counteract the

negative consequences of aging.

Ohsumi verifi ed that the process

exists in yeast cells by studying how

autophagy delivers cargo for degra-

dation in the vacuole. (In human cells,

similarly, autophagosomes fuse with

lysosomes, which contain enzymes that

degrade proteins and organelles.) He

then cultivated cells that lacked vacuolar

degradation enzymes, starved them, and

was able to observe the vacuoles fi ll with

small vesicles holding proteins to be

degraded—known as autophagosomes.

In another set of experiments, Ohsumi

exposed engineered yeast cells to a chem-

ical that randomly introduced mutations

in many genes, then induced autophagy.

As a result, he identifi ed many different

proteins and protein complexes that

regulate distinct stages of autophago-

some initiation and formation.

“Ohsumi used yeast as a model

system to identify the mechanisms it

uses to survive nitrogen starvation and

the genes essential for the autophagy

pathway,” says Eileen White, PhD,

professor of molecular biology and

biochemistry at Rutgers University

and deputy director and associate

director for Basic Science at Rutgers

Cancer Institute of New Jersey, in New

Brunswick. “By doing this, he opened

up a whole new fi eld of investigation.”

Recent research has revealed that some

cancer cells in hypoxic regions also use

autophagy to survive metabolic stress,

suggesting that the process may be a via-

ble drug target, says White. Companies

are now working on autophagy inhibi-

tors, possibly to augment the activity of

targeted drugs. Multiple clinical trials

are testing hydroxychloroquine (HCQ),

an antimalarial drug that interferes

with lysosome function, in combination

cancer therapy. For example, a phase II

trial is assessing HCQ combined with

the BRAF inhibitor dabrafenib (Tafi nlar;

Novartis) and trametinib, a MEK inhibi-

tor (Mekinist; Novartis), in patients with

advanced BRAF-mutant melanoma.

“The discovery of autophagy genes

and how they enable lysosomal deg-

radation and recycling of organelles

and proteins has provided a critical

platform for understanding how

autophagy plays a role in resistance to

cancer therapy,” says Ravi Amaravadi,

MD, a medical oncologist at the Uni-

versity of Pennsylvania in Philadelphia,

who led a series of early-phase clinical

trials testing HCQ in combination

with targeted therapies. “Ohsumi’s

work provided the framework to pro-

pose biomarkers and targets for drug

discovery that could improve the effi cacy

of cancer therapies in a number of

cancers.” –Janet Colwell ■

announcing the trial. With LLS acting

as a neutral party, more pharmaceuti-

cal companies may join the effort to

bring drugs to market more quickly.

“The secret sauce of this trial is the

idea that we’re going to work faster by

collaborating in open and transparent

ways,” said Ross Levine, MD, of Mem-

orial Sloan Kettering Cancer Center

(MSKCC) in New York, NY. In addition

to MSKCC, the Ohio State University

Comprehensive Cancer Center (OSUCCC)

in Columbus, Oregon Health & Science

University Knight Cancer Institute

in Portland, and Dana-Farber Cancer

Institute and Massachusetts General

Hospital, both in Boston, will serve as

the initial trial sites.

Researchers plan to enroll 500

patients over age 60 newly diagnosed

with AML in the trial. Participants will

have their cancer’s genome sequenced

and be put into a trial arm based on

nine different genomic signatures, said

John Byrd, MD, of OSUCCC.

Unlike other trials, none of the

participants will receive standard

chemotherapy alone. If there is not

a suitable drug match for a patient’s

genetic markers, they will be offered

chemotherapy in combination with

an existing targeted therapy, Byrd

explained. Patients who do not res-

pond to their investigational drug can

also receive conventional therapy with

the targeted therapy, he added.

Most of the patients who will be

eligible for the trial are unable to tol-

erate intensive chemotherapy, so their

outcomes are even worse than average,

said Brian Druker, MD, director of the

Knight Cancer Institute. The targeted

therapies are expected to be better

tolerated than toxic chemotherapy, and

will be given after diagnosis, when they

will likely be more effective, instead of

waiting for disease relapse, he added.

DeGennaro said that the trial will

begin by testing these four drugs:

• Alexion’s samalizumab (ALXN6000),

a humanized monoclonal antibody

that targets CD200

• Boehringer Ingelheim’s BI 836858,

which induces antibody-dependent

cellular cytotoxicity against CD33-

expressing tumor cells

• Celgene and Agios’s enasidenib (AG-

221/ CC-90007), a selective IDH2

inhibitor

on July 26, 2020. © 2016 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst October 17, 2016; DOI: 10.1158/2159-8290.CD-NB2016-127

NEWS IN BRIEF

DECEMBER 2016�CANCER DISCOVERY | 1299

Anderson Cancer Center in Houston.

“We are now trying to identify markers

of response because we don’t yet know

why these drugs work better in some

patients than others.”

Researchers are also exploring

whether ribociclib may be effective

in second- or third-line settings or in

combination with inhibitors of other

signaling pathways involved in breast

cancer, adds Hortobagyi.

Ribociclib, which has been submit-

ted for FDA approval, is one of three

CDK4/6 inhibitors either approved

or being tested in combination with

antiestrogen therapy for advanced

HR-positive, HER2-negative breast

cancer. Palbociclib (Ibrance; Pfizer)

received FDA approval last year and

abemaciclib (Eli Lilly) is in early clini-

cal trials.

Identifi cation of biomarkers is criti-

cal, considering that CDK4/6 inhibi-

tors are known to cause significant

side effects, notes V.K. Gadi, MD, PhD,

of the University of Washington and a

clinical researcher at Fred Hutchinson

Cancer Research Center in Seattle.

In the MONALEESA-2 trial, neutro-

penia and leukopenia were far more

common in the intervention versus

the control group (59.3% vs. 0.9% and

21.0% vs. 0.6%, respectively). However,

severe (grade 4) neutropenia was

relatively uncommon (9.6% vs. 0%)

and could be managed with dose

interruptions or reductions.

Although ribociclib appears to have

a similar toxicity profi le to palbociclib,

abemaciclib may be less toxic than

either drug, notes Gadi. For example,

a recent phase I study found that

single-agent abemaciclib triggered

neutropenia in just 9% of 173 patients

with breast cancer, non–small cell lung

cancer, and other solid tumors (Cancer

Discov 2016;6:740–53).

“The high rate of neutropenia seen

with ribociclib and palbociclib makes

treating these patients very challeng-

ing,” he says. “What we really need is

a good marker of response so we can

decide who actually needs this therapy

and who could be spared the toxicity.”

–Janet Colwell ■

Rib ociclib Lengthens Breast Cancer Survival

The combination of antiestrogen

therapy and ribociclib (Novartis), an

investigational CDK4/6 inhibitor, pro-

longed progression-free survival (PFS)

in women with metastatic HR-positive

HER2-negative breast cancer, according

to fi ndings presented at the European

Society for Medical Oncology’s 2016

Congress in Copenhagen, Denmark.

Data from the large phase III trial,

which were published concurrently in

The New England Journal of Medicine, may

lead to FDA approval of the second

CDK4/6 inhibitor for this disease

(N Engl J Med 2016;375:1738–48).

A planned interim analysis of the

MONALEESA-2 trial, which included

almost 700 postmenopausal women,

found that fi rst-line therapy with riboci-

clib in addition to the aromatase inhibi-

tor letrozole signifi cantly improved

outcomes. After 18 months of treat-

ment, median PFS was not reached in

the ribociclib arm compared with 14.7

months in the control group—a 44%

improvement.

“The majority of patients treated with

ribociclib completed therapy and received

signifi cant benefi t,” notes the study’s

lead investigator Gabriel Hortobagyi,

MD, of the University of Texas MD

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

NOTED

Vice President Joe Biden delivered a report on the Cancer Moonshot, summa-rizing the work of its Task Force and lay-ing out his strategic plan for transforming cancer research and care. In addition, the report notes areas of “scientific opportu-nity” as determined by a Blue Ribbon Panel and announced in September. It also outlines several new collaborative efforts between the public and private sectors. For example, the NCI, Amazon Web Services, and Microsoft are building a sustainable model for maintaining can-cer genomic data in the cloud.

Researchers at Roswell Park Cancer Institute in Buffalo, NY, got the FDA’s go-ahead to evaluate CIMAvax-EGF, a lung cancer vaccine developed in Cuba, in a U.S. clinical trial. Roswell Park also received authorization from the U.S. Department of the Treasury to establish a joint business venture with the Center of Molecular Immunology in Havana, aimed at discover-ing and developing new biotech products.

The U.S. Multi-Society Task Force on Colorectal Cancer released a consensus statement on using the fecal immuno-chemical test (FIT) for colorectal cancer screening (Ann Intern Med 2016 Oct 25 [Epub ahead of print]). FIT is “an excellent alternative” to colonoscopy for preventing this disease, the authors said, adding that “surprisingly little published evidence sup-ports the predominance of colonoscopy.”

Genentech announced that the FDA approved atezolizumab (Tecentriq) for the treatment of metastatic non–small cell lung cancer (NSCLC) that has progressed during or after treatment with platinum-containing chemotherapy. Atezolizumab is the first PD-L1 inhibitor given the green light by the agency for NSCLC; in May, it received accelerated approval for the treatment of locally advanced or meta-static urothelial carcinoma.

Celgene acquired Swiss biotech EngMab for $600 million, expanding its pipeline of immunotherapies targeting BCMA, an antigen almost exclusively expressed on plasma cells and multiple myeloma cells. EngMab is developing a bispecific anti-body that binds to BCMA on multiple myeloma cells and to CD3 on T cells, trig-gering T cell–mediated cytotoxicity.

Autophagy represents a cell’s response to chemotherapy and radiation that may be one component of resistance to therapy. H460 non–small cell lung cancer cells were exposed to the antitumor drug etoposide. The image shows the H460 cells (in green) containing acidic autophagic vacuoles (orange) that are extranuclear. The small bright green bodies are likely to be micronuclei.

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