NEWS IN BRIEF

APRIL 2017�CANCER DISCOVERY | 345

that errors introduced during library

construction can be detected among

duplicate sequences and remedied

computationally. “I like molecular bar-

coding because you’re able to directly

measure the type and degree of DNA

damage,” Pugh says. “You’re reading

out exactly what you have in the tube

and then correcting for it.”

However, repairing DNA was not the

study’s primary aim. “The goal of the

paper was to alert the community to a

potential problem,” says Tom Evans,

PhD, an enzymologist at NEB. “Solu-

tions will come later.” –Elie Dolgin ■

Protein Turnover Provides Pancreatic Cancer Target

Pancreatic adenocarcinoma is such an

aggressive and deadly cancer that fewer

than 1 in 3 patients live long enough

to see the one-year anniversary of their

diagnosis. For the majority of patients,

surgery is not an option and their

tumors have evolved to the point that

they’re not responsive to chemotherapy.

Finding new drugs for pancreatic

cancer has proven elusive. But accord-

ing to new research, one of the mol-

ecular adaptations that makes these

cells more aggressive and treatment-

resistant also presents a vulnerability

that can be exploited for therapeutic

purposes (Nature 2017;542:362–6).

“It’s a beautiful paper,” says Ben

Stanger, MD, PhD, from the Univer-

sity of Pennsylvania Perelman School

of Medicine in Philadelphia, who was

not involved in the study. “It reveals

that cancer cells have differential vul-

nerabilities in the epithelial versus the

mesenchymal state.”

In the study, a team from The Uni-

versity of Texas MD Anderson Cancer

Center in Houston identifi ed and

characterized highly aggressive malig-

nant cell populations that emerge dur-

ing pancreatic cancer progression.

These highly mobile and invasive

cells no longer depend on KRAS

signaling and rely on the aberrant

activation of mesenchymal programs

regulated by the chromatin remod-

eling factor SMARCB1. Mouse models

showed that Smarcb1 ablation could

intensify cancer spread; conversely,

restoring Smarcb1 slowed tumor

10 to 20. The researchers discovered

that the acoustic energy used to shear

DNA extracted from tumor tissue was

frequently turning guanine into 8-oxo-

guanine, a nucleotide that the sequenc-

ing machine read as a thymine (Nucleic

Acids Res 2013;41:e67). These G-to-T

transversions were not tumor-causing

mutations but artifacts of the sonica-

tion process.

Laurence Ettwiller, PhD, and her

colleagues from New England Biolabs

(NEB), a molecular biology reagents

company in Ipswich, MA, have now

extended those fi ndings and quanti-

fi ed the prevalence of such erroneous

variants in two widely used sequencing

datasets: the 1000 Genomes Project and

TCGA. The researchers compared the

reads of the two complementary strands

from each sequencing run to detect

aberrant transversions introduced by

DNA damage and scored the degree of

mismatching in a metric dubbed the

Global Imbalance Value (GIV).

Based upon the GIV, Ettwiller’s

team found that 41% of the datasets

in the 1000 Genomes Project con-

tained damaged samples. In TCGA,

73% of the 1,800 sequenced tumor

and healthy matched samples revealed

damage so extensive that at least half

of all the G-to-T variants were not true

mutations. Other nucleotide imbal-

ances such as C-to-T occurred at lower

but still appreciable frequencies.

According to Pugh, analytic tools

like MuTect and VarScan can correct

the problem, although not perfectly.

To eliminate the false variants, the

NEB researchers used a mix of enzymes

that repaired the DNA damage before

sequencing. “But,” says Ettwiller,

“we don’t know whether or not this

cocktail of enzymes will actually work

on the TGCA dataset,” because of dif-

ferences in experimental setup.

NEB markets the DNA-repair mix

used in the study, so the authors have

an inherent fi nancial confl ict, yet that

doesn’t bother Alexander Dobrovic,

PhD, a molecular geneticist from the

Olivia Newton-John Cancer Research

Institute in Melbourne, Australia.

“They clearly have a product to sell,

but it’s a useful product,” he says.

“We’ll be using that ourselves.”

Another workaround: molecular

barcoding, which involves adding

unique tags to each stretch of DNA so

growth and restored the cells to their

less invasive, epithelial form.

These fi ndings were supported by an

analysis of surgically resected specimens

from 134 patients with pancreatic ductal

adenocarcinoma for whom follow-up

data were available. Those whose tumors

had high levels of SMARCB1 lived, on

average, for around 14 months after

their diagnosis. In contrast, those whose

tumors had low expression levels had a

median survival of just 3.4 months.

“Those are the patients where mes-

enchymal subpopulations are promi-

nent,” says Giannicola Genovese, MD,

the study’s fi rst author. “As a result,

they do the worst.”

Gene expression profi ling revealed

that the reduction of SMARCB1

expression leads to an increase in MYC-

related activity that drives protein metab-

olism and the stress response pathways

that help the cell tolerate the increased

protein turnover.

Therein lies the cancer’s Achilles’

heel. Treatment with the drug AUY922

(luminespib; Vernalis), which blocks

HSP90, reduced cancer growth in

Smarcb1-deficient mice but not in

Smarcb1-profi cient animals. What’s

more, the therapeutic effect of AUY922

was enhanced with the addition of

drugs targeting the endoplasmic

reticulum–stress response pathway.

“We identifi ed two ways to target the

vulnerability,” says senior study author

Giulio Draetta, MD, PhD. “One is we

Pancreatic tumor cells with low Smarcb1 levels and mesenchymal markers show a greater potential to metastasize in mice (left) than cells with high Smarcb1 expression and an epithelial identity.

Gia

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ico

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NEWS IN BRIEF

346 | CANCER DISCOVERY�APRIL 2017 www.aacrjournals.org

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

NOTED

The NCI launched its largest study, to date, of African American cancer survi-vors. Through interviews, information from medical records, and biospecimen collection, the Detroit Research on Cancer Survivors study—funded by a 5-year, $9 million grant—will acquire comprehensive data on 5,560 patients in three counties surrounding Detroit, MI.

According to a recent study, rates of colon and rectal cancers are rising among young adults in the United States (J Natl Cancer Inst 2017;109: djw322). “Compared with adults born circa 1950, those born circa 1990 have double the risk of colon cancer and qua-druple the risk of rectal cancer,” the researchers report. Obesity, sedentary behavior, and diet are among the probable culprits; the findings suggest that some screening tests may need to begin before the age of 50, which is the age currently recommended for the average individual.

The NCI launched the NCTN/NCORP Data Archive, a centralized repository of deidentified patient-level data from phase III studies carried out by groups affiliated with the National Clinical Trials Network (NCTN) and the NCI’s Community Oncology Research Program (NCORP). For information, visit https://nctn-data-archive.nci.nih.gov/.

Genome-editing tools, such as CRISPR/Cas9, have created research opportuni-ties and potential treatments for both heritable and nonheritable health condi-tions, but many people consider the genome “ethically inviolable.” However, according to a report from the National Academy of Sciences and the National Academy of Medicine, heritable germ-line editing clinical trials could one day be permitted if certain stringent criteria are met, such as the absence of reason-able alternatives and credible data on the risks and potential health benefits. The report is available at www.nap.edu.

The Cleveland Clinic opened its new Taussig Cancer Center. Costing an esti-mated $276 million, the seven-story, 377,000-square-foot facility will house all outpatient cancer treatment services, organized by cancer type. For example, all clinical and treatment areas for breast cancer will be located on the same floor to offer greater convenience for patients.

basically force the system to accumu-

late unfolded proteins; the other way

is to block the stress response pathway

that allows the cells to survive under

proteotoxic stress—and if you combine

the two, you get synergistic effects.”

Studies with patient-derived tumor

xenograft models also found that com-

binatorial regimens employing the cyto-

toxic agent gemcitabine with AUY922

could increase mouse survival rates.

Channing Der, PhD, of the Univer-

sity of North Carolina at Chapel Hill,

welcomes the potential therapeutic leads

revealed by the study, but he notes that

“a number of mechanistic questions

remained unanswered.” First and fore-

most: What drives the loss of SMARCB1

activity? “Defi ning this may identify a

therapeutic strategy to restore expression

that’s more specifi c than the approaches

they suggested,” he says. –Elie Dolgin ■

Revised Common Rule Allows Broad Consent

The U.S. Department of Health and

Human Services (DHHS) has issued a

fi nal rule updating the Federal Policy

for the Protection of Human Subjects,

otherwise known as the Common

Rule. Published in the Federal Regis-

ter, the rule is intended to provide

stronger protections for research

participants while reducing adminis-

trative burdens on investigators (see

www.gpo.gov/fdsys/pkg/FR-2017-01-

19/pdf/2017-01058.pdf).

The revisions, slated to take effect

next January, represent the fi rst

major update of the Common Rule

since 1991 and refl ect the signifi cant

technological advances that have

changed the nature of biomedical

research. The DHHS collaborated

with 15 other federal departments and

agencies to clarify requirements sur-

rounding patient consent for ongoing

use of biospecimens and to streamline

the regulatory review process for large

studies spanning multiple institutions.

“The fi nal Common Rule signifi -

cantly reduces the regulatory burden

on researchers and patients, while

effectively protecting patient privacy,”

says Gilbert Omenn, MD, PhD, direc-

tor of the Center for Computational

Medicine and Bioinformatics at the

University of Michigan in Ann Arbor

and chair of the American Association

for Cancer Research’s (AACR) Health

Policy Subcommittee.

The AACR and other major cancer

groups objected to a provision in

the proposed rule that would have

required researchers to obtain new

consent forms for any additional use

of deidentifi ed samples. Even though

all direct personal identifiers are

permanently removed from deidenti-

fi ed biospecimens, recent technology

has made it possible to break through

those protections, says Omenn.

Nonetheless, the system works very

well overall and is accepted by most

institutional review boards (IRB).

Requiring investigators to reidentify

those samples and track down affected

individuals long after the initial

research has taken place would have

represented a signifi cant administrative

and fi nancial burden, he says. Alter-

natively, the fi nal rule allows research

participants to grant broad consent for

use of identifi able biospecimens—those

where personal identifi ers have been

removed and replaced with codes that

can be unlocked and traced back to the

source when appropriate.

Under the fi nal rule, investigators have

the option of using deidentifi ed samples

without obtaining new consent for

additional research or requesting broad

consent to use identifi able biospecimens

for unspecifi ed future research. The lat-

ter has the advantage of making it easier

for participants to be notifi ed about

actionable fi ndings resulting from future

research, notes Omenn.

The fi nal rule also encourages cre-

ation of a single IRB for federally funded

multisite studies, beginning in 2020.

“We’re pleased that the fi nal rule

allows for the use of a broad but simple

consent from a research participant

regarding the storage, maintenance, and

secondary research use of identifi able

private information and identifi able bio-

specimens,” says Omenn. “With a single

multisite IRB review it’s estimated that

investigators will spend half as much

time engaging with the review process as

they would have if separate reviews were

required at each site.” –Janet Colwell ■

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