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A Look Inside Our Cancer Medicine Cabinet

One-of-a-Kind Advances in Drug Discovery and Development

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P&PTHE S IDNEY K IMMELCOMPREHENS IVE CANCER CENTER ATJOHNS HOPK INS

DRUG DISCOVERY is complicated, difficultwork, but Kimmel Cancer Center expertsare among the best at it, a distinctionthey have held for nearly four decades.In 1979, our cancer center was one ofthe first to earn a National Cancer Insti-tute grant for new drug development,and today we remain one of the selectfew to maintain this support. From earlywork with cyclophosphamide to today’sbreakthrough immunotherapies, our experts have a proven track record ofsuccess in translating laboratory andclinical discoveries into new cancer medicines for patients.

To ensure these advances continue in a new research environment, wherethe onus of early drug discovery and development has shifted from the pharmaceutical industry to the academicresearcher, we are working to bring a reimagined drug discovery and development engine to the Kimmel Cancer Center.

Despite its difficulty, drug discoverythrives in our unique environment of collaboration and unparalleled expertisein virtually every area of bench-to-bed-side cancer research. Discoveries inthese fields are providing the cancer targets that are driving new drug development and precision medicine.

Our experts are identifying cancer-promoting molecular targets, inventing

drugs that go after them and developingtests that can identify patients who have cancers with the targeted defect. As a result, clinical trials are being designed to test new drugs only in the patients they are most likely to help—those whose cancers contain the defectthat will respond to the drug. This allowsclinical trials to progress more rapidlyand new drugs to get approved fasterand at a much lower cost.

As we near completion of the 10-storySkip Viragh Outpatient Cancer Building,we are poised to provide and move forward the most advanced and sophis-ticated cancer care. Our depth of expertisein cancer research and drug discovery,and the most technologically advancedand patient-centered clinical facilities setthe Kimmel Cancer Center apart as amongthe most talent rich and resource readyto develop and study new cancer drugs.

We are committed to providing the necessary drug development tools, resources and funding for our scientistsand doctors, and more rapid access tonew cancer drugs for our patients.

William G. Nelson, M.D., Ph.D.Marion I. Knott Professor and DirectorThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Driving DrugDiscovery

THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 1

2 PROMISE & PROGRESS

Much has changed since the early daysof developing cancer drugs. Pharmaceu-tical companies have largely pulled outof drug discovery, leaving academic cancer researchers with the charge tobring cancer medicines forward. To answer the challenge, Kimmel

Cancer Center Director William Nelsonis restructuring research programs toprovide Cancer Center investigators withthe laboratory resources they need tomaintain their leading edge, fosteringcollaborations and partnerships to getdrugs made and moved ahead. Ultimately,he envisions a reconfigured drug discov-ery program to garner the scientific andfinancial resources needed to reduce the time from discovery to clinical trial.“So much time is lost when investigatorshave to hunt for money to move drugdiscoveries to the clinic,” says Nelson.“We have the expertise to providethe specialized research support andexpertise to get promising medicines to patients faster.” Delays in funding are one of the

biggest challenges for drug discovery

and development. The biggest fundinggap comes at the most critical time, justabout the time a drug discovery is ready togo to patients. It takes about $2 millionto $3 million to make this leap, and thisis where many promisingprojects die. “Our inves-tigators can lose a year ortwo searching for funding tomove forward,” says Nelson.No one understands this

better than James Bergerand Jun Liu, who are at theepicenter of drug develop-ment for the Kimmel CancerCenter. Liu, a medicinalchemist, and Berger, a biophysicist, leadthe Chemical and Structural BiologyProgram. They are experts in decipher-ing how drugs travel through the body,where they go, how long they stay there,and how they change the behavior ofcells and genes along the way.“Drug discovery and development

are hard and expensive, but if we don’tdo it, it’s not going to get done becausepharma has divested itself of it,” says

Berger, a member of the prestigious National Academy of Sciences. Nelsonbelieves the Kimmel Cancer Center canhelp shift the curve in a more positivedirection through better research models

and expert help along the way.“We have deep expertise

in biological cancer targets. We have people who have worked on a target for 20 years and may have even discovered it,” says Berger. “They understand its potential and drawbacks better than anyone. If we give these

people a little support, it won’t take muchto figure out if it will work.”Finding new uses for old drugs is one

approach that offers both cost savingsand a faster route to the clinic. Liu helpsresearchers search for new uses of existing drugs from a large collectionsof known drugs called drug libraries. Libraries of FDA-approved drugs usedto treat other diseases, catalogs of drugsabandoned by pharmaceutical companies,

Moving Cancer Medicines ForwardReimagining drug discovery and developmentFrom scientific meetings to our own dinner tables, conversationsabout better treatments for cancer are among the most frequently discussed health care topics. Everyone wants them—the doctors andscientists who treat and research cancer, those of us who worry wemay one day hear the words “you have cancer,” and most certainly thehundreds of thousands who have already been diagnosed. Whether it’sold-school chemotherapy or a brand-new immunotherapy, when wesay “new treatment,” the form this much-sought progress usuallytakes is a drug—either a new one made from the ground up or an existing one that scientists modify to attack cancer cells.

$2 MillionJUST ABOUT THE TIME A DRUG DISCOVERY IS READY TO GO TO PATIENTS.

IT TAKES ABOUT $2 MILLION TO $3 MILLION TO MAKE THIS LEAP, AND THIS IS WHERE MANY PROMISING

PROJECTS DIE.

JAMES BERGER AND JUN LIU LEAD THE CHEMICAL ANDSTRUCTURAL BIOLOGY PROGRAM. THEY ARE EXPERTS IN DECIPHERING HOW DRUGS TRAVEL THROUGH THEBODY, WHERE THEY GO, HOW LONG THEY STAY THERE,AND HOW THEY CHANGES THE BEHAVIOR OF CELLS ANDGENES THEY COMES IN CONTACT WITH.

“If you discover a new indication for an existingdrug, you bypass some ofthe drug discovery workand cost. All of the earlyhurdles are skipped, andyou cross easily what wecall the ‘valley of death.’” —Jun Liu



and libraries of biologics or natural drugsthat target and block the communicationof specific disease-driving genes providefertile terrain for scientists hoping to minefor existing drugs they can potentiallyrepurpose as cancer-targeted therapies.Over the last decade, Liu has cataloged

a collection of known drugs that couldpotentially find a new application incancer. With more funding, he and histeam have plans to grow its scope andsize. To be most useful, drug librariesmust be continually updated to stay current as new drugs hit the market.“A drug that is very well-character-

ized may have some activity againstother targets, including cancer targets,”says Liu. Clinical trials of known, FDA-approved drugs can advance morequickly because side effects and dosinghave already been studied. Liu is building new molecular libraries

that have promise to become cancer drugs.He has already successfully traversed thelandscape in his own research, applyinga drug library find to cancer and movingit to clinical trials and, ultimately, com-mercial licensing.“If you discover a new indication for

an existing drug, you bypass some of thedrug discovery work and cost,” says Liu.“All of the early hurdles are skipped, andyou cross easily what we call the ‘valleyof death.’” This metaphorical place is very real

to investigators who uncover promisingcancer targets and drugs, only to see theirideas languish and fizzle out because theyare unable to secure funding. The sym-bolic terminology genuinely reflects acritical crossroads that connects labora-tory research to its translation into clini-cal trials of promising new treatments. Liu’s drug library approach is not a

slam dunk. Drugs typically requirechemical changes to create a cancer-specific formulation. “Drugs have to be stable and have to be absorbed andaccumulated at a certain concentrationin humans,” says Liu. “They can’t justkill cancer cells in a test tube in some-one’s laboratory. We must be able to giveit to humans, if it is going to become anew cancer medicine.”

This is familiar work to Cancer Centerclinicians and investigators. Paclitaxel is now a mainstay in the treatment of avariety of cancers, but when the drugwas first developed decades ago, it wasnearly abandoned in the transition frombench to bedside because patients couldnot absorb the drug into their blood-stream where it could circulate and killcancer cells. The Kimmel Cancer Center’sRoss Donehowerwas among the teamthat developed premedications that allowed paclitaxel to be safely given tocancer patients. In the late 1980s, theCancer Center became the first in thenation to report promising results inclinical trials of the drug to treat ovariancancer, but paclitaxel—acclaimed at the time as the most promising new anticancer drug in 15 years—might neverhave reached patients if not for the persistence of Donehower and team.

Today, Liu is doing similar work withan anti-fungal drug called itraconazole,which is used to treat toenail fungal infections. In 2006, Liu found the drugamong a library of 3,000 FDA-approveddrugs. He selected it for its ability to stoptwo cancer-promoting processes—oneknown as angiogenesis, where tumorsdevelop blood vessels to get the nour-ishment they need to grow and spread,and the other, a cancer-initiating biolog-ical pathway called Hedgehog. “We were amazed to find a single drug

with multiple anticancer properties,”says Liu.In animal studies, he found the drug

was particularly effective against prostatecancer cells. Since the drug was alreadyFDA approved, Liu was able to workwith Kimmel Cancer Center prostate

cancer experts to move the drug intoclinical trials in less than five years. Liu continues to study how the drug

works at the molecular level, and hasdeveloped new chemical formulationsto address liver toxicities and apply thetherapy to other types of cancer. His most recent research uses the

drug as a much-needed treatment alter-native for people with basal cell skincancers. “This cancer is a lifetime threatfor patients who have it. They get manytumors on various parts of their bodies,and when the tumors grow to a certainsize, they have to be removed with sur-gery,” says Liu. Until his itraconazolediscovery, there were limited treatmentoptions for this cancer. Cancers that oc-curred on the face in tricky places, suchas eyelids, were excruciatingly difficultto remove surgically and often left bothphysical and emotional scars. Liu saysitraconazole works in more than half ofbasal cell skin cancers and allows patientsto avoid surgery. “These results show that we can

quickly move our discoveries frombench to bedside,” says Liu.

Laboratory scientist Gregg Semenzaalso found success using drug libraries. Nearly 20 years ago,

he discovered a cancer target calledHIF-1-alpha. It helps cancer cells acquirethe oxygen and nutrients they need tosurvive and grow by stimulating bloodvessel growth. But HIF-1 also has a cancer-preventive property. It can blockcell division by preventing cells fromcopying their DNA. “Cancer cells want HIF-1 around to

stimulate blood vessel growth, exceptwhen they want to divide,” says Semenza.True to form, cancer cells have developeda system for accomplishing these seem-ingly incompatible tasks. They use tworelated proteins long known to be involvedin cell growth. One protein enters thepicture just before cells begin to copytheir DNA, attaches to HIF-1 and causesit to be destroyed, removing it as an obstruction to the copying process.After cells finish copying their DNA, the second protein enters and has the opposite effect. It restores HIF-1,

“Academic research bringsa lot of people working in alot of systems to the drugdiscovery arena. That givesus the ability to generatemany fresh ideas and takea lot of shots on goal. Wedon’t expect all of them to pan out.”—James Berger


[Discovery]Gary Schauder, who faced bullets and Agent Orange while servinghis country in Vietnam, was not about to let prostate cancer scarehim. When Schauder’s prostate cancer returned a few years after surgery and continued to grow on treatments aimed at slowing itsprogress, his wife encouraged him to make an appointment at theJohns Hopkins Kimmel Cancer Center. Under the care of prostate cancer expert Mario Eisenberger and nurse Vicki Sinibaldi (pictured at left), he began treatment with pharmacological testosterone—an experimental approach developed by prostate cancer researcher Sam Denmeade. “I received the drug for the first time about twoyears ago,” says Schauder. “My PSA went from 14 to undetectable.It’s starting to elevate a little now, but not much. It’s not even up toone.” The 72-year-old says he feels energetic and lifts weights forover an hour every day. “It’s nice to know I’m coming to a placewhere I feel like they’re helping me and using what they learn fromme to help others,” says Schauder. “One day, the research they’redoing here is going to wipe out this disease.” •


LABORATORY SCIENTIST GREGG SEMENZAFOUND SUCCESS USING DRUG LIBRARIES.NEARLY 20 YEARS AGO, HE DISCOVERED A CANCER TARGET CALLED HIF-1-ALPHA. IT HELPS CANCER CELLS ACQUIRE THE OXYGEN AND NUTRIENTS THEY NEED TO SURVIVE AND GROW BY STIMULATING BLOOD VESSEL GROWTH.

PROSTATE CANCER RESEARCHERSVASAN YEGNASUBRAMANIANAND ELIZABETH PLATZ FOUNDTHAT DIGOXIN, A DRUG USED TO TREAT HEART FAILURE, APPEARED TO STOP THE GROWTHOF PROSTATE CANCER CELLS.


protects it from destruction and stimulatesblood vessel growth.Semenza found several drugs in libraries

that inactivate the HIF-1-alpha-protectingprotein that are currently being tested incancer clinical trials. This research earnedhim a prestigious Lasker Award in 2016.Semenza’s work intersects with

another application of an FDA-approveddrug for cancer. In 2010, Nelson andprostate cancer researchers Vasan Yegnasubramanian and ElizabethPlatz found that digoxin, a drug used totreat heart failure, appeared to stop thegrowth of prostate cancer cells. Researchby Liu and Semenza showed that one ofthe ways digoxin works against prostatecancer is by targeting and blocking HIF-1.Although early trials with digoxin inprostate cancer did not work againstprostate cancer as hoped, the researchersbelieve the target is a good one and are nowstudying other drugs that inhibit HIF-1.Liu and Berger believe there are many

other existing drugs that have yet-to-be-realized anticancer properties. “There isno such thing as a perfectly specific drug,”says Berger. “There is always some degreeof cross-talk.”Liu and Berger attribute some of this

early success in finding drugs that mayhave anticancer properties and movingthem to the clinic to the infrastructurethat was put in place byMichael Carducciand Philip Cole, who like Albert Owens,Michael Colvin and Donehower, helpedgrow the Kimmel Cancer Center’s drugdiscovery efforts. Carducci and his prostate cancer

colleague Emmanuel Antonarakis tookitraconazole to their patients, and Car-ducci, who directs and coordinates clin-ical research among all Kimmel CancerCenter locations, and a cancer drug dis-covery expert in his own right, is con-necting Liu and Berger to other clinicalcancer experts and researchers acrossall cancer programs and cancer types.Berger and Liu understand the small

bumps along the drug discovery routethat can derail a project. There is an artto figuring out how to move a target alongand deciphering when a problem is fixable or when it means it’s time to

abandon a project. Drug discovery is nota linear process.“If a researcher doesn’t get a hit from

a drug library, it doesn’t always mean theidea is bad,” says Berger. “It could be re-lated to the testing assay. A good assayshould provide a handful of compoundsthat may work against the cancer target.If you don’t start with a good assay, itcould produce 100 hits, the majority ofwhich are false positives, and then youdon’t know where to start.” He and Liucan work with researchers in this case toadvise them on the design of a betterassay to measure the function, presenceand activity of the cancer target.

Liu and Berger have set up a web-basedportal that helps cancer researcherswalk through questions that help themdetermine if they have a good target, ifthere is already a compound that hits thetarget and whether or not their target ispatented by another researcher.“We want to cast a wide net and allow

our scientists to take some chances tosee if ideas pan out,” says Berger. “At thesame time, we built in checkpoints to shiftapproaches if things aren’t working.”His mantra is one borrowed from

successful but risky industries: “Failoften, but fail early.” His and Liu’s goalis to foster a mindset and environment

The Kimmel Cancer Center has along history of moving cancermedicines forward. Whether it

was the Cancer Center’s first director,Albert Owens, and his recruit GeorgeSantos developing a preparative drugregimen for bone marrow transplant;Michael Colvin deciphering how cy-clophosphamide works and becomingone of the first to use it in high doses totreat cancer patients; Ross Donehower,creating a pre-medication that reducedwhat seemed like the insurmountabletoxicities of paclitaxel, now a mainstayin cancer therapy; or David Ettingerensuring that studies of promisingnew cancer drugs were made avail-able to cancer patients throughout the

U.S. through outreach to communityphysicians, our experts were trailblaz-ers in drug discovery and development.

After the National Cancer Act wasannounced in 1971, Johns Hopkins became the site of one of the firstcomprehensive cancer centers desig-nated by the National Cancer Instituteand one of the first to earn a grant to begin clinical trials of new drugs.Our experts quickly earned recognitionas they aggressively tested the limitsand power of existing drugs, and invented new agents when what wehad failed to get the job done.

In 1973, when our Cancer Centeropened its doors for the first time,there was no such thing as combinedtherapies. There wasn’t a singlegenetic mutation or epigenetic changelinked to cancer, and no one understoodwhy the immune system was idleagainst cancer. Today, our expertshave led the science in each of theseareas and the translation of the scienceinto new drug therapies that targetevery kind of cancer driver. They continue to be among the best in theworld at discovering cancer-promotingchanges that can be targeted withtherapy, finding or developing drugsthat promise to go after the cancer target, and developing tests known as assays that show whether or notthe drug is having the intended effecton the target. •

Trailblazers in Drug Discovery

MICHAEL COLVIN (LEFT)WITH ALBERT OWENS


that provides researchers and cliniciansthe freedom to explore novel ideas. This is a philosophy that has becomethe signature characteristic of KimmelCancer Center research programs, but it also puts into place a mechanism forfailing projects to be redirected orstopped before millions of dollars havebeen spent. “Academic research brings a lot of

people working in a lot of systems to thedrug discovery arena,” says Berger. “Thatgives us the ability to generate many freshideas and take a lot of shots on goal. Wedon’t expect all of them to pan out.”Even when a project doesn’t work

out, Liu says, more often than not, it stillinforms. “Every step along the way con-tributes. Someone may discover a smallmolecule that never becomes a drug, butif the early research is good, it will be thefoundation for a pharmaceutical or biotechcompany to come in with its own expert-ise,” he says. “This is important becauseeven if our experts don’t see the projectall the way through, we have still con-tributed to the drug discovery process.”This is certainly the case with recent

discoveries coming from the Bloomberg~Kimmel Institute for Cancer Immunother-apy. Researchers identified several pro-teins that cancer uses to shield itself fromthe immune system. Drugs that blockthese proteins allow the immune systemto see cancer and attack it. There areseveral proteins involved in this process,but among the most notable so far arePD-1 and PD-L1. Our Cancer Center ex-perts didn’t discover the drugs that blockthese proteins, but the drugs were builtupon the researchers’ science, and theseCancer Center experts have collaboratedthroughout the process. Pharmaceuticalcompanies have now developed morethan 20 drugs that are FDA approved or in clinical testing that tear downthese shields and make cancer cells vulnerable to immune attack. Bristol-Myers Squibb’s Opdivo (nivolumab) and Merck’s Keytruda (pembrolizumab)are two examples of new FDA-approvedimmunotherapies that target PD-1 andPD-L1, and are having quite remarkableresponses in patients.

“Nivolumab plus ipilimumab was thefirst immunotherapy combination FDA-approved for any cancer,” says SuzanneTopalian, a Bloomberg~Kimmel Instituteassociate director. “Immunotherapycombinations are an active area of research, with several hundred ongoingtrials of various combinations.” Ipilimumabblocks another shielding protein calledCTLA-4. In clinical trials, Topalian sayscombining the two immunotherapies had amore powerful immediate affect againstmelanoma skin cancer than either drugbut also had increased toxicity. Right now, the drugs don’t work for

everyone, but for a small subset of patients,immunotherapy has literally meant the difference between life and death.Nivolumab is FDA approved for treat-ment of advanced nonsmall-cell lungcancer patients whose cancers progresson standard therapy, and pembrolizumabbecame the first immunotherapy to gainFDA approval as the front-line treatmentfor nonsmall-cell lung cancer patientswhose cancer cells have a lot of a PD-L1protein. Pembrolizumab works so wellin this PD-L1 subset of lung cancer patients, extending survival well beyondwhat chemotherapy was able to do, thatthese patients can now forgo chemotherapyand start with immunotherapy. Recently,a front-line combination of chemother-apy and pembrolizumab was approvedfor patients with advanced lung cancer,making this the second FDA-approvedimmunotherapy combination therapy.Lung cancer expert Julie Brahmer

led the clinical trial that produced thedata used to earn the FDA approval fornivolumab and prembrolizumab. “Theseresults represent a landmark in the historyof immunotherapy in cancer. Resultsshowed immunotherapy could be usedto treat common cancers and brought itout of the realm of specialized treatmentinto the broader realm of oncology.Nivolumab has produced the longestfollow-up to date of an immune check-point inhibitor. Five-year overall survivalquadrupled in nonsmall-cell lung cancer,compared with what we would expectfrom chemotherapy,” says Brahmer. “We are doing further studies of these

survivors to determine why they hadsuch a good outcome. We also want tobetter understand which patients canstop treatment at two years and whichof them need to continue treatment beyond two years.” Many patients con-tinue to have an immune response afterthe drug is stopped, but right now expertsdon’t have a way to distinguish those who need more therapy from those who can stop treatment.“Based on these data, I think we can

shorten the amount of time patients aretreated. But we need to identify thosepatients who develop immune memory,”says Brahmer. “I think we can safely saynot all patients need indefinite treatment.We want to personalize therapy. We arecontinuing to look for biomarkers forresponse and long-term control.”Helping with the biomarker discovery

is Topalian, Bloomberg~Kimmel InstituteDirector Drew Pardoll, and pathologistsJanis Taube and Bob Anders, who developed the test that detects andmeasures levels of PD-L1 in lung cancerpatients. It cemented the FDA approvalbecause it allows doctors to identify patients who are likely to benefit.Biomarker discovery is pivotal to

Nelson’s drug discovery and developmentplans. “The key reason drug research isso costly and frequently fails,” he says,“is that often in trials, drugs do not lookgood because we test them on everyoneinstead of testing them on the specificpatients we think it will help.”

The Kimmel Cancer Center isleading the way in precisionmedicine approaches that use

biomarker tests to guide cancer treatment.Just weeks ago, another FDA approvalfor prembrolizumab hinged on a biomarker test. This time, the approvalcame for patients with a spell-checklikefailure in their DNA called mismatch re-pair deficiency. This failure allows DNAerrors to go uncorrected, contributing tomany different types of cancer, includingcolon, breast, prostate, bladder, ovarianand pancreas cancers. However, theseerrors also arouse the immune system.Mismatch repair deficiency in cancer wasdiscovered by cancer genetics experts


BLOOMBERG~KIMMEL INSTITUTE DIRECTOR DREW PARDOLL (LEFT)AND JANICE TAUBE (BELOW LEFT) DEVELOPED A TEST THAT DETECTSAND MEASURES LEVELS OF PD-L1 IN LUNG CANCER PATIENTS. AS A RESULT, DOCTORS CAN MORE EASILY IDENTIFY PATIENTS WHO ARE LIKELY TO BENEFIT FROM CERTAIN CANCER DRUGS.

PATHOLOGIST JANIS TAUBE

LUNG CANCER EXPERT JULIEBRAHMER LED A CLINICAL TRIALTHAT PRODUCED DATA USED TOEARN FDA APPROVAL OF A NEWDRUG FOR LUNG CANCER.

[Discovery]Donald Kirk received a haploidentical bonemarrow transplant for lymphoma in 2014.“I can’t say enough about everyone here—the doctors, nurses and all of the staff.They are the best,” says Kirk, who has aspecial connection to the Kimmel CancerCenter. His company, Windsor Electric Co.Inc., is doing the electrical construction for the Cancer Center’s new Skip ViraghOutpatient Cancer Building. During hisseven-week stay in the hospital, he followedthe construction from his room in the Weinberg Building. One day, he looked out his window and saw his workers hadhung a large banner that said, “Don, GetWell Soon.”•



Bert Vogelstein, Ken Kinzler andtheir Ludwig Center team in 1993.It was linked to immunotherapyresponse in 2013 through aBloomberg~Kimmel Institute collaboration between cancer genetics and cancer immunology researchers. The discovery set the stage for the first-ever FDA approval of a drug based on cancer genetics, not cancer type. “It’s incredibly exciting that we

now can prescribe pembrolizumabfor patients with mismatch repair-deficient cancers. This could reach 2 to 3 percent of all advanced solid tumorpatients. We now have a reason to testfor DNA mismatch repair deficiency inalmost any disease given the potential for durable clinical benefit,” says DungLe, who ran the groundbreaking clinicaltrial.These kind of results support Nelson’s

belief that creating silos for cancer bysite is counterproductive to drug discov-ery and development in the high-tech erathat allows us to see the genetic structureof every cancer. Nelson believes what isinside the DNA of a cancer cell may bemuch more informative for guidingtreatment than the area of the body inwhich it occurs.“Typically, it has taken about 15 years

and $1 billion to discover and develop adrug. We are making discoveries thatpromise to reduce that to a couple ofyears and a few million dollars just bychanging the way we select patients forclinical trials,” says Nelson. “If we beginstudying drugs in the patients they arelikely to help, everyone benefits. Patientsdo better, research progresses morequickly and costs come down.”Liu and Berger believe they can get

drugs moving forward with a fraction of what it used to cost. A $20 million investment would provide the resourcesthey need to help Kimmel Cancer Centerinvestigators through the laboratorystages of drug discovery and developmentto screen targets, develop the assays tomeasure the amount of drug that gets to the target, complete animal studies,

and generally support thescience needed to figureout if the drug works andhow it works. “Just because you have

something that binds to aprotein doesn’t mean it’sgoing to cross the cellmembrane. And just be-cause something crossesthe cell membrane does-n’t mean it’s going to killcancer,” says Berger.This kind of work is

a bit costly, but it is essential to findingnew treatments, and it does not get federal funding. “NIH has a very finitepool of dollars, and everyone has a lot ofcreative ideas they would like funded,”says Berger. “To some extent, drug discovery is a bit of a fishing expedition,

and that’s why NIH and pharma don’tlike it. It’s hard and it’s uncertain, but it’salso the only path forward.”If there were a guaranteed drug that

was sure to work against cancer at theend of the research, everyone would fundit. But medicine isn’t an exact science, andthe truth is that many times the earlywork turns up nothing. Still, Bergerechoes Liu when he says even the thingsthat fail inform them about the nextsteps. “In science, you very rarely get toa point where you say ‘That was a deadend’ or ‘That was a waste of time,’” saysBerger. “Instead, it’s usually, ‘Gee, nowwe know this, and now we should go indifferent direction and try this.’”Berger says any first-of-its-kind drug—

a potential game-changer—requires theopportunity to follow leads and a will-ingness to take risks.

CLINICIAN-SCIENTIST DUNG LE HELPSBRING NEW CANCER DRUGS TO PATIENTSTHROUGH CLINICAL TRIALS.

15IT TAKES ABOUT

15 YEARS TO DISCOVERAND DEVELOP A DRUG. BY CHANGING THE WAY

PATIENTS ARE SELECTED FOR CLINICAL TRIALS,

DISCOVERIES PROMISETO REDUCE THAT TO A COUPLE OF YEARS.

However, when it comes to limitingrisk, the Kimmel Cancer Center’s trackrecord in drug discovery and developmentmakes it a good bet. This success is attributable to its people, says Berger.“We have arguably the most knowledge-able researchers in the fields of cancergenetics, epigenetics and immunology, ”he says. “Everything we enjoy todaycomes from basic science conducted 10, 20, 30, 40 or more years ago. Scientificdiscovery is not linear. The path forwardis not always clear, but every findingadds to our knowledge and builds uponthe foundation, and we have the expertsand the willingness to collaborate that make it possible to put all of thepieces together.”It is this depth of expertise in all of

the critical areas of cancer researchand a culture that supports sharinginformation and working togetherthat make it an incubator for newcancer drugs. The Kimmel CancerCenter is also a center that workslean and mean. “It is not the biggestcancer center, but it is, by any formof measurement, one of the mostaccomplished,” says Berger.The missing ingredient in what

would otherwise be a nearly perfectrecipe for drug discovery and develop-ment is sustained funding. Discovery isslowed because researchers get so far,but they have to stop and apply for morefunding before they can move forward.Precious years are lost to the search forfunding. “If we want to work quicklywith focus, it takes funds that currentlydon’t exist,” says Liu. “If we had both,we could do more great things. ” Berger and Liu want the Chemical

and Structural Biology Program to bethat resource for cancer researchers.“We have to make drugs that attack onepart of us without attacking anotherpart,” says Berger. “Investigators get stuck,and they don’t know who to turn to.”

The PipelineImmunotherapy discoveries are justpart of the drug arsenal Kimmel CancerCenter scientists are helping to assemble.Nelson’s approach is to go after every

vulnerability of the cancer cell. He hasbeen in the business long enough toknow that the cancer cell is as complexand crafty as they come. With all of thenatural processes of cell division andgrowth at its disposal, the cancer cell isa master at exploiting these processes to find new ways to cheat death. His vision is to use new technologies and reveal the genetic miscues that driveeach person’s cancer, and help find ordevelop drugs that either correct the

miscues or shut them down. There are always going to be

a small number of cancers so de-pendent on a particular geneticmiscue that they may onlyneed one approach. This isexciting when it happens,but it doesn’t apply to themajority of cancer patients.Most experts agree thatcancers, particularlythose diagnosed at an advanced stage that havehad decades to corruptmany cell processes totheir benefit, will likelyrequire combined thera-pies, including surgery,targeted therapies, im-

munotherapies and radiation therapies.“Gene mutations are like fingertips.

You cut one off, and the cancer cells justwork around it,” says Venu Raman, whois working on a drug that attacks cancercells directly and also sensitizes them to radiation.Nelson believes a combined assault

has the potential to disconnect cancercells from their survival tools and finallyoverpower them.

RK-33Raman’s drug discovery began with research to understand the effect of secondhand smoke on breast cancer. Itled him and his team to develop a first-in-class drug called RK-33. Countlesshours in the lab and hundreds of experi-ments and assays later, Raman and histeam have developed and patented a smallmolecule inhibitor of the DDX3 gene, anexciting first-in-class pharmaceutical.

Research that began in 2005 withfunding from the Flight Attendant Medical Research Institute found that a gene called DDX3 was abundantly expressed in cells exposed to cigarettesmoke. Raman’s lab took a closer look at the gene, and when they blocked itsfunction in animal models, tumorsshrank, and the cancer didn’t spread. Tumors that spread from their original

site, called metastatic, had the greatestexpression of DDX3. “This finding fasci-nated me because metastatic cancers arethe most difficult to treat,” says Raman. The DDX3 gene was already known to

be instrumental in the replication ofviruses, but no one had developed a wayto block it. Working with a medicinalchemist, Raman came up with a series ofpotential drug compounds designed toinhibit DDX3 activity. After testing dif-ferent combinations, the 33rd compoundhit the target, and RK-33 was born. “That was a big day,” Raman says.

“It’s when everything went from theoryto reality. We had discovered a new wayto attack one of the key enablers of cancerous activity.”When Raman and his team first tested

RK-33 in breast cancer cell lines, it hadlittle effect on normal breast cells withlow DDX3 expression. When they testedit in triple-negative breast cancer cellswith high DDX3 expression, however,RK-33 easily killed the cancer cells.“If you imagine your hand as a can-

cerous tumor,” he says, referring to hismutation/fingertip analogy, “many ofthe drugs that we use to attack canceract by cutting off a finger. There are stillmultiple other fingers left, and the restof the hand can still function and evolve,leading to further spread and evenadaptation of cancerous cells. RK-33acts more like it is cutting off the wrist.When targeted successfully, it preventsa tumor’s access to other survival options.Any tumor-sustaining mutations arerendered useless to the cancer cell because it cannot replicate itself.”Since RK-33 attacks overexpressed

concentrations of DDX3 with greater intensity and efficacy, it should be toxicto tumors but not to the rest of the body.


RK-33RK-33, A NEW

PATENTED DRUG INDEVELOPMENT

BLOCKS THE DDX3GENE. OVEREXPRES-

SION OF THE GENE ISLINKED TO MANY

TYPES OF CANCER.


VENU RAMAN IS WORKING ON A DRUG CALLEDRK-33 THAT ATTACKS CANCER CELLS DIRECTLYAND ALSO SENSITIZES THEM TO RADIATION.RAMAN’S DRUG DISCOVERY BEGAN WITH RESEARCH TO UNDERSTAND THE EFFECT OF SECONDHAND SMOKE ON BREAST CANCER. ITALSO APPEARS TO BE ONE OF THE FEW DRUGSTHAT WORK AGAINST METASTATIC CANCER CELLS.




Studies of the drug’s toxic effects onnormal cells followed, and as Raman increased the dose of RK-33, it began towork against cancer cells with differentlevels of DDX3 expression but did notharm normal cells. “We did extensivetoxicology experiments,” says Raman.“Even at four times the therapeuticdose, it was not toxic in animal models.”Since the project that originally led

him to RK-33 involved smoking-associ-ated cancer, Raman decided to also lookat lung cancer, and he found it also hadsignificant overexpression of DDX3.“I thought it was too good to be true,”

says Raman. “We repeated and repeatedthe lung cancer studies, and we found outthat in sample after sample, this gene wasoverexpressed. It couldn’t be a coincidence.”Further studies showed the gene was

overexpressed in many cancer types, including triple-negative breast cancer,one of the most treatment-resistantforms of breast cancer; lung cancer;prostate cancer; sarcoma; and colorectalcancer. With his DDX3 gene target appearing to play a role across cancertypes and his DDX3-blocking drug RK-33patented and in development, Raman wentback to the laboratory to decipher exactlyhow his drug worked at the cellular level. “The gene is a critical part of the body’s

DNA repair mechanism,” says Raman.“Cancer cells use it to reproduce andmaintain the genetic stability essential totheir survival.” Raman found that block-ing the gene with RK-33 not only killedcancer cells directly but also sensitizedthem to treatment with radiation therapy.Radiation therapy kills cancer cells

by damaging cell DNA beyond its abilityto make repairs. Cancer cells that sur-vive treatment do so because they areable to repair their DNA. Raman saysRK-33 helps disable this repair mecha-nism. “If you irradiate cells, their DNAstrands break, but over a short period oftime, they get repaired. When you addRK-33, the strands remain broken. Thecells cannot make repairs.” This finding led Raman to patent his

drug as a radiation therapy sensitizer, butthe evidence from his research shows itdoes more. One of the most exciting

characteristics of RK-33 is its ability todestroy metastatic cancers—the often-lethal cancers that spread from the original site of a tumor and seed new,treatment-resistant tumors in differentparts of the body. Metastatic breast cancers have very high levels of DDX3.“Metastasis to the bone, brain and

lung is common in cancer, but there arefew drugs that have any long-lasting impact against metastatic cancers,” saysRaman. RK-33 could be the critical difference-maker in the fight againstthese entrenched, often terminal, cancers. “Currently, there is no curative treat-

ment for brain cancer metastasis,” hesays. “It’s hard to find a silver bullet forcancer, but because RK-33 is nontoxicand a phenomenal radiosensitizer, thereare so many opportunities, includingmetastatic cancers.”The potential to offer better outcomes

to patients with the most difficult diag-noses is what Raman is most excitedabout. He offers a list of possibilities.“Advanced prostate and colon cancer,sarcoma (bone cancer), brain tumors,

inflammatory breast cancer—all theseindications are looking promising inmultiple cancer models,” he says. “Wethink RK-33 will work in any cancerthat requires DDX3. And so far, all thesedifficult cancers require DDX3. “My father is a colon cancer survivor,”

says Raman, “but unfortunately, notevery patient responds to our currenttreatments. This compound represents achance to change outcomes and save lives,and that’s the best of what advanced biological research is about.”Raman is now in the last stages of

refining RK-33. Because of its broad application, low toxicity and ability tosensitize cancer cells to radiation ther-apy, Raman wants a formulation thatcan be used in both adult and pediatricpatients. His goal is to have a drug readyto go to patients in clinical trial withinthe year. “We have a lot of pediatric cancer pa-

tients at Hopkins, and we are constantlylooking to develop solutions that improvetheir outcomes,” says Raman.Raman draws inspiration from a par-

ticular patient. “Tara is a young girl whowas diagnosed with a metastatic bonecancer called sarcoma two weeks beforeher 4th birthday,” says Raman. “Currently,there is no standard of care for her dis-ease because all treatments have workedso poorly. Nearly 80 percent of metasta-tic sarcoma patients relapse within twoyears of being diagnosed, and five-yearsurvival is less than 20 percent.“Hopefully this drug will offer new

hope and better outcomes for patientslike Tara and their families,” Raman says.“That’s why we’re pushing to get RK-33into human trials as fast as we can.”Despite these promising discoveries,

Raman is now facing what is known asthe “valley of death.” Funding needs escalate rapidly as the drug is tested inhumans and then across larger popula-tions, and progress on the new drug willlikely slow, or even stop, as he appliesfor more grants and appeals to more donors.His immediate goal is to obtain enoughfunding to complete the costly experimentsrequired to file an Investigational NewDrug application with the FDA.

[Discovery]Tara was diagnosed with advanced sar-coma two weeks before her 4th birthday.Venu Raman is working to get his experi-mental drug, RK-33, into clinical trials. In laboratory studies, the drug workswell against metastatic cancer cells, andhe is hopeful it will provide new options to patients with advanced cancers, like Tara. •

[Discovery]Trina Isaac has advanced colon cancer and is amongthe many cancer patients who look to clinical trials ofpromising new drugs to gain an edge against aggres-sive cancers. “This journey isn’t easy,” says Isaac,who has a young son. “I worry about not being therefor him. I’ve prayed, and I’ve cried, but I refuse to letit control me,” says Isaac, whose motto is MMOP—make memories on purpose. “I have cancer, but cancer doesn’t have me.” •


The Flight Attendant Medical ResearchInstitute, Safeway, the Dutch CancerFoundation, Alex’s Lemonade StandFoundation, TEDCO and other fundingpartners have brought RK-33 this far,but Raman says that he needs about $3 million to $4 million more.“Like it or not,” Raman says, “the

reality of the life sciences industry todayis that the pace of getting new drugs topatients is controlled by investigators’ability to find financial partners.”Standing by anxiously are his Kimmel

Cancer Center clinical collaborators: ra-diation oncologist Phuoc Tran, pediatricsarcoma expert David Loeb and breastcancer expert Vered Stearns, who willlead the clinical studies in patients.“I am so lucky to work in a place like

Hopkins. I have a great team working withme. From day one, all of them wanted tohelp—with no conditions. They are in itfor the patients,” says Raman. “That’sessential because if you are trying tomake advances against cancer, you needscientists and clinicians working together.I can’t think of an institution that does itbetter than the Kimmel Cancer Center.”

FLT3 InhibitorsPediatric Oncology Director and leukemiaexpert Donald Small understands theimportance of bridging the laboratoryand clinic to bring new drugs to patients.Working with Mark Levis in the labora-tory and Doug Smith and Patrick Brownin the clinic, his FLT3 (pronounced flitthree) discovery brought a new leukemiadrug to adult and pediatric patients.Small’s research of hematopoiesis—

how blood cells grow and expand—ledhim to clone the first human FLT3 gene.Next, he proved that it was very activein acute myeloid leukemia and somecases of acute lymphoid leukemia. In fact, FLT3 turned out to be the

most frequently mutated gene in acutemyeloid leukemia. About one-third ofpatients diagnosed had the mutation—an alteration that made it almost impos-sible to cure them. “Having a FLT3mutation reduces the chances of curingan AML patient from about 50 percentto less than 20 percent,” says Small.

He had a target in FLT3, and if hecould find a drug to neutralize it, Smallbelieved combining such a drug withchemotherapy would improve cure ratesfor these patients, at least to rates of non-FLT3 AML and potentially even better.Searching for such a drug proved to

be a laborious, time-consuming process.He began by screening a library of morethan 4,000 drugs known to target thefamily of proteins to which FLT3 be-longed. He set up 96 wells, filled eachone with FLT3-positive leukemia cellsand tested each one of the 4,000 drugsto see if any of them killed the cancercells. One by one, a specific amount of each drug was placed in the wells. “If the color changed, it meant the drug didn’t work. If there was no color change, we knew we hadan active drug,” says Small.When he found a drug thatworked, he systematically de-creased the amount put in thewells to see how low he couldtake the drug and still getan anticancer response.It wasn’t high-tech, but

at the time, it was the onlyway to get the job done,Small says. Now, there isan automated drug dis-covery tool called high-throughput screening thatallows researchers toquickly perform millions of chemical,genetic or pharmacological tests, but in the late 1990s when Small began hisresearch, low-tech was the only optionfor most university-based researchers.When all of his tests were completed,

CEP-701 stood out as the best drug.With a FLT3 inhibitor identified, Levisjoined Small and began testing the drugin his laboratory and animal models tohelp figure out how to best use the drugin patients.Since the drug had already been

tested in clinical trials, this eliminatedmany of the FDA hurdles needed tomove a drug into clinical trials, andSmall and Levis partnered with Smith to take it to patients.As Berger points out, drug discovery

is not a single path. There is much back

and forth between the laboratory andthe clinic, following the science and theclinical data rather than a predeterminedand straightforward path to get to theright drug. The essential ingredient ofscientist/clinician collaboration is thereason the Kimmel Cancer Center is theperfect environment for drug discovery. “We’re not as big as other places,

but we’re really, really good at workingtogether,” says Smith. “We’re also out-standing at basic science, clinical researchand clinical practice, and that’s thetranslational machinery that makes drugdiscovery and development possible.”When Smith took CEP-701 to patients,

it was a mixed bag of results. The drugcleared leukemia cells out of the blood-stream and, in some patients, out of the

bone marrow where new bloodcells are made and leukemia origi-nates. But, the responses weretemporary, a result not completelyunexpected in phase I trialswhere the sickest of the sickare typically treated.Levis developed an assay

for FLT3, a test that tells ifthe drug is actually hittingits intended target. “Wewere excited to see it waskilling leukemia cells, andwe had an assay to measureit, but we still needed to dig deeper,” says Levis.

The group’s goal was to get patientsinto remission using a combination of aFLT3 inhibitor and chemotherapy sothey could receive a bone marrow trans-plant, a potentially curative therapy thatreplaces the patient’s diseased bonemarrow with healthy marrow from adonor. Levis’ assay proved the drug washitting its target, but in larger studies, it also showed it had a serious flaw.The target was a good one, but in many

patients, the drug’s chemistry allowed theproteins in their bodies to suck up toomuch of the drug before it hit its target. Levis went to the inpatient unit,

watched patients take CEP-701, gotblood samples from patients, carried theblood back to his laboratory himself andthen used his assay to test the samplesto see if the drug was hitting the FLT3

FLT3FLT3 IS THE MOST FREQUENTLYMUTATED GENE IN ACUTEMYELOID LEUKEMIA. NEW

DRUGS THAT NEUTRALIZE FLT3ARE NOW HELPING ADULT ANDPEDIATRIC LEUKEMIA PATIENTS.

PEDIATRIC ONCOLOGY DIRECTOR AND LEUKEMIA EXPERT DONALD SMALL UNDERSTANDS THE IMPORTANCE OFBRIDGING THE LABORATORY AND CLINIC TO BRING NEWDRUGS TO PATIENTS. HIS DISCOVERY BROUGHT A NEWLEUKEMIA DRUG TO ADULT AND PEDIATRIC PATIENTS.

MARK LEVIS DEVELOPED AN ASSAY FOR FLT3, A TEST THAT TELLS IF THE DRUG IS ACTUALLYHITTING ITS INTENDED TARGET.LEVIS IS CONSIDERED THE WORLDWIDE EXPERT ON FLT3 ACTIVITY. HE, AND OTHERS AROUND THE WORLD, CONTINUE TO WORK ON NEW VERSIONS OF FLT3 INHIBITORS.


target. If his assay showed the drug washitting FLT3, Levis knew that patientwould respond to treatment. “The correlation between the drug

hitting the target and clinical responsewas key,” says Smith. “You can’t get anymore bench to bedside than that.”In that not-so-straight path to a drug,

it often takes many chemical modificationsto get it right.Newer formulations of FLT3 inhibitors,

built upon Small and Levis’ science andother clinical studies, have overcomethe limitations of the original drug.Levis is considered the worldwide expert on FLT3 activity. He, and othersaround the world, continue to work onthese better versions of FLT3 inhibitors,and there are several better drugs nowbeing studied in patients. Brown wouldlike to study the newer, more potentversions of FLT3 inhibitors in pediatricleukemia patients, particularly in a subset of leukemia patients he believeswould respond well, but currently, studies are limited mostly to adults. Levis’ assay is considered the gold

standard, and every major FLT3 drug is sent to him to see if it works.

“We’ve now demonstrated in patients,through studies here and at other centers,that people who got FLT3 inhibitors—with or without bone marrow transplant—did better,” says Smith. “Now we have tocontinue our clinical trials with thenewer versions of the drugs.” Smith says FLT3 inhibitors are being

studied in combination with other tar-geted therapies to see if they have broaderuses. “Ultimately, a good FLT3 inhibitorin the right combination therapy couldreplace bone marrow transplant in certain patients,” says Smith.“We would love to give patientsa cocktail of a few targetedtherapies and no toxic chemo-therapy, and eliminate theneed for other treatments.That’s the goal, but we’re not quite there yet.”As a cancer clinician who

connects the laboratory to theclinic, Smith finds the drugdiscovery process one of themost rewarding. “I love havingsomething new to offer my patients,” hesays. “It’s exciting to see a discovery inthe laboratory move ahead and becomea new drug I can offer to patients.”

DONOne of the other new drugs in thepipeline is built around depriving can-cers cells of the nutrients they need tooutgrow and overpower normal cells. Cancer cells are really just normal

cells in hyperdrive. “To grow, cancercells need fuel—lots of fuel—so theysuck up all available nutrients,” saysJonathan Powell, an associate directorof the Bloomberg~Kimmel Institute forCancer Immunotherapy. The process is called tumor metabolism, and it hasbecome a promising new cancer target. In essence, cancer cells devour all of

the nutrients in their vicinity. They stealglucose and another nutrient called glutamine away from other cells to sustain their growth, creating a positionof power for the cancer and, at the sametime, weakening normal, healthy cells,including immune cells. While cancercells are feasting, immune cells arestarving and unable to fight the cancer.“An immunotherapy like anti-PD-1

might do a great job in activating T cells,but when they show up to an environmentlike this, they can’t do their job. Theyneed the nutrients that the cancer is taking,” says Powell.Powell’s idea was to create a drug

that cuts cancer cells off from the nutrients that feed them so that whenimmunotherapy is given, T cells showup to a different environment, one thathas nutrients available to them so theycan energize and go to work against thecancer. “We’re not actually targeting

the immune system, but rathercreating a friendlier environmentfor the immune system,”says Powell.Coincidentally, Powell

and drug development expert Barbara Slusherwere working together on a student thesis committee.It turned out that theSlusher lab had alreadybeen designing drugs forthe same target. He shared

his idea, and she offered up some compounds for the Powell lab to try.Slusher was Johns Hopkins trained

but had been working for a pharmaceu-

DONOTHER NEW DRUGS IN THE

PIPELINE ARE BUILT AROUND DEPRIVING CANCERS CELLS OF THE NUTRIENTS THEY NEED TO

OUTGROW AND OVERPOWER NORMAL CELLS. DON, A

GLUTAMINE-BLOCKING DRUG ORIGINALLY EXTRACTED

FROM SOIL IN PERU, IS SUCH A DRUG.

CANCER CLINICIAN DOUG SMITHCONNECTS DRUG DISCOVERY TOTHE CLINIC.

DRUG DISCOVERY EXPERT BARBARA SLUSHER AND CANCER IM-MUNOLOGY EXPERT JONATHAN POWELL ARE COLLABORATINGON A NEW DRUG CALLED DON THAT RE-ENERGIZES IMMUNECELLS TO ATTACK CANCER.


Pediatric cancer expert Patrick Brownrecognizes the promise of new drugdiscovery and development in makingprogress against cancer, and it’s at theheart of his frustration. Brown, whohas taken FLT3 inhibitors and other investigational drugs to pediatricleukemia patients, says children areoften the last to benefit from newdrugs for many reasons.

“Access to drugs and the ability toexplore them are the biggest barriersto changing standard of care for pediatric patients,” says Brown.

Even when Kimmel Cancer Centerresearchers make a drug discovery,they typically can only take it so far.“We can’t mass-produce drugs, so weusually rely on drug companies toprovide drugs for clinical trials,” saysBrown. The much smaller number ofpatients with pediatric cancers com-pared to adult cancers and the risk ofsomething going wrong with a drugbeing tested in children can makepharmaceutical companies reluctantto provide drugs. This has hinderedaccess to promising new drugsgreatly and slowed progress againstpediatric cancers, Brown says.

For new FDA-approved drugs, it ispossible to get them for study in pedi-atric patients by purchasing the com-mercial drugs outright, but costs canvary from $1 million to many millions,and these costs are not typically covered by federal research grants.

There are a few federal laws meantto encourage drug companies to invest in pediatric clinical trials, butBrown says they are largely not veryeffective. In pediatric oncology, large,multi-institutional studies are the onlyway to include enough patients to accurately evaluate a new drug, butdrug companies are not often willingto support these studies.

“Getting therapies for individualpatients in small studies is fine, but if we can’t do a large-enough trial todemonstrate survival benefit overstandard of care, we can’t changestandard of care,” says Brown. “We are constantly pitching ideas,and experts agree drugs should betested in kids, but frequently we can’t get the drug for our studies.”

Most large trials are done collabo-ratively with pediatric oncologistsfrom the 220 institutions that makeup the Children’s Oncology Group. The group recently proposed a studyto look at an immunotherapy drug asupfront treatment for acute lymphocyticleukemia (ALL). “We are completely at the mercy of the drug company as to whether or not it will provide thedrug for this study,” says Brown.“If it says no, which is the most likely answer, the study doesn’t happen. Immunotherapy could be a game-changer for kids with ALL, and we’restruggling to get the drugs in a timelyway. That’s very frustrating for us.”

Brown says these large studies arereally the only way they can begin tomove pediatric oncology treatmentaway from the toxic chemotherapiesthat can have devastating latent effects in children to the new, short-and long-term targeted therapies that

are already benefiting adult patients.Brown and his colleagues try to workwith drug companies to form clinicalresearch agreements that include providing drugs for pediatric studies.But, Brown says, “There is not muchfinancial upside for companies to givetheir drugs away for pediatric clinicaltrials when they could otherwise sell them.”

Still, they keep trying, and occa-sionally they’re successful. Amgen isproviding a drug and significant fundingto support a clinical trial comparingchemotherapy alone to a combinationof chemotherapy and immunotherapyfor ALL. “If successful, this study willchange standard of care for ALL,” says Brown. “There might be some financial payoff for them because ALLis the most common pediatric cancer,but mostly this an altruistic ventureon their part.”

Celgene is another example. Thecompany is providing one of its drugs,azacytidine, for an infant leukemiastudy. Infant leukemia is an extremelyrare but very deadly cancer badly inneed of new drugs, but Brown says it’s very difficult to get companies toprovide drugs for studies.

Brown says one solution would bean independent funding source thatcould purchase FDA-approved drugsand provide them for pediatric studies.Kimmel Cancer Center Director WilliamNelson will explore such a mechanismas part of the Kimmel Cancer Center'sdrug discovery and development program.

“We all have to be invested in doingbetter for kids,” says Brown. “If thereis a way to treat patients and get better cure rates with lower toxicities,we should be doing the studies thatmake these treatments available topediatric cancer patients.”•

Drug Discovery a Challengefor Pediatric Cancers

“Access to drugs and the ability to explorethem are the biggestbarriers to changingstandard of care forpediatric patients.”—Patrick Brown


PATRICK BROWN


tical company for the last 18 years, whereshe was senior vice president of researchand translational development. Whenanother pharmaceutical company acquired the business in 2009, Slusherreturned to Johns Hopkins with a sea-soned team of medicinal chemists, assaydevelopers, and pharmacology/toxicologyand pharmacokinetics experts. She is also founder and president of a

world consortium of academic drug dis-covery centers. Started just three yearsago, it has already grown to 150 univer-sities and 2,000 members, reflecting thegrowing role of the academic researcherin drug discovery. As the pharmaceuti-cal industry has largely withdrawn fromdrug discovery research, the universityresearcher has tried to pick up the slack.

“There are so many good ideas andtherapeutic target discoveries in academia,but the ability to synthesize drugs againstthe newly identified targets has not typ-ically existed within universities,” saysSlusher. “We will never be set up to com-mercialize drugs. That remains pharma’srole, but now we are required to moveour basic science discoveries farther alongthe translational path than we did in thepast. As a translational leader, Hopkinsis set up to do this—we can synthesizenew drugs, show their benefit and takethem to a point where a pharmaceuticalcompany becomes interested in pickingthem up for clinical development.”Among the compounds Slusher and

Powell began working on was one calledDON, a glutamine-blocking drug origi-nally extracted from soil in Peru. In theearly assaults against cancer, it wascommon to use bacteria and other toxins found in soil around the world

to make drugs to kill cancer cells. Thegoal is to give patients the highest dosepossible to kill as many cancer cells aspossible without harming too many normal cells. It was a delicate balancingact that led to the dose-escalating para-digm that has dominated cancer drugdiscovery for decades. In the era of precision medicine and targetedtherapies, however, that paradigmis slowly but surely shifting. Earlier versions of glutamine-

blocking drugs showed they hadcancer-fighting potential butwere too toxic to normal cells.Although Powell and Slusher’sDON was not new, what Slusherdid to make it work was. Shechanged the drug’s chemistry,sticking something to the activedrug that makes it inactive as itcirculates throughout the body.The drug only becomes activewhen it gets inside cancer cells. Once incancer cells, that extra thing she stuckon the drug gets clipped off, and thebenevolent passenger traveling throughthe bloodstream is transformed into acancer cell killer. The approach is calleda prodrug strategy, and the selective activation decreases toxicity to normalcells. Since the active drug is only releasedin cancer cells, it requires very low dosesto work. “I consider this our real contribution,”

says Slusher. “We’ve been able to changethe distribution of DON so that they hitmore of the target and less normalcells.” Slusher plans to use the conceptfor other drugs. She is already workingon a modification to 5-azacytidine, anepigenetic-targeted cancer drug thatcorrects chemical alterations that support cancer growth.“Using existing drugs as starting points

is one way to expedite drug discovery,”says Slusher. “It doesn’t mean it’s easy.As in this case, we still have to do me-dicinal chemistry and pharmacokineticsto get it just right, but it is a faster startwith higher probability of success.”Powell first envisioned the drug as a

way to extend the benefits of immuno-

therapy to more patients. “I thought itwould help in tumors that currentlydon’t respond to immunotherapy,” says Powell. It could be given before im-munotherapy to create a better environ-ment for T cells to thrive. Targetingtumor metabolism increases the num-bers of cancer-fighting T cells, and

anti-PD-1 drugs remove ashield cancers use to hidefrom T cells, creating

the perfect one-twopunch for an immuneassault against cancer. When he studied

the drug in animalmodels, he found itwas a potent cancerfighter by itself. “Weseemed to unleash the normal immuneresponse just by targeting the nutrients

in the microenvironment of the tumor,”says Powell. “It makes us think that patients will develop antitumor immuneresponses when treated with our prodrugalone, but when we add anti-PD-1 to it,we really finish off the job.”Since all cancers are dependent on

glucose and glutamine, tumor-targetedDON prodrugs should work across allcancer types. Slusher and Powell wereparticularly excited to see some of theirprodrugs pass the often-impenetrableblood-brain barrier, making it a poten-tial new option for brain cancers, whichare among the most treatment-resistantcancers. Powell is optimistic that theirnew drug will work in many cancers thathave been resistant to chemotherapyand immunotherapy. In animal studiesof cancers given time to grow very large,anti-PD-1 immunotherapy eliminatedthe cancer in about 10 percent of the mice.When our DON prodrugs were added,that number jumped to 90 percent. “We’re very excited about taking this

drug to patients with cancers that havenot responded to other therapies. Wethink it has the potential to really helpthem,” says Powell. Ongoing studiesproved that their modified drug is so

“Using existing drugs is one way we expedite drugdiscovery. It doesn’t meanwe’re done. As in this case,we still have to do medicinalchemistry to get it just right,but it is a faster start.”—Barbara Slusher

90%IN ANIMAL STUDIES OF

CANCERS GIVEN TIME TO GROW VERY LARGE,

ANTI-PD-1 IMMUNOTHERAPY ELIMINATED THE CANCER IN ABOUT 10 PERCENT OF

THE MICE. WHEN DONWAS ADDED, THAT NUMBER

JUMPED TO 90 PERCENT.


[Discovery]Allison Uzupus became an oncologynurse two years ago after working asa laboratory researcher for leadingpancreatic cancer expert ElizabethJaffee. “I was really interested in thescience, but I knew I wanted a careerseeing patients,” says Usupuz. “Theinteraction I have with patients as aclinic nurse is particularly meaningful.It is the realization of everything I didin the lab.” Clinic nurses care for patients on many different kinds ofdrugs and clinical trials, and have thechallenging job of staying informedon all of the new drugs and the different reactions that could occur.“There is a lot to look forward to soearly in my career,” she says. “It’s exciting to see these experimentaldrugs become standard of care andsee patients living longer.” •


“The world is changing,” says BarbaraSlusher, a drug discovery expert whoworked for a pharmaceutical companybefore coming to Johns Hopkins. “Acad-emic centers are taking on a larger rolein drug discovery. We’ve always been onthe front end of discovering targets andon the back end with clinical trials. It’s themiddle piece of going from a target to adrug that is new for us.”

This is another area where the KimmelCancer Center is blazing uncharted terri-tory, forming unique collaborations withpharmaceutical partners to fund and advance promising new cancer drugs.

Bristol-Myers Squibb PartnershipA new, five-year collaboration betweenBristol-Myers Squibb and the Bloomberg~Kimmel Institute for Cancer Immunotherapywill advance research aimed at uncover-ing ways that cancer cells hide from theimmune system and new immunotherapy-based approaches for killing cancer cells.

“We’re at an inflection point of under-standing the root causes of response andresistance to immunotherapy, and thiscollaboration will help propel the researchneeded to identify ways to expand immunotherapy effectiveness to morepatients,” says Drew Pardoll, Director of the Bloomberg~Kimmel Institute.

It is a natural partnership, as KimmelCancer Center experts are on the forefrontof immune checkpoint research, uncover-ing the ways cancer cells hide from theimmune system, and Bristol-Myers Squibbhas developed several drugs that blockthese checkpoints and make cancer cellsvisible to the immune system.

“Our priorities aligned,” says BrianLamon, the global lead for clinical oncol-ogy and immuno-oncology in Bristol-MyersSquibb’s business development group.“The Kimmel Cancer Center and

Pharma’s New Role


on lung, colorectal, breast, prostate andhematological cancers.

The partnership is a bit of a reunion,as AbbVie’s cancer division is managedby Gary Gordon, a former Johns Hopkinsresearcher. “As an alumnus and a formerfaculty member of the Johns HopkinsUniversity School of Medicine, I knowfrom my own experience that we will beable to combine AbbVie’s expertise inoncology with some of the most talentedacademic researchers in the field of medicine today,” says Gordon, vice pres-ident of oncology clinical development.

The agreement gives Kimmel CancerCenter physicians and scientists accessto explore new therapies developed byAbbVie for use in preclinical researchfunded by the collaboration. In addition,the relationship includes opportunitiesfor research and development teamsfrom both organizations to work closely to promote scientific knowledge exchange. AbbVie also gains an option for an exclusive license to certain JohnsHopkins Medicine discoveries madeunder the agreement.

“The importance of cancer research iscritical to developing new therapies thatcould have life-changing implications,”says Kimmel Cancer Center DirectorWilliam Nelson. “Opportunities to advancescience and further research help move usin a direction to yield positive outcomes.”

As part of the collaborative agreement,a joint steering committee consisting ofrepresentatives from each organizationwill determine the research projects thatthe collaboration will undertake. MichaelCarducci, Jonathan Powell and VasanYegnasubramanian are representing the Kimmel Cancer Center. Researchersfrom Johns Hopkins and AbbVie will alsoparticipate in an annual symposium todiscuss their joint research and evaluatepotential new projects. •

Bloomberg~Kimmel Institute are hugeintellectual powerhouses. We know theyunderstand what our medicines can doand how they work, but this partnershipisn’t just about drug development. Weare committed to the science. Getting newmedicines into patients is the endgamefor all of us, but we want to make surewe follow the science. That’s where thestrength of the Kimmel Cancer Centermakes a difference. There is pretty broadexpertise to do a lot of different things,and the ability to put it all together. Theseare complex, dynamic systems, and Hopkins has the expertise to take it on.”

The collaboration will include labora-tory research and clinical trials to decipherwhy immunotherapy works in some patients and not others. Combined im-munotherapies and their use as first-linetreatments are among the approachesbeing studied.

Celgene PartnershipThe Kimmel Cancer Center was one offour National Cancer Institute-designatedcomprehensive cancer centers selectedto participate in a unique cancer consor-tium aimed at speeding up the processof cancer drug discovery. The collabora-tive nature of the consortium should expand access to expertise, eliminate duplication of effort and increase thepayoff—to the private sector, the cancercenters involved and, most importantly,to patients worldwide. The cancer centersat the University of Pennsylvania, Columbia University Medical Center andthe Icahn School of Medicine at MountSinai are the other consortium members.

Through team science, the participat-ing institutions will have access to finan-cial resources from Celgene Corporationand will share in revenue generated fromdiscovery. Together, the participating

institutions initially received $50 million—$12.5 million to each—but Celgene ismaking $300 million to $1.5 billion avail-able to the consortium to advance re-search. All consortium member institutionswill share in any revenue generated fromdiscoveries, with the cancer center orcenters responsible for discoveries receiving the largest return. The KimmelCancer Center was selected for the consortium for its long history and pioneering roles in new drug discoveryand clinical research.

Kimmel Cancer Center DirectorWilliam Nelson and Cancer Chemicaland Structural Biology Program leadersJames Berger and Jun Liu will direct efforts and serve as liaisons to the consor-tium. Nelson sees opportunities for pri-vate philanthropy to further acceleratediscoveries made through the consortium.

AbbVie PartnershipLast December, AbbVie, a global bio-pharmaceutical company, signed a five-year collaboration agreement with JohnsHopkins, with the goal of advancing cancer drug discovery at both organiza-tions. The agreement focuses primarily

“The world is changing.Academic centers are tak-ing on a larger role in drugdiscovery. We’ve alwaysbeen on the front end ofdiscovering targets and onthe back end with clinicaltrials. It’s the middle pieceof going from a target to adrug that is new for us.” —Barbara Slusher


cancer specific that it only releases itspower in cancer cells, virtually remain-ing nontoxic in all other cells. Their research also shows signs that the drugmay also sensitize cancer cells to radia-tion therapy.Slusher and Powell hope to have the

drug in clinical trials in two years. To getthere, they will need to complete addi-tional studies to get the FDA approvalneeded to take their investigational newdrug to patients. Deerfield Managementrecently announced plans to invest $40.5million in Dracen Pharmaceuticals, Inc.,a start up company founded by Powelland Slusher to develop DON and othercell metabolism-tartgeting drugs.Powell echoes Berger’s and Liu’s

emphasis on more resources to help investigators bridge the funding gapsthat limit drug discovery. “Until we gotdedicated funding from the Bloomberg~Kimmel Institute, we were funding this research with bake sales, cobblingtogether small amounts from differentplaces to keep it going,” says Powell. “If we had a fully supported program

for drug discovery, it would make a hugedifference in speeding progress.”The collaborative environment at

Johns Hopkins makes it a fertile groundfor scientific progress. “The value ofdiscovery is underrated. It’s messy andrisky, but it’s essential,” says Powell. Hepoints to a time early on in the researchwhen one of the compounds wasn’tworking at all in the laboratory studies.Powell was disappointed until he received a call from Slusher who, unaware of his laboratory outcomes, advised him not to use the compound.She spotted a problem with her com-pound’s stability and knew it wasn'tgoing to work. “Her team on the drug

discovery side and our team on the cancer research laboratory side came tothe same conclusion independent of oneanother and provided extra confirmationfor what we were seeing. Her observationof the drug confirmed what I was seeingin the laboratory, and my observation inthe laboratory confirmed that she was right about the problem she spottedwith the compound,” he says. “That’s the beauty of science. You

put people together with diverse skills,and they find something unexpected,”says Powell. “There is no formula for it. You just put people together and letthem work. This kind of collaborationthrives in the Kimmel Cancer Center.”

[Discovery] In 1999, when Janice Paulshock (second from right) was diagnosed withovarian cancer, her doctor gave her no hope. She worried that she would never see her 8-year-old daughter and 6-year-old twins grow up. She decided to seek a second opinion at the Johns Hopkins Kimmel Cancer Center. Her doctors assured her there were manytreatments they could try, including a promising drug called paclitaxel. Janice received thedrug in 1999 and again in 2001 when her cancer came back. She has been cancer-free since2008. She has seen her children grow up and graduate from high school and college. Last yearshe celebrated her oldest daughter’s wedding, and in 2018, she will become a grandmother.

“Knowing that there are doctors always looking for new and better cancer drugs givespatients like me such hope,” says Janice. “They never gave up on me, and I’m alive becauseof that. It’s the greatest gift.” •

BMH-21“When we think about radiation therapy,it is high-tech, but the complexity ofcancer requires that we have a betterunderstanding of the biology,” saysMarikki Laiho, the Willard and LillianHackerman Professor of Radiation Oncology and vice chair of research forthe Department of Radiation Oncologyand Molecular Radiation Sciences.“Now, we combine technology with biology, and that ultimately means improved treatments for patients.”This biological underpinning led

Laiho to an exciting discovery that ap-pears to stop cancer cells in their tracks.She identified an unexpected target forcancer therapy and developed a drugthat hits the target. The drug goes after a kind of

cellular machinery called theRNA polymerase 1, or POL1.The genetic instructions inour DNA are read out byRNA polymerases. Cells have three main ways—

POL 1, 2 and 3—to read the instructionmanual that is our DNA and help convertthose instructions into protein-basedactions that are dictated by genes. Errors in the genetic code, known asmutations, alter how proteins areformed and function, and ultimatelyhow cells behave. POL2 is studied mostin cancer because it executes the primaryprogram that leads to the defective proteins related to the majority of cancer mutations identified to date. The other two polymerases, however,provide essential molecular tools thathelp make the actual proteins. “POL1 is fundamentally important

for every cell, so it has not been consid-ered an actionable target for cancer

therapy. If you hit it, the thought was that you would harm every cell, not just cancer cells,” says Laiho.Laiho proved that was

not the case after devel-oping a drug that targetsPOL1 and studying it in

the laboratory. She found that cancercells rely on it more than normal cells,so it was possible to interfere with thepathway without causing excessivedamage to normal cells. “Cancer cellscan’t survive without this program.They can’t function, ” says Laiho. “Justas important, however, normal cellsdon’t take much notice.”She has spent the last three years

deciphering how POL1 works and developing tools to measure its activity in cancer cells. Working with prostatecancer expert and pathologist AngeloDe Marzo, Laiho used these tools, and alarge Challenge Award from the ProstateCancer Foundation, to develop a testthat identifies prostate cancers that relyon POL1. This was the first step to aclinical approach.Laiho discovered a drug called BMH-21

from a drug library screen and thenworked with her research team to identify the target, POL1. Now Laiho isworking with Johns Hopkins medicinalchemist James Barrow to refine it. She

MARIKKI LAIHO DEVELOPED A DRUGTHAT PREVENTS CANCER CELLS FROMACCESSING A CELLULAR MACHINERYTHEY NEED TO SURVIVE.

BMH-21BMH-21, A CANCER DRUG NOWBEING STUDIED IN PROSTATE

CANCER AND MELANOMA, APPEARS TO WORK IN MANY

OTHER CANCER TYPES.


was surprised by how well the drugworked in preclinical proof-of-principlestudies. “Without this transcription ma-chinery, cancer cells couldn’t recover,”says Laiho. “They cannot function.” BMH-21 showed exceptional activity

against cancer cells from many tumortypes. In fact, in these studies, the drugfunctioned better against the cancercells than many FDA-approved cancerdrugs. “We have been able to confirmthat BMH-21 works by binding to DNAand are very near the optimal stage ofdrug development,” says Laiho. “Typi-cally, many revisions to the lead moleculeare required before it is ready for clinicalstudies. We are very excited because thatis not the case with our drug, and thatmeans we are closer to the clinic than wecould have ever imagined.”With most of the science in place,

the research could be translated into anew treatment in a little over a year.Still, Laiho and team face some hurdles.She needs funding and a pharmaceuticalpartner to make the leap from laboratoryto clinic. Bluefield Innovations, a Deer-field Management and Johns HopkinsUniversity collaboration aimed at sup-porting the commercialization of earlystage drug research at Johns Hopkinsannounced that it will take on Laiho’sdrug as its first project. A prestigiousHarrington Discovery Institute Scholars-Innovator Award, the Patrick C. WalshProstate Cancer Research Fund and theAllegheny Health Network have alsoprovided much-needed funding to helpmove her drug to the clinic. “It has taken a long time to get here

because this was uncharted territory forme,” says Laiho. “From the day I had mymolecule, I was walking around askingabout how to do the molecular modeling,how to make derivatives, and how to doa PK experiment. I had an endless lineof questions.”PK, refers to pharmacokinetics.

Literally translated, it means movementof drugs—how a drug gets into the blood-stream and then travels to tissues and organs, how the body breaks the drugdown, how long it stays in the body and howthe body gets rid of it. Experiments directed

at understanding how a drug movesthrough the body and what it does are anessential part of new drug development.The collaborative nature of the Kim-

mel Cancer Center certainly worked inLaiho’s favor, and she found answers toher PK experiments questions and otherquestions by making connections withexperts, but this took time. She believesNelson’s vision for the drug discoveryprogram in the Kimmel Cancer Centerrepresents a complete package of all thenecessary elements that would speeddrug discovery and development. “We need financial support, but we

also need knowledge support,” saysLaiho. “The knowledge already existshere, so we’re one step ahead already.We just need to bring all ofthe elements together.”As Laiho inches closer to

moving her drug to patients,one of the things she is mostexcited about is its applicationacross many cancer types.“Even though we are looking atprostate cancer and melanomasnow, BMH-21 appears to workin many solid tumors with highdependency on the POL1 path-way,” says Laiho. “The more a tumordepends on this pathway, the better thistreatment should work.” She hopes tobe able to obtain enough support tosoon launch clinical trials in prostatecancer patients who have exhausted all other treatment options and to makethe necessary modifications to BMH-21to expand studies to other cancers.

Aptamers and siRNAThe merging of two discoveries mayprovide a novel way to deliver cell destruction to prostate cancer. At thecenter of the research are two things familiar only to scientists—aptamersand small interfering RNA (siRNA).Aptamers are small molecules that

work much like antibodies to targetthings—like cancer—that don’t belong inour bodies. They are really good at bind-ing to other molecules. Prostate cancerexpert Shawn Lupold developed an aptamer that targets the prostate-specific

membrane antigen (PSMA), a proteinfound in most prostate cancer cells. Aptamers aren’t designed to have a

particular shape or binding site for atarget protein. Instead, they are selectedfrom a pool of billions of different molecules by a stringent and complexprocess. When Lupold first took on theproject as a graduate student, it tookhim five years to drill down to just theright chemical formulation. Today, thiscan be chemically synthesized in just afew days. At the same time Lupold was work-

ing on his aptamer, Theodore DeWeese,Director of Radiation Oncology and Mo-lecular Radiation Sciences, was workingon another technology called siRNA

that have the ability toturn off genes. Radiationtherapy kills cancer cells

by damaging their DNA.Some cancer cells, how-ever, are able to repair thedamage and survive, soDeWeese’s plan was to use siRNA to turn offgenes that help performthese repairs. Lupold’saptamer allows him to

do it selectively, causing harm only tocancer cells.Lupold’s prostate cancer-targeted

aptamer was the perfect delivery vehi-cle for DeWeese’s radiation-sensitizingsiRNA. Their final product was an aptamer that used PSMA as a chemicalGPS system to guide the siRNA toprostate cancer cells, where they blockDNA repair mechanisms, makingprostate cancer cells ultrasensitive toradiation therapy.“It’s almost as if we turned up the

radiation, but we did it molecularly,”says Lupold. Actually increasing thedose of radiation therapy would surelykill more cancer cells but be far tootoxic to normal cells. This approach hasthe same effect, but it has the potentialto do it more safely.Their treatment worked well in animal

models, and aptamers are already FDAapproved for other medical purposes, soLupold and DeWeese do not anticipate

siRNAA PROSTATE CANCER-

TARGETED MOLECULAR VEHICLE, CALLED AN

APTAMER, DELIVERS SIRNA,A RADIATION-SENSITIZING

THERAPY TO CANCER CELLS.


PROSTATE CANCER EXPERTS THEODORE DEWEESE (LEFT) ANDSHAWN LUPOLD MERGED THEIR INDIVIDUAL DISCOVERIES TODELIVER DESTRUCTION TO PROSTATE CANCER CELLS.


“Despite its difficulty, drug discoverythrives in our unique environment of collaboration and unparalleled expertise in virtually every area ofbench-to-bedside cancer research.Discoveries in these fields are providing the cancer targets that are driving new drug developmentand precision medicine.” —William Nelson



PROSTATE CANCER EXPERTSAMUEL DENMEADE USED APHARMACOLOGIC VERSION OF TESTOSTERONE TO TRICKCANCER CELLS INTO DEATH.


any safety problems. To move the therapyto clinical trials, they will need about $1million to outsource the production ofclinical-grade aptamers and to evaluatethem in FDA-relevant preclinical models.DeWeese says their siRNA aptamers

are unique to Johns Hopkins and thefirst to sensitize cancer cells to radiation.The current version is specifically targeted to prostate cancer, but he sayswith an adjustment to the chemicalGPS, they can be adapted to target essentially any cancer.

Testosterone as a DrugThe male hormone testosteronecan feed the growth of prostatecancer, but in an interesting twist,when given in a very specific way, it may also cause its demise. Drugs that block the action of

testosterone are commonly used totreat men with advanced prostatecancer therapy. Cutting off the sup-ply of testosterone to the cancerworks for a time, but eventuallyprostate cancer cells figure out a wayaround it and begin to grow again. Otherdrugs work at the molecular level to cut offprostate cancer cells’ access to testos-terone, but their impact is temporaryand comes with unpleasant side effects. “Men who have long-term hormone

ablation have a good response initially,but eventually they become resistant to therapy, and then there aren’t manyoptions left for them,” says prostate cancer expert Samuel Denmeade.These are the men most at risk of dyingfrom prostate cancer.With testosterone viewed as a fuel

for prostate cancer, most researchersare reluctant to explore it as potentialtherapy. However, what Denmeade andfellow prostate cancer researcher JohnIsaacs envisionedwas different, and it all came down to the delivery.Taking a play right out of cancer’s

playbook, Denmeade and Isaacs figuredout what prostate cancer cells weredoing to survive hormonal therapy and then beat them their own game.After prolonged treatment with

testosterone-blocking drugs, prostate

cancer cells adapted to living with lowlevels of the hormone by ramping up theactivity and amount of receptors withinthe cell surface to suck up every bit oftestosterone available.With prostate cancer cells in this

state, adapted to an environment withlow levels of testosterone, Denmeadewondered what would happen if heflooded the cancer cells with a shortburst of high-dose testosterone, usingthe hormone like a drug. “If we give testosterone acutely

through injection to cause a sharp risein the hormone, prostate cancer cells

won’t like that, and some will die,”says Denmeade.

“Prostate cancer cellsmight be killed bythe hormone shock,and the cells that survived would makefewer receptors,making prostate cancer cells vulnera-ble once again to

hormone-lowering therapies.”At first glance, it seems paradoxical

to give testosterone to a prostate cancerpatient, but Denmeade and Isaacs saythis approach is very different from thechronic, ongoing supply of testosterone

that naturally occurs in men or testosterone replacement therapy. “It’s pharmacologic testosterone, notphysiological testosterone,” says Isaacs.Prostate cancer cells are not expecting

an intense dose of testosterone, and theydon’t know that it’s a short burst. Cancercells that survive will adapt again, thistime turning down the activity of thosecell surface testosterone receptors. “They will downregulate their receptorsat a time when the drug is wearing off, sowe will see a period of low testosterone,low receptor, and that’s not good for cancer cells,” says Denmeade.As the cells are continually challenged

with these short bursts of testosterone,they are constantly adapting levels ofcell surface receptors up and down. “Weare taking the cancer cells’ options outof play by making the testosterone levelsrise and fall rapidly,” says Denmeade.Denmeade turned the idea in a clini-

cal trial of testosterone as a prostatecancer drug therapy. Following a pilotstudy funded by the One-In-Six Fund,the National Institutes of Health, and a$5 million Transformative Grant fromthe Department of Defense, he began toperform two studies—one at one at theKimmel Cancer Center, and another at18 sites across the U.S. Both clinical trials in asymptomatic men with prostate

[Discovery] Riley, 11, has a slow-growing and rare benign brain tumor called a pylocytic astrocytoma. She calls her tumor Roger, and says, “I kicked his butt.” The tumor,located between her optic nerve and pituitary gland, can’t be taken out surgically. It willrequire lifelong monitoring, and drug therapy and radiation therapy when she is older—to keep it from growing into her optic nerve and affecting her vision. This is the kind oftumor that Sonia Franco’s minibrain model could impact, providing new informationabout how they grow and the therapies that may work best. •

2/3ABOUT TWO-THIRDS OF MENTREATED WITH A MONTHLY

INJECTION OF TESTOSTERONE TO HELP BOOST THEIR

TESTOSTERONE LEVELS RESPONDED WELL TO THE

THERAPY, HELPING KEEP THEIRPROSTATE CANCER STABLE.

Michelle Rudek runs the Kimmel Can-cer Center’s Analytical PharmacologyCore. Like other drug discovery laboratories, Rudek leads a team thatconducts tests to see how promisingnew drugs travel through the body;how they are absorbed, distributedand metabolized; how long they stayin the body; and ultimately what effect they have on cancer cells. However, Rudek’s lab is different fromothers in that it supports cancer drugdiscovery throughout the Kimmel Cancer Center, Johns Hopkins and beyond, with as many as 90 projectswith varying degrees of complexityongoing at any time. She and MichaelCarducci lead the lab’s role in testingdrugs being used in the National Cancer Institute’s (NCI) ExperimentalTherapeutics Clinical Trials Network,and her lab also supports NCI’s AdultBrain Tumor Consortium and AIDSMalignancy Consortium.

Rudek’s personal research is focusedon helping cancer patients who haveother health conditions. She deciphersand manages drug interactions anddosing so that cancer patients takingmedications for other health conditions,such as AIDS malignancies, or whohave liver or other organ dysfunctioncan safely receive cancer drugs.

“It’s so rewarding,” says Rudek,who is one of the few drug expertsdoing this kind of work. “We’rechanging the standard of care forthese patients and making it possiblefor more patients to participate incancer clinical trials.”

Rudek was recently honored withthe NCI’s Michaele Christian OncologyDevelopment Lectureship and Award.The award recognizes her leadershiprole in translational research and clinical pharmacology in early-phaseclinical trials and special populations.She is the first nonphysician recipient.

Early Phase Clinical Trails



MICHELLE RUDEK (LEFT) LEADS A DRUG DISCOVERYLABORATORY AND HELPS MAKE IT POSSIBLE FOR PATIENTS WITH UNDERLYING HEALTH CONDITIONSTO PARTICIPATE IN CANCER CLINICAL TRIALS.


cancer that has progressed on hormonetherapy were designed to see if a monthlyinjection of testosterone to make thetestosterone level rise sharply for about a week would kill cancer cells.Denmeade says about two-thirds of the men treated responded well to thetherapy, at least keeping their prostatecancer stable. But Denmeade noticed that some of

the men treated were resensitized tohormone therapy. That observation wasthe impetus for his Transformer Study, a new clinical trial to see if givingtestosterone in sequence with hormonetherapy could prevent or reverse hormonetreatment resistance.One patient in the study had his cancer

completely disappear for two years.

Denmeade is now looking for biomarkersthat predict which patients will respondbest to the testosterone therapy. Prostatecancer expert Emmanuel Antonarakisidentified a subset of patients with a vari-ation in their cell surface receptors thatpredicts a more aggressive and resistanttype of prostate cancer. Denmeade’stestosterone treatment may convert it to a less aggressive form of cancer.A new study, called the Batman Study,

is funded by the Patrick Walsh Foundation,and is helping Denmeade and colleagueslook more deeply into the specific mo-lecular and cellular mechanisms that makethis therapy work. With the exceptionof patients with prostate cancer that hasspread to the bone, the short burst oftestosterone makes most men feel better.

[Discovery] Cindy Lersten has spent more than a decade of her 50 years battling cancer. Her journey began in 2001, when she was diagnosed withmelanoma. The cancer stayed in check for years—until 2012, when it returned andbegan to spread. “I thought that was it,” recalls Lersten, a mother of four. “I thoughtmy life was over.” She traveled to another hospital for immunotherapy. The treat-ments worked for a time, but in 2017, it came back. She then came to the KimmelCancer Center for additional treatment. New studies of combined immunotherapies—trials that tested two, and sometimes even three, different drugs had begun. She participated in a clinical trial of one of these immunotherapy combinations and alsoopted for surgery. Currently, there is no evidence of cancer. “The first treatmentbought me time so that when my cancer came back, there were new options forme,” says Lersten. The combination of surgery and new drugs are holding her cancer at bay once more. It is working so well for Lersten that she was healthyenough to climb Mt. Fuji with her 15-year-old son. “These drugs gave me renewedhope,” she says. •

“Men were hugging me because they feltso good. People are clamoring for it,”says Denmeade. “We get emails frommen all over the country and the world.”Denmeade says they are still learning

about the best way to safely give thetherapy. “So far, the side effects havebeen low grade, as long as the treatmentis limited to men who are asymptomaticwithout any pain due to prostate cancer,”he says. “In some cases, the testosteronetherapy makes men feel increased energy,less fatigue and restored sexual function.”To date, 150 men have been treated withvarying responses. “We have some patientswhose PSA drops after treatment andtheir scans get better; we have otherswhose PSA doesn’t drop and even havesome initial rises. For most patients, theirprostate cancer is at least held in check,”he says. PSA stands for prostate-specificantigen. Tests that measure rising levelsof PSA in the blood are used to screen forprostate cancer.Denmeade is studying cells from the

one complete responder more closely inhopes it may provide critical clues. “Ifwe can understand what happened inthis one guy, it would provide a wealthof information,” he says. One possibilityis that the up and down of the testos-terone attracts the attention of the im-mune system, which is always on patrolfor things that look out of the ordinary.Deciphering what underpins these varied responses could reveal biomark-ers that will help them decide who arethe best candidates for the treatmentand how long to give it.“There has been a groundswell of in-

terest,” says Denmeade. “Right now, wehave plenty of anecdotes and some evi-dence of how it works, but we need to domore research and test it in more patients.”The treatment with generic testos-

terone is a bargain at about $100 a month,but lacking a pharmaceutical partner,Denmeade and Isaacs are struggling to find funding to do additional combi-nation studies. “Since we are using ageneric form of testosterone we mayhave difficulty getting support frompharmaceutical companies,” says Isaacs.“So for now, it remains a completelyhomegrown project.”

[Fusions] Artist Maria Lanas accompanied her father-in-law to the Kimmel Cancer Centerwhen he received a new experimental drug for his advanced melanoma cancer.“The infusions took several hours, and as I watched the drops slowly go down the tube into his body, I began to imagine the fight that was taking place in hisbody as the drug mixed with his blood,” says Lanas. She calls the artwork infusions.“It represents the life and hope these new drugs offer to cancer patients, so I usedthe brightest colors on my paint palette,” says Lanas. She gave the paintings asgifts to the doctors and nurses who cared for her father-in-law, and one was auc-tioned to raise money for cancer research at the Kimmel Cancer Center. •


COMPLEX, ORGANIZED SPHERES OF HUMAN NEURAL ANDNERVE CELLS ARE DUBBED ORGANOIDS OR MINIBRAINS.THEY CANNOT THINK OR LEARN LIKE A HUMAN BRAIN, BUTTHEIR STRUCTURE IS SIMILAR ENOUGH TO THE ANATOMY OF A DEVELOPING BRAIN THAT MOLECULAR RADIATION SCIENTISTSONIA FRANCO BELIEVES THEY CAN BE USED TO REPLICATEHOW PEDIATRIC BRAIN CANCERS NATURALLY GROW ANDSPREAD. SHE IS USING THE MINIBRAINS TO STUDY DRUG AND RADIATION TREATMENTS.

New Models of DiscoveryAn important element of drug discoveryis the scientific models used to studydrugs. Increasingly, the laboratory mod-els scientists use to determine if, howand why a drug works don’t work wellin cancer. To address that weakness,Kimmel Cancer Center investigators arepushing the boundaries and developinginventive new ways to study drugs.

“Minibrains” Tiny structures about the size of a fly’seye provide a new futuristic opportunityto study pediatric brain cancers. Thesecomplex, organized spheres of humanneural and nerve cells are dubbedorganoids or minibrains. They cannotthink or learn like a human brain, buttheir structure is similar enough to theanatomy of a developing brain that mo-lecular radiation scientist Sonia Francobelieves they can be used to replicatehow pediatric brain cancers naturallygrow and spread and to study moreclosely how these cancers respond to radiation and drug treatment.It takes about three months to grow

the minibrain structures in the lab. They grow to about 4 millimeters andprovide a window of four to six monthsfor research before the cells begin to die off. Hundreds of them can be created simultaneously The research is in its infancy, making

its way into the laboratory about four yearsago. They were stumbled upon almostaccidentally as Austrian researcherswere growing neural stem cells, the Ccells that give rise to all other braincells. The cells were placed in a rotatingflask so they would form into smallspheres. Checking on the cells one day, aresearcher noticed a tiny black speck onher organisms and thought the cells hadbecome contaminated. A closer lookunder the microscope revealed that thetiny black spot was a primitive eye. “They had self-organized and differ-

entiated into 3-D, brainlike structures,”says Franco. The cells took cues from

their environment—a nutrient-enrichedgel in a constantly rotating flask that allowed the nutrients and oxygen to getdeeper into the tissue, Franco explains.It closely mimics the natural environmentof how brains develop in an embryo sothat cells developed into a very earlyversion of a human brain.Minibrains are best known as the

model used to help scientists figure outhow the Zika virus causes undersizedbrains in the infants of infected pregnantwomen. Franco is the first to grow cancers in the minibrains. Implantingtiny remnants of human brain tumorsinto the minibrains will provide new insights about how tumors grow andwhat drugs work best against them. Ultimately, she would like to use the research model to create a precisionmedicine stand-in for patients.

Minibrains can be created from thecells of any person. For example, research-ers have the ability to coax simple skincells to regress to their earliest form—flexible stem cells that, with the rightenvironment, can be developed into anytype of cell. Franco envisions creating aminibrain stand-in for a patient receivingtreatment and implanting it with cellsfrom the patient’s brain cancer. Testingdrugs in the personalized model couldhelp guide doctors toward the most effective therapies for each patient.

Unexpected Lead on a New Brain Cancer DrugAfter treating mice with the anti-para-sitic drug mebendazole for a pinwormoutbreak, neurosurgical oncologistGregory Riggins noticed they could nolonger grow brain tumors. The obser-vation led Riggins to take a closer lookat the drug as a possible new therapyfor brain cancer. His research revealedthe drug blocked blood vessel growthin tumors, slowing their growth. Riggins and team modified the drug’sformulation to make it more effectiveagainst cancer and began a clinical trialof the drug in 21 glioblastoma patients.The drug was well-tolerated by patientsin the early study, leading to anotherclinical trial in children.•


Franco expects the new minibrainmodel to be less expensive and workbetter than the animal models typicallyused in the laboratory. “The minibrainswill show the natural physiological waycancer cells migrate and spread into thebrain,” says Franco. “Animal models donot have this ability, so findings don’ttranslate well into the clinic.”Franco is collaborating with Kimmel

Cancer Center at Sibley radiation oncol-ogist and brain tumor expert MatthewLadra to perfect her model. Ladra re-ceived funding from Children’s NationalPediatric Cancer Center to explore theeffects of radiation therapy on pediatric


patient is receiving and it’s not working,it would alert us that we might need tochange the patient’s treatment plan.”Franco is also collaborating with

radiation physicist John Wong, who invented the Small Animal RadiationResearch Platform. It is a miniature version of human equipment and theonly realistic laboratory representationof the therapy radiation oncologists provide in the clinic. Right now, it isused on animal models, but Franco and Wong believe its size provides thepotential to conduct radiation researchwith the minibrain model.The minibrain model could provide

new clues about radiation resistance.Surgery followed by radiation therapy isa mainstay in children being treated forbrain cancer, but brain cancers almostalways come back. Franco wants to usethe minibrains to study drugs that pre-vent cancer cells from repairing theirDNA after radiation therapy. These repairs allow cancer cells to survive. “If we give drugs before radiation treat-ment that prevent these repairs, radiationtherapy would kill more cancer cells,”says Franco. There is also research evidence that pediatric brain cancer patients may benefit from drugs knownas HDAC inhibitors. The minibrainmodel could provide valuable informa-tion about how these drugs work aloneand in combination with other braincancer therapies. “This method could really accelerate

drug discovery,” says Franco. “Right now,it is difficult to get drug companies todevelop and provide drugs for pediatriccancer. Using such a humanlike modelcould provide convincing results aboutthe effectiveness and toxicity to braincells needed to get drug companies onboard.”

EMT and HarmineCancer cells are crafty—just ask clinician-scientist Phuoc Tran, who has identifieda new drug and created a new model tostudy it.In his current research, he is studying

how cancer co-opts an exquisite process

tumors and the surrounding normal brain.The joint effort is the result of a uniquecollaboration between pediatric oncolo-gists and surgeons from Children’s Na-tional and radiation oncologists at theKimmel Cancer Center to create the firstdedicated pediatric radiation oncologyprogram in the national capital region. Ladra is sharing tumor samples with

Franco she can implant in her minibrains.“We have the potential to make mini-

brains for different pediatric brain cancertypes, including medulloblastoma andglioblastoma, and measure responses todrugs,” says Franco. “If we are treating aminibrain with the same therapy the

Drug Discovery Revolutionized Bone Marrow TransplantJohn Hilton’s and Michael Colvin’s research more than three decades ago to decipherhow the popular anticancer drug cyclophosphamide worked against cancer pavedthe way for major advances in bone marrow transplantation. The Kimmel CancerCenter’s first director, Albert Owens, and bone marrow transplant program leaderGeorge Santos performed research that used the drug at high doses instead oftotal-body radiation to destroy diseased bone marrow before transplanting patientswith healthy donor marrow. The first successful bone marrow transplant followedhigh-dose cyclophosphamide.

Their early research also hinted at the usefulness of the drug after bone marrowtransplant to limit the major complication of the procedure, graft-versus-host disease(GVHD), where the new donor immune system attacks the bone marrow and othernormal tissues. These findings were pursued years later by Santos-trained bone marrowtransplant expert Richard Jones and his colleagues.“Post-transplant cyclophosphamiderevolutionized the field,” says Jones, director of the Cancer Center’s HematologicMalignancies and Bone Marrow Transplant Program. His team continued the earlycyclophosphamide research, expanding the drug’s ability to limit GVHD withoutharming the blood stem cells that give rise to new, healthy blood cells. As a result of this work, today it is possible to do transplants inall patients, even those who do not have matchingdonors. GVHD limited the ability to do mismatchedtransplants in the past, but now, it is so well-man-aged—in large part due to cyclophosphamide—thatnearly 95 percent of patients survive transplant,and it results in unmatched transplants that are thesame as matched transplants.

African-Americans, Hispanics and other minori-ties, who have historically been excluded fromtransplants because of the inability to find match-ing donors, now have the highest accrual to bonemarrow transplant clinical trials in the history ofthe therapy. Jones is excited about new researchon the horizon, including combining transplant forsolid tumors with anticancer agents to enhance immune reaction against cancers.

A novel twist in prostate cancer research includes using bone marrow donatedby daughters of patients. Women do not have prostates, so the immune system ofthe female donors will never have seen prostate cancer, a disease that only occursin men, and should immediately recognize the cancer cells as foreign invaders. “All of these advances are possible because of cyclophosphamide,” Jones says. •

Today it is possible to do transplants inall patients, eventhose who do nothave matching donors.The immune side effect is so well- managed that morethan 95 percent ofpatients survive.


“We need to provide the necessary drug developmenttools, resources and fundingfor our scientists and doctors,and more rapid access to newcancer drugs for our patients.”—William Nelson


of human development to undergo itsmost lethal transformation. A processthat normally directs an embryo to growfrom a single cell into a fully developedhuman being may be the same one usedby cancer cells to invade other parts ofthe body. This cellular guidance program is

called EMT, and Tran says a cell under-going EMT to form an embryo looks exactly the same as a rogue cancer cellas it spreads from its place of origin to adifferent organ in the body.“The program isn’t bad, but the timing

is,” explains Tran. The downstreamconsequences of this bad timing are themost critical event in the timeline of acancer development, a sentinel eventthat often distinguishes a curable cancerfrom an incurable one. It is calledmetastasis, and it occurs when a cancermigrates to another part of the body.This is the stage that ups the ante because it usually causes cancers to become resistant to treatment. Stopping or reversing the event is a

priority of Tran’s. “Local disease is oftencurable with standard therapies,” he says.“It is metastatic disease that patients aredying from, and deciphering EMT couldbe an important step toward helpingthese patients.” EMT is a program that should be

turned off and filed away after full embryo development. What reactivatesit is not completely understood, butTran suspects it is an ongoing injury tocells, such as chronic inflammation.“Cancer cells select the processes theyneed to survive. They don’t reinvent the wheel. Everything cancer needs isalready there,” says Tran. “It pulls theprograms it needs from our DNA anduses them to its advantage.” What’smore, there is a natural cellular resist-ance built into EMT. It’s an importantsafeguard that allows embryos to growand survive, but in cancer, this resiliencymakes for a resistant cancer. “A spread-ing cancer is like an astronaut going intospace. He has special equipment toadapt and survive in a foreign environ-ment. EMT provides survival gear to

cancer cells, allowing them to travel andinvade distant parts of the body, and resist external stimuli that would killnormal cells,” says Tran.To prove his theory, Tran is using a

uniquely engineered mouse model thatallows him to turn genes on and off. By manipulating genes, he is able tomake the mice get spontaneous tumorsin different organs, creating an animalresearch model representative of theway humans develop cancers. With this realistic model, Tran can study therole of EMT in many cancer types. Byincorporating luciferase, the gene infireflies that causes their iconic glow,into the model, Tran and team are ableto make all genes related to EMT glowin the mice. He has identified a plant-based drug

called harmine that directly interfereswith the EMT program. Now, he cantest the drug in his unique animal modeland other laboratory models to see ifcan block EMT, and convert resistantcancers to radiation treatment and anticancer drug-responsive cancers.

The Next NewCancer TreatmentsCancer is challenging because it is verydifferent from every other disease. It ispart of our own cells. “We have to makedrugs that attack one part of us withoutattacking another part,” says Liu. He andBerger look at the ideas and discoveriescoming from Kimmel Cancer Center experts, including recent advances inimmunotherapy, and they wonder wherethe next revolutionary cancer treatmentwill come from. “There is something waiting there,”

Berger says. They think of themselves asscouts, surveying the clinics and the lab-oratories of the Kimmel Cancer Centerfor promising new therapies they can helpresearchers push forward. “We are for-tunate to work in a place where so manyare pursuing interesting science,” hesays. “We want to capture the power ofthis science and be a bridge between lab-oratory discoveries and new therapies.“We still have cancers that don’t have

good therapies. We know there are solutions. We just have to find them.”•

When you hear the words, “You have cancer,”the next words you want to hear from your doctor are, “We have a drug to treat it.”

The Kimmel Cancer Center is where the nextgeneration of cancer cures will be made.

Help us bring new cancer drugs to patients.

For more information or to make a tax-deductible donation: Johns Hopkins Kimmel Cancer Center Development Office750 E. Pratt St., Suite 1700Baltimore, MD 21202

Please contact our fundraising team at: 410-361-6391 or [email protected]

To make a gift online, go to: hopkinscancer.organd click “Make a Gift.”

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Coming in the next issue:

The Johns Hopkins NationalProton Therapy Center at Sibley Memorial Hospital The Kimmel Cancer Center is becomingone of only 20 proton therapy centers inthe nation, providing a form of targetedradiation treatment that zeroes in on tumors while sparing normal cells.

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